Section 26: Disorders of the Cardiovascular System

Development of the Cardiovascular System

INTRODUCTION

Cardiogenesis involves a precisely orchestrated series of molecular and morphogenetic events that combines cell types from multiple lineages. Subtle perturbations of this process can result in life-threatening congenital heart defects (CHDs). As an organ essential for life, the heart is the first organ to form and must support the rapidly growing embryo before it has the opportunity to become a four-chambered organ. The combination of the complex morphogenetic events necessary for cardiogenesis and the superimposed hemodynamic influences may contribute to the exquisite sensitivity of the heart to perturbations as reflected in the estimated 10% incidence of severe cardiac malformations observed in early miscarriages. The fraction of congenital heart malformations that are compatible with development composes the spectrum of CHD observed clinically in nearly 1% of live births. An additional 1% to 2% of the population harbor more subtle cardiac developmental anomalies that only become apparent as age-dependent phenomena reveal the underlying pathology. A more precise understanding of the causes of CHD is imperative for the recognition and potential intervention of progressive degenerative conditions, such as heart failure, among survivors of CHD.

Although CHD was classified in the 19th century based on embryologic considerations, the advent of palliative procedures and clinical management led to a descriptive nomenclature founded on anatomic and physiologic features that governed surgical and medical therapy. However, seemingly unrelated CHD could be argued to share common embryologic origins from a mechanistic standpoint, suggesting that the etiology of CHD may be better understood by considering their developmental bases. The ability to go beyond descriptions of the anatomic defects to developing an understanding of the genes responsible for distinct steps of cardiac morphogenesis has raised the prospects that the future of pediatric cardiology will involve more directed therapeutic and preventive measures.

Although human genetic approaches have been important in understanding CHD, detailed molecular analysis of cardiac development in humans has been difficult. The recognition that cardiac genetic pathways are highly conserved across vastly diverse species from flies to man has resulted in an explosion of information from studies in more tractable and accessible biologic models. These include fruit flies, zebrafish, chicks, and mice as model systems. Clinical lessons combined with experimental studies in mice, fish, and flies have led to a model, suggesting that unique regions of the heart have been added from distinct fields of progenitor cells in a modular fashion during evolution. In this model, defects in particular regions of the heart arise from unique genetic and environmental effects on distinct cell lineages during developmental windows of time. In addition to the classic review of cardiac development by Dehaan in 1966, more recent publications provide additional details into anatomic events that are required for normal cardiac morphogenesis.

ORIGIN OF CARDIOMYOCYTE PRECURSORS

The more recent discovery of distinct pools of progenitors that contribute to individual chambers or regions of the heart provides an important basis for considering the causes of many forms of CHDs. The early cardiac progenitors arise from mesodermal cells that migrate from the primitive streak toward the anterior portion of the developing embryo. Two distinct mesodermal heart fields that share a common origin organize themselves into a crescent shape. The well-studied “first heart field” is derived from cells in the anterior lateral plate mesoderm that align in a crescent shape at approximately embryonic (E) day 7.5 in the mouse embryo, roughly corresponding to week 2 of human gestation (Fig. 476-1). By mouse E8.0, or 3 weeks in humans, these cells coalesce along the ventral midline to form a primitive heart tube, with an interior layer of endocardial cells and an exterior layer of myocardial cells, separated by extracellular matrix.

The heart tube provides a scaffold that enables a second population of cells to migrate and expand into cardiac chambers. These additional cells arise from an area often referred to as the “second heart field (SHF),” anterior and medial to the crescent-shaped first heart field (Fig. 476-1). Both heart fields appear to be regulated by complex positive and negative signaling networks involving members of the bone morphogenetic protein (Bmp), sonic hedgehog (Shh), fibroblast growth factor (Fgf), Wnt, and Notch proteins. Such signals often arise from the adjacent endoderm, although the precise nature and role of these signals remain unknown (reviewed in 13). SHF cells remain in an undifferentiated progenitor state until incorporation into the heart, and this may in part be due to closer proximity to inhibitory signals emanating from the midline of the embryo.

As the heart tube forms, the SHF cells also migrate into the midline and position themselves dorsal to the heart tube in the pharyngeal mesoderm. Upon rightward looping of the heart tube, SHF cells migrate through the pharyngeal mesoderm into the anterior and posterior portions, populating a large portion of the outflow tract, future right ventricle, and atria (Fig. 476-1). The left ventricle region is sparsely populated by the SHF and appears to be largely derived from the FHF. Once within the heart, FHF and SHF cells appear to proliferate in response to endocardial-derived signals such as neuregulin and epicardial signals dependent on retinoic acid, although the mechanisms through which these events occur remain poorly understood. The distinct contributions of SHF and FHF cells to the right and left ventricles, respectively, suggest that some forms of hypoplastic right or left ventricle may be due to a specific loss of the progenitor cell types during development.

TRANSCRIPTIONAL REGULATION OF CARDIAC PRECURSORS

Regulation of the SHF involves numerous signaling and transcriptional cascades (Fig. 476-2). Factors secreted from the anterior portion of the heart tube may serve as chemoattractant signals to induce the migration of SHF cells. Islet1 (Isl1), a transcription factor, is necessary for development of the SHF. Progeny of Isl1+ cells contribute to most of the heart except the left ventricle, but Isl1 expression is extinguished as progenitor cells begin to express markers of cardiac differentiation. Interestingly, Isl1+ cells mark niches of undifferentiated cardiac progenitor cells in the postnatal heart, suggesting that understanding the regulation of SHF-derived progenitor pools may be useful in developing approaches for cardiac repair (discussed later in this chapter).

The first evidence of distinct transcriptional regulation between the right and left ventricle was found through the discovery of Hand2, required for expansion of the right ventricle, and its relative, Hand1, active only in the left ventricle. We now know that Hand2 is highly expressed in the SHF, and the right ventricular hypoplasia that results from disruption of Hand2 likely represents a failure of SHF cells to expand into the right ventricle. Similarly, disruption of numerous genes that resulted in right ventricular hypoplasia or outflow tract defects were a direct result of loss of SHF cells. Conversely, mutation of genes such as TBX5, the Holt-Oram gene, affect only FHF cells.

Epigenetic factors also contribute to cardiomyocyte differentiation and chamber morphogenesis. Disruption of the muscle-specific chromatin remodeling proteins Smyd1 or Baf60c results in a phenotype reminiscent of Hand2 mutants: a small right ventricular segment (Fig. 476-2). Whether mutations in these or other epigenetic factors contribute to CHD remains unknown, but the recent discovery of a chromatin remodeling protein, CHD7, as the cause of CHARGE association suggests an important role for this class of regulators.

MICRORNA REGULATION OF CARDIOMYOCYTE DIFFERENTIATION

Whereas transcriptional and epigenetic events regulate many critical cardiac genes, translational control by small noncoding RNAs, such as microRNAs (miRNAs), has recently emerged as another mechanism to “fine-tune” dosages of key proteins during cardiogenesis. This is particularly important, as most known genetic causes of CHD involve heterozygous mutations that only affect protein dosage by 50% or less. MicroRNAs are genomically encoded 20 to 25 nucleotide RNAs that target mRNAs for translational inhibition or degradation. More than 650 human microRNAs have been identified, but the biologic function and mRNA targets are known in only few.

One of the better studied miRNAs is miR1, which is specific to cardiac and skeletal muscle. The sequence of miR-1 is 100% conserved from worms to humans and is specifically expressed in developing cardiac and skeletal muscle progenitor cells as they differentiate. miR-1 and another miRNA, miR-133, are transcribed in a polycistronic message therefore sharing common regulation, and both are coexpressed in heart and skeletal muscle. miR-1 promotes the differentiation of cardiac progenitors and skeletal myoblasts, but, miR-133a has the opposite effect, inhibiting differentiation and promoting the proliferation of myoblasts. Other miRNAs have been identified that pattern the developing heart and help establish the vasculature, and it is likely that the dosage of most other cardiac developmental pathways will be controlled by yet unknown miRNA function. It will be important to determine if mutations in miRNAs or their target-binding sites contribute to human disease.

COMPLEX REGULATION OF CARDIAC MORPHOGENESIS

Dorsal-Ventral Polarity

Beyond the asymmetric addition of SHF cells along the anterior-posterior axis, a discrete dorsal-ventral (DV) polarity occurs in the primitive heart tube. As the heart tube loops to the right, the ventral surface of the tube rotates to become the outer curvature of the looped heart, and the dorsal surface forms the inner curvature. The outer curvature becomes the site of active growth, while remodeling of the inner curvature is essential for the ultimate alignment of the inflow and outflow tracts of the heart. A model in which individual chambers “balloon” from the outer curvature in a segmental fashion has been proposed. Consistent with this model, numerous genes are expressed specifically on the outer or inner curvature of the heart. Remodeling of the inner curvature allows migration of the inflow tract to the right and the outflow tract to the left, facilitating proper alignment and separation of right- and left-sided circulations.

Left-Right Asymmetry and Cardiac Looping

Rightward looping of the heart tube is the first obvious sign of the break in left-right symmetry. When considering the mechanisms for cardiac looping, it is important to distinguish between the process of looping and the directionality of looping. Directionality of looping reflects overall asymmetry throughout the embryo, which is superimposed on the morphogenetic mechanisms for looping.

Abnormalities in the process of cardiac looping underlie a number of CHD. Folding of the heart tube positions the inflow cushions adjacent to the outflow cushions and involves extensive remodeling of the inner curvature of the looped heart tube. In the primitive looped heart, the segments of the heart are still in a linear pattern and must be repositioned considerably for alignment of the atrial chambers with the appropriate ventricles and the ventricles with the aorta and pulmonary arteries. The atrioventricular septum (AVS) begins to divide the common atrioventricular canal (AVC) into a right and left AVC that subsequently shifts to the right to position the AVS over the ventricular septum (Fig. 476-3). This allows the right AVC and the left AVC to be aligned with the right and left ventricles, respectively. Simultaneously, the conotruncal region becomes septated into the aorta and pulmonary trunks as the conotruncus moves toward the left side of the heart such that the conotruncal septum is positioned over the AVS (Fig. 476-3). The rightward shift of the AVS and leftward shift of the conotruncus converts the single-inlet, single-outlet heart into a four-chambered heart that has separate atrial inlets and ventricular outlets.

Arrest or incomplete movement of the AVS or conotruncus might result in malalignment of the inflow and outflow tracts (Fig. 476-3). A scenario in which the AVS fails to shift to the right would result in communication of the right and left AVCs with the left ventricle, a condition known as double-inlet left ventricle (DILV). Incomplete shifting may be the basis for “unbalanced” AVC defects, where the right AVC only partly communicates with the right ventricle. Similarly, if the conotruncal septum fails to shift to the left, both the aorta and pulmonary artery would arise from the right ventricle, causing a double-outlet right ventricle (DORV). From this embryologic perspective, it is not surprising that double-outlet left ventricles and double-inlet right ventricles are rarely seen clinically. In contrast, any abnormality in cardiac looping can be associated with DILV or DORV, along with other manifestations of improper alignment of specific regions of the heart.

The elegant molecular network regulating left-right (LR) asymmetry of the body plan has been reviewed and is not summarized here.

How do the insights into LR asymmetry affect our understanding of CHD? It is likely that patients with situs inversus totalis have a well-coordinated reversal of LR asymmetry and thus have a lower incidence of defects in visceral organogenesis. However, the majority of patients with LR defects have visceroatrial heterotaxy and thus have randomization of cardiac, pulmonary, and gastrointestinal situs where coordinated signaling is absent. Such patients can have defects in almost all aspects of cardiogenesis. Often, either the right or left side predominates with patients either having bilateral right-sidedness (asplenia syndrome) or bilateral left-sidedness (polysplenia syndrome). In such patients, features of the right or left side of the lungs, heart, and gut are duplicated. Disruption of cascades determining either the left or right side of the embryo might result in asplenia or polysplenia syndromes, respectively. Indeed, mutations in LR pathway members are found in some patients with heterotaxy. Familial examples of heterotaxy have also led to identification of mutations in a zinc-finger transcription factor, ZIC3, that result in LR axis abnormalities.

Cardiac Outflow Tract Regulation

Congenital cardiac defects involving the cardiac outflow tract, aortic arch, ductus arteriosus, and proximal pulmonary arteries account for 20% to 30% of all CHD. This region of the heart undergoes extensive and rather complex morphogenetic changes with contributions from neural crest cells and the SHF, as discussed previously. The cardiac outflow tract can be divided into the muscularized conus and the adjacent truncus arteriosus, collectively termed the conotruncus, as it arises from the primitive right ventricle. The conotruncus normally shifts to the left to override the forming ventricular septum. The truncus arteriosus then becomes septated by neural crest–derived mesenchymal cells into the aorta and pulmonary arteries, with a muscular ridge known as the conotruncal septum forming between the two vessels (summarized in Fig. 476-4). However, at this stage, the aorta communicates with the right ventricle and the pulmonary artery with the left ventricle. Subsequent rotation of the two vessels in a spiraling fashion places the aorta more dorsal and leftward and the pulmonary artery more ventral and rightward. This spiraling event achieves the normal alignment of the aorta and pulmonary artery to the left and right ventricles, respectively.

Mesenchyme cells originating from the crest of the neural folds are essential for proper septation and remodeling of the outflow tract and aortic arch. Such neural crest–derived cells migrate away from the neural folds and retain the ability to differentiate into multiple cell types (Fig. 476-4). The migratory path and ultimate fate of these cells depends on their relative position of origin along the anterior-posterior axis and are partly regulated by the Hox code. Neural crest cells differentiate and contribute to diverse embryonic structures, including the cranial ganglia, peripheral nervous system, adrenal glands, and melanocytes. Neural crest cells that arise from the otic placode to the third somite migrate through the developing pharyngeal arches and populate the mesenchyme of each aortic arch artery, and the mesenchyme necessary to septate the outflow tract septum (Fig. 476-4).

Abnormalities in septation or incomplete spiraling of the conotruncus result in many CHDs. For example, the conotruncal septum between the aorta and pulmonary artery forms in tetralogy of Fallot (TOF), but because of malalignment of the great vessels, the conotruncal septum and aorta are shifted to the right. This results in an overriding aorta and failure of the conotruncal septum to connect to the muscular ventricular septum, resulting in a ventricular septal defect (Fig. 476-3). Similarly, any malalignment of the conotruncus results in an obligatory VSD that, unlike muscular VSDs, does not have the potential to close spontaneously after birth.

The conotruncus gives rise to six bilaterally symmetric vessels known as aortic arch arteries. The aortic arch arteries arise sequentially along the AP axis, each traversing a pharyngeal arch before joining the paired dorsal aortae (Fig. 476-4). The first and second arch arteries involute, and the fifth arch artery never fully develops. The third, fourth, and six arch arteries undergo extensive remodeling to ultimately form distinct regions of the mature aortic arch and proximal pulmonary arteries. The majority of the right-sided dorsal aorta and aortic arch arteries undergo programmed cell death leading to a left-sided aortic arch. The third aortic arch artery contributes to the proximal carotid arteries and right subclavian artery. The left fourth aortic arch artery forms the transverse aortic arch between the left common carotid and left subclavian arteries. Finally, the sixth arch artery contributes to the proximal pulmonary artery and the ductus arteriosus (Fig. 476-4). Extrapolating from their embryologic origins, it is believed that aberrant right subclavian arteries and other subtle arch anomalies are the result of third aortic arch defects, interrupted aortic arch from fourth arch defects, and patent ductus arteriosus and proximal pulmonary artery hypoplasia/discontinuity from defects in sixth arch artery development.

Disruption of many signaling cascades that affect neural crest migration or development, including the endothelin and semaphorin pathways, cause outflow tract defects similar to those observed in humans. These include TOF, persistent truncus arteriosus, doubleoutlet right ventricle, ventricular septal defects, and defects of aortic arch patterning. Thus, abnormalities in neural crest migration or differentiation likely underlie many of the conotruncal and aortic arch defects seen in humans. Indeed, human mutations of the neural crest–enriched transcription factor TFAP2β result in persistent patency of the ductus arteriosus, a specialized aortic arch vessel essential for fetal cardiac physiology (Fig. 476-4). It is likely that other genetic mutations affect specific regions of the aortic arch.

Disruption of SHF development by mutation of genes such as Tbx1, Fgf8, and Islet1 results in defects similar to those observed with neural crest disruption (Fig. 476-2), including persistent truncus arteriosus (failure of outflow septation), malalignment of the outflow tract of the heart with the ventricular chambers, and ventricular septal defects. Because SHF-derived myocardial cells neighbor neural crest–derived cells and secrete growth factors such as Fgf8 in a Tbx1-dependent manner that influence neural crest cells, reciprocal interactions between the SHF and neural crest–derived cells in the outflow tract are likely essential for normal development. Consistent with this, humans with deletion or mutation of the SHF gene TBX1 who have DiGeorge syndrome (22q11 deletion syndrome) appear to have cell-autonomous defects of SHF development and non–cell-autonomous anomalies of neural crest–derived tissues. It will be interesting to determine if a large number of human cardiac outflow tract defects are a direct result of SHF migration, differentiation, or proliferation.

Cardiac Valve Formation

Appropriate placement and function of cardiac valves is essential for chamber septation and for unidirectional flow of blood through the heart. A molecular network involving Bmp2 and Tbx2 defines the position of the valves relative to the chambers. During early heart tube formation, “cushions” of extracellular matrix (ECM) between the endocardium and myocardium presage valve formation at each end of the heart tube. Reciprocal signaling, mediated in part by TGF-β family members, between the myocardium and endocardium in the cushion region induces endocardial cells to transform into mesenchymal cells that migrate into the ECM cushion. These mesenchymal cells differentiate into the fibrous tissue of the valves and are involved in septation of the common atrioventricular canal into right- and left-sided orifices.

Later in development, the endocardial cushions form condensed mesenchymal protrusions that represent the primitive valves. These condensed mesenchymal protrusions subsequently “elongate” to provide the true cardiac valve leaflets (Fig. 476-5). The elongation of primitive valves appears to be a result of restricted proliferation of endocardial cells overlying the mesenchymal projections on the vascular side of the valve and selective cell death under the expanding endocardial rim. The growth of the endocardial edge and evacuation of apoptotic cells underneath the proliferating endocardial rim sculpt the swollen mesenchymal primitive valves into a typical excavated shape and results in morphogenesis of the sinuses of Valsalva.

Many forms of congenital heart disease involve thickened, hyperplastic valve leaflets that can result in obstruction of blood flow. Neurofibromatosis is associated with thickened valves and is caused by mutation of the NF1 gene. NF1 loss of function is mimicked by gain of function mutations in the Noonan syndrome gene, tyrosine phosphatase SHP2/PTPN11, which encodes a tyrosine phosphatase that activates Ras-Erk signaling, increased proliferation, and decreased apoptosis. The net result is semilunar valve and atrioventricular valve hyperplasia. Hypomorphic mutations in SOS1, an essential RAS guanine nucleotide-exchange factor (Ras-Gef), also result in enhanced RAS-ERK activation and can account for as many as 20% of the cases of Noonan syndrome not explained by SHP2 mutations.

In humans, heterozygous NOTCH1 mutations disrupt normal development of the aortic valve and, occasionally, the mitral valve, with thickened valve leaflets. The Notch signaling pathway is required for cell fate and differentiation decisions throughout the embryo. The severity of valve disease associated with NOTCH1 mutations in humans varies widely from mild disease in which the aortic valve has two rather than three leaflets (bicuspid aortic valve) to severely thickened valves and defects in valve patency resulting in critical aortic stenosis in newborns or even left ventricular growth failure. Consistent with this genetic finding, 15% of “normal” relatives of children with hypoplastic left heart syndrome (HLHS) have subclinical bicuspid aortic valves, suggesting that disruption of the NOTCH signaling cascade may underlie a spectrum of aortic valve disease. Although not specifically affecting valves, human mutations in JAGGED1, a NOTCH ligand, also cause outflow tract defects associated with the autosomal-dominant disease, Alagille syndrome.

EPICARDIUM AND CORONARY VASCULARIZATION

The epicardium originates as a villous projection of cells in the area of the sinus venosus termed the “proepicardial organ.” This cluster of cells extends to the atrioventricular region and migrates out over the myocardial surface to completely encase the heart. Angiogenic sprouts from the subepicardial endothelial plexus form endothelial strands that grow into the aorta and develop multiple communications with all three cusps of the developing aortic valve. However, lumens develop only in two semilunar sinuses with resorption of the strands to the noncoronary cusp. These observations have implications for determining the factors that direct coronary artery anatomy in congenital heart diseases.

ADULT CONSEQUENCES OF CARDIAC MALFORMATIONS

As human survivors of cardiac malformations ranging from simple atrial septal defects to more complex heart disease enter their third and fourth decades of life, new cardiac disease processes are becoming apparent, including abnormal conduction of electricity within the heart and diminished contractile function of the heart. The etiology of these “secondary” defects had in the past been ascribed to abnormal hemodynamics, but more recent evidence suggests that the same genes that cause early morphologic defects in heart development might later be directly involved in cardiac dysfunction and cell lineage disturbances in adulthood.

For example, human and mouse mutations in NKX2.5 not only cause a developmental atrial septal defect, but also progressively disrupt electrical conduction through the cardiac chambers and can result in sudden death later in life. The atrioventricular (AV) node, which serves as the essential site of electrical communication between the atria and ventricles, is smaller than normal in adult Nkx2.5 mouse mutants; over time, the specialized muscle-derived conduction cells are lost and replaced by fibrotic tissue, resulting in progressive defects in electrical conduction.

Another example of a congenital heart malformation causing disease later in life involves the aortic valve. Worldwide, 1% of the population is born with a bicuspid aortic valve, typically silent in childhood. However, two thirds of bicuspid aortic valves develop premature age-dependent calcific stenosis, resulting in poorly mobile, nonfunctioning valves, often in the fifth, sixth, or seventh decades of life. As a result, calcific aortic stenosis is the third leading cause of heart disease in adults and requires more than 30,000 surgical valve replacements per year in the United States. The more recent discovery that NOTCH1 mutations in humans cause bicuspid aortic valves and later calcification provides firm genetic evidence that the early developmental and later degenerative disease share a common genetic cause. Some family members with NOTCH1 mutations had normal tricuspid valves but still developed calcification, supporting the idea that the premature and severe calcification was primarily due to the genetic mutation itself rather than solely to hemodynamic effects on the valve leaflets.

SUGGECTED READINGS

Fetal Cardiology

INTRODUCTION

The origins of fetal cardiology were in the novel and still relevant fetal lamb investigations of Rudolph and Heymann. From these early studies, we began to understand normal fetal cardiovascular physiology and developed hypotheses regarding the evolution of congenital heart disease (CHD) in utero and its influence on fetal circulation. With advances in ultrasound technology in the late 1970s and 1980s, it became possible to demonstrate normal fetal cardiac anatomy and document growth of the cardiac chambers and great arteries. Doppler investigations in the 1980s and 1990s added insight into developmental changes in normal human fetal circulation and cardiovascular function. Initial reports describing prenatal detection of fetal CHD documented a more severe spectrum of disease than that encountered after birth. This was at least in part a consequence of the ease with which the more severe pathology, including fetal hydrops, was recognized at routine ultrasound assessment.

Advances in ultrasound technology over the past 30 years have led to monumental improvements in our ability to define fetal cardiovascular anatomy and to evaluate normal and altered myocardial function in greater detail. To date, most forms of CHD can be detected prenatally. It has even become possible to define fetal cardiovascular anatomy, function, and rhythm in detail. Fetal cardiac imaging can be performed as early as 10 to 14 weeks of gestation, only a short time after completion of cardiac morphogenesis. With rapid advances in technology, fetal cardiology has evolved as its own subspecialty that merges maternal-fetal medicine and pediatric cardiology. This chapter reviews unique aspects of this field and its role in the management of neonates with significant structural and functional CHD.

FETAL ECHOCARDIOGRAPHY

Pregnancies at increased risk for fetal CHD, whether structural, functional, or rhythm related, are evaluated by the fetal echocardiogram. Indications for fetal echocardiography include maternal indications (eg, maternal diabetes, autoimmune disease, infection, or exposure to teratogens), fetal indications (eg, suspected cardiac abnormality at routine ultrasound; suspected extracardiac abnormality including a chromosomal abnormality known to be associated with CHD; and conditions associated with altered fetal heart function such as twin-twin transfusion syndrome, acardiac twins, and anemia), and family history (eg, CHD in mother, father, or sibling). Although many pregnancies are referred as a consequence of maternal disease or a family history of CHD, the majority of positive referrals (pregnancies with fetal CHD) come from the low-risk patients who are referred because of a suspicion of CHD during routine ultrasound assessment. Recognition of this has prompted educational initiatives to train obstetrical ultrasound personnel for better screening of the heart at the time of routine obstetrical scanning.

Pregnancies at risk for fetal CHD as a consequence of a known family history and maternal disease are often referred electively for fetal echocardiography at 17 to 23 weeks of gestation, prior to the gestational age limit for elective pregnancy termination in most North American practices. Many pregnancies with fetal CHD and extracardiac pathology are identified at the time of routine fetal ultrasound and are referred in a timely fashion. Over the past 2 decades, there has been an increasing interest in earlier fetal diagnosis, with reports of cardiac pathology identified as early as the late first and early second trimesters. In our experience, early transabdominal fetal cardiovascular imaging studies can be performed as early as 12 to 13 weeks of gestation and should be considered with CHD in a first-degree family member (eg, prior child with CHD), along with positive nuchal translucency assessment and positive noninvasive prenatal testing (NIPT) screening. Increased fetal nuchal translucency at 11 to 14 weeks of gestation is observed in trisomy 21 and other aneuploidies, conditions associated with structural and functional fetal CHD. In the absence of aneuploidy, increased fetal nuchal translucency is associated with a broad spectrum of structural and functional fetal CHDs, occurring in 2% to 9% of affected pregnancies, with an exponentially increasing risk the greater the nuchal translucency.

Fetal echocardiography is best performed by a fetal cardiologist trained in pediatric echocardiography with additional experience in fetal diagnosis and management, at times with the assistance of a fetal ultrasound technician. The assessment includes detailed 2-dimensional imaging of cardiac and vascular structures. Fetal imaging represents a challenge because the pediatric echocardiographer must image the fetus through the maternal abdomen. Orientation to the position of the fetus within the maternal uterus, including left and right sides, head and feet, and anterior and posterior aspects of the fetus, is a critical first step in obtaining decipherable images. Limited maternal acoustic windows, suboptimal fetal position, and the diminutive size of fetal cardiac structures contribute to difficulty in scanning. Once the assessment is complete, the fetal cardiologist must be able to interpret the pathology and provide accurate counseling to the anxious pregnant woman and her partner.

STRUCTURAL FETAL HEART DISEASE

Most major and even minor structural CHD can be detected before birth. Detection rates of fetal cardiac defects vary widely. In the hands of an experienced echocardiographer, the fetal echocardiogram can yield significant anatomic detail regarding the cardiovascular pathology, similar to that obtained after birth. The segmental anatomy, including visceral and atrial situs, systemic and pulmonary venous connections, ventricular morphology, ventricular and great artery connections, and ductus arteriosus and aortic arch morphology, is typically defined, and blood flow is demonstrated in each structure by pulsed and color Doppler. Despite the accuracy of fetal echocardiography, there are limitations in image resolution that result in an inability to define all of the anatomy. Small- to moderate-sized atrial and ventricular septal defects, minor valve abnormalities, and isolated pulmonary vein and coronary artery abnormalities may not be detected at fetal echocardiography. Unique aspects of the fetal circulation, including the presence of fetal shunts (the foramen ovale and ductus arteriosus, which permit a redistribution of flow and equalization of pressures), and the role of the placenta and the ductus venosus are considered in the interpretation of the findings. For instance, a discrepancy in ventricular or great artery size suggests possible left or right ventricular heart obstruction, despite the absence of detectable gradients. Retrograde flow in the ductus arteriosus or aortic arch can indicate critical pulmonary or aortic outflow tract obstruction, respectively. Evaluating fetal structural CHD requires consideration of what can complicate the prenatal and postnatal outcome of an affected fetus, including additional structural or functional cardiac pathology, some of which may not be evident on the first evaluation but may progress later in gestation or only manifest after birth.

Structural CHD most frequently detected before birth includes lesions associated with an abnormal 4-chamber view or lesions associated with significant extracardiac pathology, all of which may be detected at routine fetal ultrasound screening. Hypoplastic left heart syndrome (HLHS), one of the most common critical neonatal heart lesions, is one of the more commonly diagnosed fetal CHD. In many centers, more than 50% of affected fetuses are identified before birth. Its recognition is facilitated by the obvious abnormality in the 4 chambers (Fig. 477-1). In contrast, tetralogy of Fallot, another commonly detected form of fetal CHD, is not associated with an abnormal 4-chamber view other than levorotation of the heart, and its detection in isolation requires recognition of the outflow tract and great artery abnormalities (Fig. 477-2). It is, however, frequently associated with chromosomal abnormalities, including aneuploidy and 22q11.2 deletion (DiGeorge syndrome) and extracardiac structural pathology including renal, gastrointestinal, and limb anomalies, findings that may prompt referral for fetal echocardiography. To improve prenatal detection rate of cardiac defects, fetal cardiac screening should include the 4-chamber view and outflow tract views including the 3-vessel view.

Most structural CHD in the fetus has the potential to evolve prenatally, necessitating serial evaluation during the pregnancy (Table 477-1). Mechanisms of progression usually involve development of more severe disease—structural, functional, or both. Left and right heart obstructive lesions including semilunar and atrioventricular valve obstruction are among the forms of fetal CHD with the greatest potential to evolve. Critical aortic or pulmonary stenosis in the mid-trimester, for instance, leads to left or right ventricular hypertrophy, respectively, and eventual dysfunction. As long as the function of the unobstructed ventricle is not affected, blood is redistributed toward that ventricle, which provides the equivalent of a biventricular output. If this is a gradual process, the single functioning ventricle can sustain this additional output without decompensation (the combined ventricular output in the fetus is about 450–500 mL/kg/min). With a redistribution of flow, there is diminished filling of the obstructed ventricle and, with time, progressive hypoplasia of that side of the heart including the atrioventricular and semilunar valves, the ventricle, and the great artery. The aortic arch or ductus arteriosus provides blood flow to the fetal body with retrograde filling of the vessel distal to the obstruction, either the pulmonary arteries in critical pulmonary stenosis or the ascending aorta in critical aortic stenosis. More rapid evolution of ventricular dysfunction, or significant atrioventricular valve regurgitation, when both ventricles are compromised, may lead to fetal heart failure and even demise.

There may be abnormalities of the fetal circulation that result in progressive fetal cardiovascular pathology, most commonly fetal heart failure, including constriction of the ductus arteriosus, which may occur in the second and third trimesters, foramen ovale restriction, and even absence of the ductus venosus, a condition associated with a progressive high cardiac output state. Knowledge of the potential for evolution is critical in prenatal counseling and perinatal management of affected pregnancies.

A short period of maternal oxygen administration can aid in refining diagnoses. Maternal hyperoxygenation increases fetal oxygenation, which in healthy fetal lungs after 34 weeks of gestation causes pulmonary vasodilation and decreased pulmonary vascular resistance. These pulmonary arterial resistance changes can be measured with the pulsatility index. Decreased pulmonary vascular reactivity in the fetus with HLHS and a highly restrictive or intact atrial septum can aid in identifying fetuses requiring urgent postnatal intervention. Another diagnostic use for maternal hyperoxygenation is in the fetus with an aneurysmal atrial septum bowing to the left atrium, which can cause significant limitation of left-sided filling through the foramen ovale as well as retrograde flow in the aortic arch. Improved left-sided filling through pulmonary arterial dilation with maternal hyperoxygenation can result in antegrade flow in the aortic arch and aid in confirming this typically benign diagnosis. Future investigations are necessary to determine if maternal oxygen can aid in a therapeutic manner to promote growth of borderline left-sided structures in the latter part of pregnancy.

Brain magnetic resonance imaging (MRI) studies in fetuses with CHD have demonstrated delayed brain maturation supporting the desire for term delivery. Altered cerebral metabolism has also been shown. There may be a benefit for increasing oxygen delivery or administration of agents like progesterone to promote neural growth and development. Further investigations are under way.

FETAL CATHETER–BASED AND SURGICAL INTERVENTION

To prevent disease progression, invasive fetal cardiovascular procedures have been attempted, directed largely at ameliorating the less severe lesion early in its course. Fetal intervention through catheter-based techniques is increasing in frequency, and issues around patient selection, optimal timing of intervention, and technical aspects of the procedures are still evolving. Access to the fetal heart through percutaneous needle puncture of the maternal abdomen, uterus, and fetal chest is possible under ultrasound guidance. Fetal aortic valvoplasty for aortic stenosis is possible, with data suggesting that in some fetuses, left ventricular recruitment can promote growth and prevents the development of HLHS (Fig. 477-3). Successful balloon dilation of the fetal pulmonary valve has been described, but its benefit in changing the clinical outcome, especially need for single-ventricle palliation, is not as yet established. Opening of the atrial septum in utero in HLHS with intact or restrictive atrial septum in attempt to prevent abnormal pulmonary vascular development is technically possible; however, the efficacy of this intervention and optimal timing remain unclear (Fig. 477-4). The principles of fetal surgery for a variety of noncardiac conditions have been well established and are currently applied to anomalies such as spina bifida and chest masses with good success. Fetal surgery for cardiovascular conditions that may not require cardiopulmonary bypass such as pericardial teratoma are currently also possible.

FETAL ARRHYTHMIAS

ECHOCARDIOGRAPHIC DIAGNOSIS OF FETAL ARRHYTHMIAS

Fetal cardiac arrhythmias have been noted in up to 5% of all pregnancies. Fortunately, the vast majority are benign, largely premature atrial beats, which are very common in the third trimester. Occasionally a more serious or persistent fetal arrhythmia is present. Pregnant mothers usually are referred for persistent fetal tachycardia (heart rate > 170 bpm), bradycardia (heart rate < 110 bpm), or irregular rhythm, as detected by a Doppler listening device. The mechanism of the fetal arrhythmia is deciphered by fetal echocardiography, which permits assessment of the temporal relationships of atrial and ventricular contraction. M-mode with placement of the cursor through 1 of the atria (usually the right) and either left or right ventricle demonstrates wall motion of the chambers (Fig. 477-5). Simultaneous pulsed Doppler interrogation of left ventricular inflow and outflow, superior vena caval and ascending aortic flow, or pulmonary venous and pulmonary artery flow permits an indirect evaluation of the relationship between atrial and ventricular contraction (see Fig. 477-5). Although fetal electrocardiography and magnetocardiography have permitted more definitive evaluation of fetal heart rhythm, lack of availability and technical limitations have prevented more widespread use in clinical practice. Most types of arrhythmia detected in the pediatric population have also been identified before birth.

FETAL TACHYCARDIAS

Atrial and ventricular ectopy with isolated extrasystoles is usually benign. Ventricular tachycardia is very rare but can occur in isolation or with myocardial disease or intracardiac tumors. Premature atrial beats are detected in the fetus in 2% of pregnancies and can be associated with intermittent supraventricular tachyarrhythmia. The 2 most common forms of fetal tachycardia are supraventricular tachycardia, usually associated with an accessory ventricular-atrial pathway, and atrial flutter (see Fig. 477-5). In recent years, fetal cardiologists have made a greater effort to define the mechanisms of these tachyarrhythmias, resulting in more accurate counseling and more effective treatment strategies. Tissue Doppler, which uses Doppler shifts of the myocardium using very high sampling rates and with postprocessing capabilities, may ultimately facilitate definition of arrhythmia mechanism.

Fetal supraventricular tachyarrhythmias can be associated with fetal heart failure, likely caused by reduced filling time and secondary increases in central venous pressures. Elevated central venous pressure not only affects umbilical venous return and leads to placental edema and dysfunction, but it may also impair liver function, leading to reduced serum protein production. This accelerates the evolution of effusions and skin edema. Based on the findings of an experimental animal model, altered systolic and diastolic function in fetal tachycardia may also be related to the rapid utilization of glycogen stores. When fetal hydrops is present, the morbidity and mortality associated with fetal supraventricular tachycardia range from 23% to 50%. Even after conversion to sinus rhythm, fetal supraventricular tachyarrhythmias with hydrops are associated with a 10% loss rate. Cerebral vascular events have also been reported in fetal supraventricular tachyarrhythmias and hydrops. Given these observations, maternal/transplacental antiarrhythmia therapy is often initiated before the evolution of gross fetal cardiovascular compromise. Risk factors for the evolution of heart failure include incessant tachycardia, presentation prior to 32 weeks, tachycardia > 230 bpm, and structural heart disease (eg, Ebstein anomaly). Maternal administration of digoxin has been the antiarrhythmic medication used most widely in the treatment of fetal supraventricular tachyarrhythmias, with success (absence of hydrops) reported in 32% to 71% of treated pregnancies. Placental transfer of digoxin, however, is significantly reduced when placental edema is present, resulting in inadequate treatment of affected fetuses. In addition, digoxin is usually not effective in atrial flutter and less common forms of supraventricular tachycardia, including ectopic atrial tachycardia and permanent reciprocating junctional tachycardia. As a consequence, more potent antiarrhythmics including sotalol, flecainide, amiodarone, propranolol, and procainamide have been employed. As is true postnatally, no one medication has been uniformly effective for fetal supraventricular tachycardia, and most of these medications have important side effects, including the potential to cause more serious arrhythmias in both mother and fetus. Mothers are usually monitored closely and even hospitalized when more potent antiarrhythmic medications are used until a therapeutic dose is tested. Maternal-placental antiarrhythmic therapy for fetal supraventricular tachycardia is very successful with conversion in up to 85% of affected fetuses. Success rates of as high as 80% have been reported in the presence of fetal hydrops, although these patients typically require the use of more than 1 medication and may take longer to achieve sinus rhythm. Rarely, intraumbilical or intramuscular delivery of an antiarrhythmic medication for refractory fetal supraventricular tachycardia may be necessary.

FETAL BRADYCARDIAS

The most common form of fetal bradycardia is sinus bradycardia, typically associated with a gradual slowing of the fetal heart rate and rapid resolution. Persistent fetal bradycardia is more worrisome because it may be due to fetal atrioventricular block (Fig. 477-6). Fetal atrioventricular block can be associated with certain forms of structural CHD, including left atrial isomerism (polysplenia syndrome) and congenitally corrected transposition of the great arteries. It is also observed in pregnant mothers with anti–SSA-Ro and SSB-La autoantibodies in the absence of structural fetal heart disease, and, in the neonate, is 1 component of the clinical picture referred to as “neonatal lupus erythematosus.” These autoantibodies are observed in autoimmune disease such as systemic lupus erythematosus and Sjögren syndrome, but also occur in the absence of clinical autoimmune disease, a more common finding in mothers of affected fetuses. Fifteen to 20% of fetuses with maternal autoimmune-mediated atrioventricular block can develop more diffuse myocardial disease. Clinical myocardial dysfunction places them at high risk of mortality and morbidity. Myocardial disease may even be observed in the absence of atrioventricular block. Without myocardial disease, the clinical outcome of fetuses with autoimmune-mediated atrioventricular block is generally good with a greater than 85% survivaland may be at least in part attributed to the use of maternal corticosteroids and sympathomimetics and to improved perinatal and postnatal management of affected infants. In contrast, the clinical outcome of atrioventricular block and structural CHD is very poor, particularly in left atrial isomerism, which can present very early in gestation and be associated with very low, monotonous ventricular rates.

FETAL HEART FAILURE

In the fetal circulation, blood is oxygenated in the placenta and returns through the umbilical vein to the fetal cardiovascular system. Typically, in the normal fetus, undulations in umbilical venous blood flow of low velocity typically occur only during fetal breathing. Umbilical venous return requires low downstream central venous pressures. Any cardiovascular or extracardiac abnormality that alters these pressures can compromise umbilical venous return and lead to fetal hypoxemia and placental edema. Fetal lymphatic flow is significantly higher than that of the newborn and the adult. Thus, small changes in ventricular and consequent central venous pressures can reduce lymphatic flow and lead to fetal edema, the manifestation of cardiac failure. Much like the clinical picture of right heart failure observed after birth, fetal heart failure is associated with the evolution of ascites, pleural and pericardial effusions, and skin edema (Fig. 477-7). In its most severe state, with 2 or more fluid-filled cavities, fetal heart failure is referred to as hydrops fetalis. In addition to the fetal-placental circulation and the unique nature of the fetal lymphatics, other factors that place the fetus at higher risk for the development of right heart failure and effusions include high compliance of the interstitial space; high capillary filtration coefficient, which allows large water flux at low vascular pressure; low colloidal osmotic pressure; and high capillary permeability.

The fetal circulation requires that there be at least 1 patent and competent inflow, 1 patent and competent outflow, 1 ventricle that fills normally and can maintain the equivalent of a combined ventricular output, and a well-functioning placenta. If there is a problem with any one of these, fetal heart failure and even spontaneous intrauterine demise with or without hydrops can occur. As is true for most fetuses with critical outflow obstruction, severe dysfunction of 1 ventricle does not usually lead to the evolution of heart failure unless it alters the function of the other ventricle. There are structural cardiac lesions in which abnormal function of 1 ventricle more consistently leads to altered function of the other. This is particularly true for lesions associated with severe atrioventricular or semilunar valve insufficiency in which a significant volume load of 1 ventricle can alter the ability of the other ventricle to fill. When this occurs, without an ability to redistribute flow toward the “unaffected” ventricle, atrial filling pressures increase, leading to increased central venous pressures. Furthermore, this pathophysiology makes it difficult for the fetus to adjust to acute physiologic demands, which may put the fetus at risk for intrauterine fetal demise in the absence of hydrops. These observations have been reported in both Ebstein anomaly of the tricuspid valve and tetralogy of Fallot with absent pulmonary valve syndrome. Other cardiovascular abnormalities associated with the evolution of fetal hydrops include cardiomyopathies, particularly those associated with altered ventricular filling, tachycardias and bradycardias, high cardiac output states, high ventricular afterload as observed in the recipient twin in twin-twin transfusion syndrome, and extracardiac pathologies that prevent filling of the fetal heart (Table 477-2). For many of these pathologies, fetal echocardiography plays an important role in the assessment of an affected pregnancy, determining optimal time for prenatal interventions, monitoring after prenatal interventions, and planning delivery.

Although the outcome for most hydropic fetuses with cardiovascular pathology is guarded, postnatal survival is possible if the hemodynamic condition can be improved. For example, in pregnancies with fetal hydrops caused by abnormalities of the fetal circulation, including agenesis of the ductus venosus and premature constriction of the ductus arteriosus, delivery can result in rapid improvement in the hemodynamic condition of the infant and survival. In Ebstein anomaly of the tricuspid valve, if there is patency of the pulmonary valve, even with severe tricuspid insufficiency, delivery of the fetus, allowing the ductus arteriosus to close and the pulmonary vascular resistance to fall, may be sufficient to promote forward pulmonary blood flow and decrease tricuspid insufficiency. Early pacemaker therapy in the neonate with atrioventricular block and mild or moderate hydrops may result in survival if the structure of the heart is normal or correctable. If there is no means of medically or surgically improving the hemodynamic abnormalities that led to the evolution of hydrops before birth, delivery only adds an additional hemodynamic burden associated with the transition from fetal to neonatal circulation and may result in progressive cardiovascular compromise and death.

PRENATAL COUNSELING

Once a diagnosis of fetal CHD is made, the fetal cardiologist counsels the pregnant woman and her partner regarding the diagnosis, the potential for evolution, associated morbidity, and when appropriate, the need for additional testing. Diagrams of the cardiac defect are typically provided and compared with a normal heart diagram for better understanding. The counseling usually takes into account the additional cardiovascular lesions that may or may not be detectable but that can affect the clinical course. The Fetal Cardiovascular Disease Severity Scale can function as a common means to communicate disease severity to patients. A postnatal algorithm of clinical outcome and management may be presented for lesions in which the severity of pathology and postnatal clinical picture is not entirely predictable. The potential for extracardiac pathology must be considered in the counseling. Fetal CHD is often associated both with chromosomal abnormalities and extracardiac structural pathology that may not only affect the clinical course of the fetus, but may also not be recognized prenatally. The incidence of aneuploidy, for instance, in fetal CHD ranges from 15% to 25%, depending on the series and the type of fetal CHD. For certain forms of CHD, chromosomal abnormalities are common, including conotruncal lesions (eg, tetralogy of Fallot, truncus arteriosus, double outlet right ventricle) and coarctation of the aorta, whereas other kinds of CHD, including complete transposition of the great arteries and that associated with heterotaxy syndrome, have a lower risk. These relative risks must be incorporated into the decision regarding chorionic villous sampling or amniocentesis. Depending on the timing of diagnosis, the fetal cardiologist and obstetrical staff provide options available to the pregnant mother with respect to continuation of the pregnancy. For more severe cardiovascular lesions or a combination of cardiovascular and extracardiac pathology associated with high risk of fetal and neonatal compromise and with a more guarded prognosis, discussions regarding aggressive prenatal and neonatal management are necessary. For very severe pathologies, planned compassionate/palliative perinatal and neonatal care may be chosen. Such discussions ideally involve personnel from all of the disciplines caring for the pregnant mother and infant to avoid unnecessary confusion or inappropriate management of both mother and fetus.

PERINATAL AND NEONATAL MANAGEMENT PLANNING

A multidisciplinary approach to diagnosis, counseling, and perinatal and neonatal management of fetal CHD is an important factor in optimizing the outcome of fetal CHD, particularly when severe. The team consists of an obstetrician or perinatologist as the primary caregiver, a fetal cardiologist, a geneticist, a neonatal specialist, other pediatric and surgical subspecialists (depending on the cardiac and extracardiac pathology), and supportive services including an experienced perinatal or neonatal social worker.

For most fetal CHD, vaginal delivery at term is desired. A mother who lives far away from the tertiary care center may require a scheduled induction of labor to ensure the delivery occurs in the appropriate facility. Although term delivery is most desired, when there is fetal stress or evolving fetal hydrops, a premature delivery may be preferable. With multiple gestations, an early delivery may occur or be necessary, and this should be taken into consideration in counseling and delivery planning.

For minor CHD and fetal CHD not likely to be a problem within the neonatal period (eg, isolated ventricular septal defect, balanced atrioventricular septal defect, and minor valve abnormalities), it may be acceptable for the delivery to occur in a local hospital with pediatric assessment shortly after birth and planned early pediatric cardiology evaluation. This allows the pregnant mother to deliver close to home, in a familiar environment with her primary obstetrician.

For lesions of moderate or uncertain severity, and therefore with an uncertain clinical presentation after birth, a more conservative approach with delivery of the infant at the tertiary or quaternary care center is usually considered. Such lesions include isolated coarctation of the aorta, moderate semilunar valve stenosis, and tetralogy of Fallot with anterograde flow through the ductus arteriosus. If the lesion is more severe than expected, the appropriate care can be provided, including medical and surgical intervention. In coarctation of the aorta, for instance, the arch obstruction may not always be severe enough to warrant prostaglandin therapy to maintain ductal patency. The neonatal and pediatric cardiology team may choose to observe the infant until the ductus arteriosus has closed to confirm the absence of severe distal arch obstruction and its sequelae. In fetal tetralogy of Fallot, it is difficult to consistently predict the degree of cyanosis that will occur after postnatal ductal closure.

Critical fetal CHD, which requires maintaining ductal patency after birth or immediate medical or surgical intervention, warrants delivery in a tertiary/quaternary care center, obviating the need to transport the infant to another center and ensuring that the mother and family are nearby. For many, initiation of prostaglandin therapy is necessary to stabilize the infant’s circulation. Some forms of complex CHD, however, may not require immediate medical and surgical intervention, including some forms of heterotaxy syndrome and functional single ventricle with no outflow tract obstruction or with mild or moderate degrees of pulmonary stenosis. Such babies should be delivered at a tertiary care center to ensure appropriate monitoring of the newborn occurs by experienced personnel as the ductus arteriosus closes. If these patients do not develop more severe pathology with ductus arteriosus closure, they can be discharged with close surveillance as an outpatient.

There are some conditions that are known to potentially manifest with severe instability at birth, most requiring emergent interventions, such as HLHS with intact atrial septum or congenital complete heart block with fetal heart rate less than 50 bpm. These fetuses are at increased risk for compromise in the delivery room, and ensuring immediate postnatal access to a cardiac team for a procedure is indicated. Finally, there are rare situations in which, due to the lethality of the cardiac or extracardiac pathology, either palliative or compassionate care without intervention is chosen by the family and care team. Involvement of an experienced palliative care team to generate a well-documented plan for the course of events during labor and at delivery to optimize the comfort of the neonate and time for the family to be together and reduce unnecessary interventions is critical. Delivery in a local hospital close to the family’s home may also be considered in this situation.

IMPACT OF PRENATAL DIAGNOSIS AND FETAL CARDIOLOGY

The clinical impact of fetal diagnosis has been documented best in structural CHD. Planned management of critical CHD before birth avoids the potential cardiovascular compromise that may acutely evolve as a consequence of ductus arteriosus constriction and may be associated with an improved preoperative condition, with less acidosis and end-organ damage and better postoperative survival, and long-term myocardial and neurodevelopmental function may also be improved. Prenatal diagnosis with medical intervention has resulted in improved survival in fetal tachyarrhythmias and bradyarrhythmias.

Although less emphasized, timely prenatal diagnosis of severe CHD, with subsequent pregnancy termination, has the potential to alter the clinical spectrum of disease observed after birth. This was first recognized in the United Kingdom in the early 1990s, where, concomitant with increasing rates of prenatal diagnosis of HLHS, a decrease in the number of neonates diagnosed with the condition was observed.

Even when a pregnancy is continued, prenatal diagnosis also has an important psychological and emotional impact for the pregnant woman and her family. Prenatal diagnosis provides time to prepare for having an affected child. However, research has demonstrated that a significant percentage of mothers exhibit substantial psychological distress, which may influences maternal health and, in turn, may negatively influence the developing fetus.

Fetal cardiology has evolved significantly over the past 2 decades. Although there is no question that it has had an important impact in fetal and neonatal medicine, its potential impact is limited by current prenatal detection rates that are still far from desired internationally. Ongoing efforts to improve prenatal ultrasound screening and even identify more objective and less technician-dependent strategies to improve detection are necessary if fetal cardiology is to achieve its full potential.

SUGGESTED READINGS

The Neonate and Infant with Cardiovascular Disease

INTRODUCTION

Cardiac defects are the most common congenital malformation, occurring in up to 1% of all live births (even excluding bicuspid aortic valve and very small atrial and muscular ventricular septal defects), and present symptomatically in about 20% of such neonates. It is thus essential that the clinician diagnose symptomatic cardiac disease expeditiously. Because of the concern for serious cardiac disease, many clinicians consider the presence of a murmur as the most definitive evidence of heart disease. A murmur, however, is not an accurate sign of symptomatic neonatal heart disease. Many normal neonates have murmurs at some time during the first few days of life, whereas several common symptomatic cardiac defects, such as total anomalous pulmonary venous connection and simple transposition of the great arteries, are not associated with murmurs. In the neonatal period, the presence of a murmur is neither sensitive nor specific to the diagnosis of heart disease, yet it is commonly used both to consider and, most concerning, to exclude the presence of a significant cardiac defect.

The change from a fetal circulatory system to a transitional circulation occurs immediately at birth, and the mature circulation develops within weeks. Because of these dramatic alterations in blood flow and oxygen uptake patterns, the fetus with a stable cardiovascular status can become a newborn with severe cardiovascular symptoms. On the other hand, advances over the last few decades have given the clinician the tools to rapidly stabilize these critically ill neonates, and subsequently correct or ameliorate even the most complex defects. Thus, it is essential that the pediatrician be able to recognize the infant with symptomatic heart disease quickly, so that the appropriate diagnostic and therapeutic interventions can be initiated as soon as possible.

Although there are literally thousands of different congenital cardiac defects, in general, there are only three different, overlapping, modes of presentation of symptomatic heart disease in the newborn and infant, each very easy to recognize during a routine examination. These modes of presentation are cyanosis, decreased systemic perfusion (hypoperfusion), and respiratory distress/failure to thrive.

Prior to considering the modes of presentation of symptomatic heart disease in the newborn, it is worthwhile to review fetal physiology to understand why symptomatic heart disease is rare in the fetus.

FETAL PHYSIOLOGY

The fetal circulation is unlike the postnatal circulation in that there are 3 major circulatory beds rather than 2 (the additional placental circulation) and that the 2 ventricles eject into the vascular beds that are not fully separated. There are 3 main connections, or shunts, between circulatory beds and/or cardiac chambers that allow for admixture of venous return to the ventricles and of their outputs to the arterial beds. These connections allow one ventricle to take over the work of the other when a congenital cardiac defect is present. Those shunts, along with the far lesser oxygen demand of the fetus compared to the newborn, are the main reasons that most forms of critical congenital heart disease do not present until after birth.

Although there is overlap in the function of the ventricles, they still primarily perform their postnatal tasks prior to birth. Postnatally, the right ventricle is the oxygen uptake ventricle, ejecting poorly oxygenated blood into the pulmonary circulation for oxygen uptake. The left ventricle is the oxygen delivery ventricle, ejecting highly oxygenated blood into the systemic circulation for oxygen utilization by the tissues. In order for the ventricles to perform these tasks in the fetus reasonably efficiently, the right ventricle should receive relatively deoxygenated blood and eject the majority of its output to the placenta, because that is the oxygen uptake organ, and the left ventricle should receive relatively highly oxygenated blood and eject the majority of its output to the most metabolically active tissues.

To understand how the fetal circulation supports the efficient function of the right and left ventricles, it is best to consider, in order, the components of venous return, the distribution of these components within the heart, and the various vascular beds into which the ventricles eject (Fig. 478-1). Because these venous and arterial components are not separated in the fetus, one cannot talk about “venous return” as representing systemic or pulmonary venous return, or “cardiac output” as representing pulmonary or systemic blood flow. The amount of blood that composes all of the venous components will be called the “combined venous return,” and the amount of blood that the ventricles together eject will be called the “combined ventricle output” (CVO). The latter is equivalent to 2 “cardiac outputs” of the normal postnatal circulation, as the sum of pulmonary and systemic blood flow.

There are 5 components of venous return in the fetus: the upper body systemic venous return via the superior vena cava (SVC); the lower body systemic venous return, via the inferior vena cava (IVC); the placental return, also via the IVC; the coronary venous return, primarily via the coronary sinus (CS); and the pulmonary venous return, via the pulmonary veins. The right atrium receives the vast majority of venous return in the fetus because the pulmonary venous circulation, the only one that drains directly into the left atrium, composes only about 8% of combined venous return (Fig. 478-2). Despite the fact that over 90% of combined venous return drains exclusively into the right atrium, flow patterns within the veins and the right atrium, in association with the foramen ovale, which shunts blood from the right atrium into the left, allow for the left ventricle to receive a large amount of relatively highly saturated blood and the right ventricle to receive primarily poorly oxygenated blood.

To understand this remarkable phenomenon, it is best to view blood flow patterns, shown in Figure 478-3. The least saturated blood comes from the coronary and upper body circulations and preferentially flows to the right ventricle. The CS orifice is near the atrioventricular groove, just above the tricuspid valve, and below the foramen ovale. Thus, essentially all coronary venous return via the CS passes inferiorly via the tricuspid valve to the right ventricle. Similarly, the position of the eustachian valve and the SVC ensures that well over 90% of SVC flow passes inferiorly and laterally, to the tricuspid valve and right ventricle. Unlike blood returning via the SVC and CS, that in the IVC is not well mixed just before it enters the right atrium but is composed of relatively separate streams of blood returning via the intrahepatic IVC, the ductus venosus, and the right and left hepatic veins. The intrahepatic IVC receives blood primarily from the lower limbs, the kidneys, and the adrenals, and that relatively poorly oxygenated blood is also directed laterally via the eustachian valve, across the tricuspid valve to the right ventricle. The 3 other venous streams have more complicated sources of blood flow, as shown in Figure 478-4. Umbilical venous blood first reaches the portal sinus, where the majority ascends via the ductus venosus to the medial aspect of the junction of the IVC and right atrium. This highly oxygenated ductus venosus blood primarily is directed through the foramen ovale, to the left atrium and ventricle. The remainder of the umbilical venous blood enters the left portal venous system, whereas the splanchnic venous blood, consisting of intestinal, stomach, and splenic venous return, goes via the portal sinus primarily to the right portal veins. The portal venous blood in each lobe mixes with a much smaller amount of hepatic arterial blood and returns to the IVC near the right atrium. The right hepatic veins, containing primarily the less oxygenated splanchnic blood, drain along the lateral wall of the IVC with the intrahepatic venous return, and its blood flows primarily to the right ventricle, whereas the left hepatic venous blood, composed in large part of highly oxygenated umbilical venous blood, enters the medial aspect of the IVC with the ductus venosus and flows across the foramen ovale to the left atrium and ventricle. In the human, flow patterns in the central venous components and the atria lead to 55% of combined venous return entering the right ventricle and 45% entering the left (see Fig. 478-2). Although it has not been measured in the human, left ventricular blood is likely to be about 15% more saturated with oxygen than right ventricular blood, which would benefit its role as the oxygen delivery ventricle, and it also has a higher glucose concentration, because it receives the vast majority of umbilical venous return, the source of substrate to the fetus. Thus, it is well set up to deliver oxygen and substrate to the highly metabolic tissues, as long as that is where its blood is delivered.

The organs that require the most nutrients, and thus blood flow, per gram are the heart, brain, and adrenal glands, although the latter are extremely small and thus are not of great consequence when considering blood flow distribution. The heart receives about 3% to 5% of CVO, and the brain receives about 32% (Fig. 478-2). Because both of these organs receive blood from vessels arising from the ascending aorta (Fig. 478-3), both receive blood entirely from the left ventricle in the normal fetus. Only a small amount of left ventricular blood, about 8% to 10% of CVO, is not delivered to the heart and upper body, but crosses the aortic arch and isthmus to the lower circulation (Fig. 478-2). About two-thirds of the blood traveling down the descending aorta goes to the placenta for oxygen and substrate uptake, while the other third goes to the lower body of the fetus. Thus, only a small amount of left ventricular blood goes to the placenta. Conversely, the majority of right ventricular blood crosses the ductus arteriosus to the descending aorta, with only a minority going into the lungs, because of the high resistance in the pulmonary vascular bed. Over 80% of right ventricular output goes down the descending aorta, two-thirds of which goes to the placenta. Thus, the majority of right ventricular blood indeed goes to the oxygen uptake circulation, whereas the majority of left ventricular blood goes to the highly metabolic tissues for oxygen and substrate utilization.

Although the ventricles perform their normal postnatal tasks relatively efficiently in the fetal environment, the intravascular and intracardiac shunts allow them to easily take over the other’s function in the presence of cardiac defects, something that is not possible in the postnatal circulation. Alterations in gene expression in embryonic life alter cardiac and vascular structures, often leading to decreased blood flow through 1 ventricle or the other. These aberrations in structure lead to alterations in flow, which, although homeostasis is maintained, cause further changes in cardiac and vascular structures. The combination of primary molecular events and secondary flow events creates the specific congenital heart abnormality seen when the baby is born, but we often do not know which is the primary event and which is flow related.

For example, one form of cyanotic congenital heart disease is tricuspid atresia with ventricular septal defect. In this condition, all of the blood flow returning to the right atrium must pass through the foramen ovale to the left atrium and left ventricle. The ventricular septal defect allows flow into a right ventricle, which is usually diminutive, and pulmonary valve and arteries, which almost always form normally. There is invariably a large secundum atrial septal defect, and the aortic arch is widely patent, without a coarctation of the aorta, unless the great arteries are transposed.

It is likely that the secundum atrial septal defect and widely patent aortic arch are secondary events caused by markedly increased flow through them—the foramen ovale in this lesion, for example, takes 92% of combined venous return, rather than the normal 37%, and a secundum atrial septal defect, in which the 2 limbs of the fossa ovalis are separated further and cannot appose, is the expected result. However, is atresia of the tricuspid valve a primary event, or is it secondary to lack of adequate resorption of the tissue between the sinus venosus and primitive atrium, as suggested by echocardiographic studies postnatally, in which the eustachian valve is frequently very large and redundant? It is possible that this elongated eustachian valve redirects venous return toward the leftward component of the embryonic atrioventricular canal, leading to abnormal development of its components. And is the ventricular septal defect also a primary event, or is it secondary to the large inflow of blood into the left ventricle relative to the right, preventing apposition of the plates of muscular septal tissue? As developmental biologists continue to expand our rapidly increasing knowledge of cardiac embryogenesis, answers to these questions will come quickly. But for the clinician, it is most important to know that primary embryonic events lead to abnormal blood flow patterns that cause other important cardiac defects as well. Such associations allow the clinician to search for possible associated defects when considering a particular congenital lesion in a patient and to exclude other defects because of the unlikelihood of various lesions to coexist. Examples of these points will be presented throughout each component of this chapter in relation to specific modes of presentation of heart disease in the newborn and infant.

TRANSITIONAL CIRCULATION

At birth, dramatic changes in blood flow and cardiac function unfold, leading to a circulation that is more efficient at the uptake and delivery of oxygen but that depends on a nearly normal heart and circulation. The most dramatic changes occur within seconds and minutes of birth, followed by gradual changes, which lead to a mature circulatory pattern within weeks of birth. These changes are required for the healthy survival of infants who underwent normal cardiovascular development but are potentially lethal for those with congenital cardiac defects.

The 3 most important changes at birth are the dramatic decrease in pulmonary vascular resistance, the abolition of the central vascular and cardiac shunts, and the increase in output of the 2 ventricles. Of the 3, the driving force toward the achievement of the normal postnatal circulation is the dramatic and remarkable fall in pulmonary vascular resistance.

Pulmonary vascular resistance is extremely high in the fetus, allowing only about 8% of CVO to enter the lungs until near term. The intense vasoconstriction occurs in the distal pulmonary arteries, which have a thick medial smooth muscle layer. Pulmonary vascular resistance actually begins to decrease substantially before birth, as a result of a large increase in vessels in late gestation, increasing the cross-sectional area of the vascular bed. They remain vasoconstricted, however, largely due to their hypoxemic environment, the lack of vasodilating substances, and the presence of vasoconstrictors. Immediately at birth, there is an abrupt and large decrease in pulmonary vascular resistance, which leads to an enormous increase in pulmonary blood flow of 10-fold to 20-fold. Although increased oxygenation is thought to be a major contributor to this fall in resistance, ventilation with fetal gases has been shown to be capable of causing up to two-thirds of the fall that is seen, so that other mechanisms must be in play. The decrease in pulmonary vascular resistance induced by ventilation alone may in part be caused by a direct effect, as changes in surface tension at the alveolar air–liquid interface reduce perivascular tissue pressures, but likely is also caused by an increase in local (endothelium-derived) and circulating PGI₂ and PGD₂ induced by gaseous distension, and by an increase in endogenous NO, which may also mediate the oxygen responsiveness of the pulmonary arteries. Other mediators of the oxygen effect are potassium channel activation and stimulation of various local and circulating vasodilators.

The large increase in pulmonary flow is essential to the second major component of the transitional circulation, the abolition of the central shunts. These are the foramen ovale, between the left and right atrium; the ductus arteriosus, between the main pulmonary artery and descending aorta; and the ductus venosus, between the portal sinus and IVC. In fetal life, the foramen ovale is like a windsock, directing blood from the ductus venosus and left hepatic veins toward the left atrium, and remains open because of the far greater right atrial venous return than that of the left. As pulmonary vascular resistance falls immediately at birth, pulmonary venous return to the left atrium increases dramatically, often exceeding that of the right atrium as the shunt through the ductus arteriosus reverses its direction, now going from the descending aorta to the main pulmonary artery. Once left atrial venous return and pressure exceed that of the right, the flap of the foramen, which is in the left atrium, presses against the floor of the fossa ovalis, abolishing the foraminal shunt. The shunt through the ductus venosus is maintained primarily by umbilical venous return from the placenta. This source of blood is instantly abolished when the umbilical cord is cut. Even before this, however, umbilical flow almost entirely ceases, due to the vasoconstrictor effects of oxygen and mechanical stretch on the umbilical artery. Ductus venosus flow ceases completely within 3 to 7 days after birth, likely due to the passive effects of diminished blood flow, although it has been shown to vasodilate with elevations in prostaglandin E₁ (PGE₁).

The shunt through the ductus arteriosus is reversed as pulmonary vascular resistance falls, as mentioned above. The ductus arteriosus has a large amount of medial smooth muscle and thus is a very reactive vessel. In the fetus, its patency is maintained in part by high levels of PGE₂, which are about 4-fold higher than those after birth, but it is uncertain whether it is the circulating levels or local levels that exert the greater control. After birth, the ductus arteriosus is functionally closed in most term infants within 10 to 15 hours, and permanent closure, caused by thrombosis, intimal proliferation, and fibrosis, is seen usually within 3 weeks.

Last, there is a large, nearly 3-fold, increase in ventricular output at birth. The increase in left ventricular output exceeds that in the right because the right ventricle ejects more blood than the left in fetal life, whereas they eject the same amount (or the left may eject a little more than the right because of the early left-to-right shunt through the ductus arteriosus). This increase in output is driven by a similarly large increase in oxygen consumption, which has been shown to increase 3-fold in newborn lambs. The increase in oxygen consumption is likely driven by the need of the newborn to maintain thermoregulation and to breathe, neither of which consumes much oxygen in the fetal environment.

The increase in left ventricular output is caused by increases in both heart rate and stroke volume. This is intriguing because the fetal left ventricle cannot come close to achieving a similar increase. At most, fetal left ventricular output can increase only about 50% in response to alterations in load, heart rate, and contractility. The newborn left ventricle is capable of increasing its output nearly 3-fold even without evidence of an increase in contractility. From a variety of studies, it appears that the primary reason that the neonatal left ventricle is able to increase output is because its filling and contraction are no longer constrained by the right ventricle after birth. Other contributing factors may include increased β-adrenergic receptor activity in association with thyroid hormone and cortisol surges in the perinatal period, a decrease in ventricular afterload, and an improved relationship between preload and afterload.

SYMPTOMATIC HEART DISEASE IN THE NEWBORN AND INFANT

Most patients who eventually present with symptomatic heart disease do so during the neonatal period or early infancy, during either the rapid transition from the fetal to the transitional circulation during the first days of life, the slower transition to the mature circulation as pulmonary vascular resistance continues to fall over the subsequent 6 weeks, or the period of physiologic anemia that occurs during the second and third months of life.

Symptomatic heart disease in the newborn and infant presents either primarily with cyanosis, inadequate systemic perfusion, or respiratory distress/failure to thrive (from excessive pulmonary blood flow, without either cyanosis or hypoperfusion). Cyanosis can be appreciated by careful visual inspection, hypoperfusion by examination of the extremities, and respiratory distress/failure to thrive by observing the respiratory rate and pattern and by plotting the infant on the appropriate growth chart. A simple evaluation of the infant at each examination will undoubtedly uncover the possibility of congenital heart disease, and a thoughtful and rational approach will lead to the appropriate differential diagnosis and plan. Admittedly, this approach is imperfect; some lesions are complex with overlapping manifestations (eg, an infant with truncus arteriosus may present with cyanosis in the first hours of life as pulmonary vascular resistance is high, but becomes tachypneic without cyanosis over the next few hours and days). In addition, the differential diagnosis includes noncardiac disease, so that the initial evaluation points only to the possibility of heart disease, not to its definite presence. However, by focusing on these few signs of congenital heart disease and evaluating each infant throughout infancy, the pediatrician will not miss the diagnosis and will ensure that each infant is treated appropriately.

Cyanotic Heart Disease

The newborn who presents with cyanosis without significant respiratory distress almost always has structural congenital heart disease. Cyanosis is the most common manifestation of symptomatic congenital heart disease in the newborn and may be associated with critically decreased oxygen delivery; therefore, it is important for the pediatrician to be able to quickly and accurately exclude its presence. Although central cyanosis is often readily apparent by visualization of the tongue and buccal mucosa (vascular beds with limited vasoconstrictor tone), it may be difficult to appreciate for a variety of reasons: the presence of a ductus arteriosus may maintain levels of systemic arterial oxygen saturation above the limits of visual cyanosis by increasing pulmonary blood flow over the time that the newborn is in the hospital, anemia decreases the amount of reduced hemoglobin in the blood for the same level of saturation and similarly obscures cyanosis, and the absence of a heart murmur may decrease the physician’s appreciation of the possibility of a cardiac defect and thus not carefully evaluate the newborn for cyanosis. Because of these and other considerations, routine pulse oximetry screening has been implemented nearly universally in most resource-rich countries, as recommended by the American Heart Association and the American Academy of Pediatrics, in addition to other groups. This has dramatically decreased the likelihood of missing the diagnosis of cyanotic congenital heart disease prior to hospital discharge.

Hemodynamic Categories

As with the other forms of symptomatic congenital heart disease, it is best not to memorize the various lesions associated with cyanosis, but rather to understand the pathophysiologic processes that lead to the finding; moreover, as with each of the 3 hemodynamic categories, cyanosis can be divided into 2 processes. Infants present with cyanosis due to heart disease either because the amount of blood going through the pulmonary vascular bed is decreased (decreased pulmonary blood flow) or the amount is normal or even increased, but the desaturated systemic venous blood is preferentially directed across the aortic valve rather than across the pulmonary valve (transposition complexes). It is useful to consider these 2 hemodynamic categories of cyanotic lesions separately, because lesions within each category tend to have similar presentations, associated findings in the fetus and after birth, and therapeutic approaches.

Decreased Pulmonary Blood Flow

Most lesions with decreased pulmonary blood flow have obstruction either to the inflow of blood to the right ventricle or the ejection of blood from it. A much smaller number of lesions, occurring with much less frequency, are associated not with obstruction but with insufficiency of 1 of the right-sided valves, either of the inflow (tricuspid valve) or outflow (pulmonary valve). All of these lesions can be considered sequentially, along lines of blood flow (Table 478-1). Systemic venous blood arrives in the right atrium and, from there, crosses the tricuspid valve to enter the right ventricle. Thus, the first level of obstruction occurs at the tricuspid valve, which may be totally absent (tricuspid atresia) or narrowed (tricuspid stenosis, or hypoplasia). The former is almost always associated with a ventricular septal defect, whereas the latter is associated with hypoplasia of the right ventricle and secondary pulmonary valve atresia. The most common cause of insufficiency of the tricuspid valve is Ebstein anomaly, in which the septal leaflet is displayed inferiorly, toward the apex of the right ventricle, preventing coaptation of the leaflets and leading to severe valve insufficiency. Because the right ventricle cannot generate much pressure in the presence of severe insufficiency, there may be acquired pulmonary valve atresia, although often, this is just functional (evidence that the valve is patent but cannot be opened by the right ventricle is the presence of pulmonary insufficiency on color Doppler echocardiography).

The next level of obstruction occurs within the right ventricle. Right ventricular hypoplasia, as mentioned earlier, is usually secondary to tricuspid valve hypoplasia and may include abnormalities in the volume of all 3 components of the right ventricle—the inflow, apex, and outflow. Outflow obstruction alone occurs most frequently when the outlet ventricular septum is malaligned anteriorly so that it does not meet the muscular and membranous septum, leading to an outlet ventricular septal defect. The association of anterior malalignment of the outlet ventricular septum, a ventricular septal defect, and outlet (infundibular) obstruction leading to a right-to-left shunt across the ventricular septal defect is called tetralogy of Fallot and is one of the most common forms of cyanotic congenital heart disease. Because tetralogy of Fallot involves abnormal embryonic movement of the outlet septum, it may be associated with a microdeletion of 22q11 (eg, DiGeorge syndrome, velocardiofacial syndrome), which has many other manifestations thought primarily to be caused by abnormal migration of the cardiac neural crest tissue. In the most severe form of tetralogy of Fallot, the pulmonary valve is atretic. In this situation, the branch pulmonary arteries may arise from a ductus arteriosus or may not form normally. If that occurs, the vascular segments of the lung are fed by major aortopulmonary collateral arteries, and surgical reconstitution of a normal vascular bed is very complex. Absent pulmonary valve syndrome is a very rare and interesting variant of tetralogy of Fallot in which the pulmonary valve leaflets are vestigial, causing unrestricted pulmonary insufficiency along with moderate pulmonary stenosis. More importantly, the branch pulmonary arteries are massively dilated and frequently cause severe airway obstruction at birth. In fact, the primary cause of morbidity and mortality from this lesion in the neonatal period is bronchial compression, not the congenital cardiac defect that is the cause of the compression.

Outflow obstruction without a ventricular septal defect rarely leads to cyanosis. There are 2 primary causes of outflow obstruction without an associated ventricular septal defect. The course of the moderator band, between the body and outflow of the right ventricle, can be anomalous and partially obstruct the outflow tract. Because there are high-pressure and low-pressure components to the right ventricle in this lesion, it is called double-chamber right ventricle. However, it usually occurs later in life, often in patients with a ventricular septal defect (which may have since closed), so that it is not commonly considered in the differential diagnosis of cyanosis in the infant and newborn. More commonly, right ventricular outflow tract obstruction without a ventricular septal defect can occur in hypertrophic cardiomyopathy of the newborn, often associated with maternal diabetes. In some cases, the massive septal hypertrophy can preferentially obstruct the right ventricular outflow tract, leading to a right-to-left atrial shunt and cyanosis.

The next level of obstruction is at the pulmonary valve, which may be stenotic or atretic. The presence of well-developed ventricle allows for a transcatheter perforation and dilation of the valve, obviating the need for a surgical shunt (see Chapter 490). Above the pulmonary valve, supravalvar pulmonary stenosis may occur, usually in association with branch pulmonary artery stenosis, which are seen together in Williams syndrome, a genetic defect of the elastin gene, which has been mapped to chromosome 7. However, the arterial obstruction in Williams syndrome usually occurs over time, is rarely severe, and rarely presents with cyanosis in infancy. Branch pulmonary artery stenosis is also seen in Alagille syndrome, in which there is an associated paucity of bile ducts in the liver, leading to liver dysfunction. It also has a defined genetic basis, as about 88% of patients show a mutation of the JAG1 gene.

Finally, obstruction can occur at the pulmonary arteriolar level. This is not cyanotic congenital heart disease, but is pulmonary hypertension of the newborn, in which the arterioles do not dilate normally at birth. It is discussed in a separate chapter.

Lesions causing decreased pulmonary blood flow and cyanosis after birth have similarities in their fetal circulation and, thus, in their secondary manifestations. Because the right side of the heart is obstructed, or right atrial pressure is elevated due to valvar insufficiency, blood flow across the foramen ovale is generally increased in the fetus, particularly with critical obstruction or atresia. Thus, a secundum atrial septal defect is often a secondary lesion, obviating the need for a balloon atrial septostomy at birth, unlike patients with transposition of the great arteries (see below). Similarly, the decreased flow across the pulmonary valve in the fetus must be associated with increased flow across the aortic valve. This, in turn, is associated with increased flow across the aortic isthmus, making coarctation of the aorta exceedingly unlikely. With this knowledge of fetal physiology, the clinician can be confident that an infant who presents with upper body cyanosis and decreased femoral pulses almost certainly has one of the transposition complexes rather than decreased pulmonary flow.

Just as fetal patterns are similar in infants with decreased pulmonary blood flow, similar postnatal findings determined by postnatal flow patterns help greatly with the clinical diagnosis and stabilization. In infants with decreased pulmonary blood flow, the decreased pressure and flow through the pulmonary valve implies that a ductal shunt, if present, must be left to right. Thus, upper and lower body pulse oximetry must be the same, whatever the lesion (Table 478-2). The presence of differential saturations excludes a lesion associated with decreased pulmonary blood flow, as does the presence of decreased lower body pulses, as mentioned above.

It is important to be aware that pulse oximetry in the right hand does not necessarily represent upper body saturation. Occasionally the right subclavian artery arises from the descending aorta below the ductus arteriosus (anomalous origin of the right subclavian artery), in which case it represents lower body blood flow. Even more rarely, it can arise from the right pulmonary artery. In order to be certain that pulse oximetry represents upper body flow, it should be obtained from the ear or nose.

The time course of cyanosis can also lead the clinician to this category of lesions. In most lesions with decreased pulmonary blood flow, the ductus is widely patent at birth, supplying adequate flow for several hours or days. With the rapid fall in pulmonary vascular resistance, pulmonary blood flow may be 2 to 4 times systemic, causing saturations to be in the high 80s to low 90s, and delaying the appearance of cyanosis. Cyanosis may then progress gradually, over hours to days, or, as often happens, it may first be noticed when the newborn cries or is fed, both of which increase oxygen utilization and decrease pulmonary blood flow, by increasing pulmonary impedance in the former and decreasing systemic vascular resistance in the latter. This time course is very different than that seen in the transposition complexes, which will be presented below.

Lastly, blood flow patterns may also allow for the distinction of inflow lesions associated with decreased pulmonary blood flow from all other causes of cyanosis by simple physical findings. When the right ventricle does not fill appreciably, in tricuspid atresia or severe hypoplasia (with a hypoplastic right ventricle and pulmonary atresia), it ejects a minimal amount of blood, and thus does not generate a parasternal impulse. In all other causes of cyanosis (decreased pulmonary blood flow with outflow obstruction, transposition complexes, and pulmonary hypertension of the newborn), the right ventricle ejects a reasonable amount of blood under high pressure, and thus there is a normal to increased parasternal impulse. Thus, the careful physical examination can lead to the rapid diagnosis of cyanosis secondary to decreased pulmonary blood flow caused by inflow obstruction to the right ventricle, and a simple electrocardiogram can usually differentiate the 2 possible lesions (Fig. 478-5).

Because blood flow patterns are similar in the fetus and newborn with most lesions causing decreased pulmonary blood flow, the means to stabilize the patient prior to definitive diagnosis and cardiac interventions are similar as well. The atrial septum is rarely restrictive, so that there is rarely a need for a cardiologist to perform a balloon atrial septostomy. Because pulmonary blood flow is usually maintained adequately when the ductus arteriosus is widely patent, these infants can almost always be stabilized by giving PGE₁, as long as the side effects of that drug are properly considered and avoided. The ductus arteriosus may close even more rapidly than normal in these patients because it is often long and thin. Most importantly, care needs to be taken to ensure adequate ventilation, because apnea is a common occurrence, and the volume status and arterial perfusion pressure must be maintained, because PGE₁ is also a potent systemic vasodilator.

Transposition Physiology

The second group of congenital heart defects associated with cyanosis in the newborn and infant can be considered together as lesions in which the aorta is anteriorly and rightwardly displaced, committed to the systemic venous, or usually, right, ventricle. The aorta is transposed over the ventricular septum, and systemic venous rather than pulmonary venous blood preferentially flows across the valve to the body via the ascending aorta. Pulmonary blood flow may be normal, increased, or decreased in this group of lesions, depending on the associated lesions, but in most, it is either normal or increased.

The classic and most common lesion in this group is transposition of the great arteries with intact ventricular septum, also called simple transposition. Details of the diagnosis and management of this lesion are provided elsewhere. In this lesion, the pulmonary artery is also malposed, sitting over the left ventricle. It is best to consider the various lesions in this group of patients along lines of flow as well, but in this group, that consideration relates to associated defects rather than the primary pathophysiology, which, in all lesions, is cyanosis due to preferential streaming of systemic venous flow across the aortic valve. There are also several very complex lesions beyond the scope of discussion in this chapter in which the aorta is malposed. The most common is asplenia syndrome, or right atrial isomerism. However, this syndrome usually has associated pulmonary valve atresia or critical pulmonary valve stenosis with a single ventricle, so that the cyanosis is caused by decreased pulmonary blood flow rather than the malposition of the aorta, because both pulmonary venous and systemic venous blood enter the same ventricle (and almost always across a single atrioventricular valve).

When the aorta is malposed over the right ventricle in the fetus, a normal or slightly increased amount of blood will cross the valve into the ascending aorta, but it will have moderately less oxygen and glucose, because the shunt of placental blood across the foramen ovale directs blood with high oxygen and glucose concentrations to the left ventricle. Flow across the aortic isthmus is normal or slightly increased so that coarctation of the aorta is possible, as discussed above. Because neonates with decreased pulmonary blood flow do not have coarctation of the aorta, a newborn who presents with upper body cyanosis and decreased lower body pulses can be assumed to have transposition of the aorta; as with acyanotic patients, a large percentage of these patients have an associated ventricular septal defect. It is most common when the ventricular septal defect underlies the pulmonary valve, often with anterior displacement of that valve to commit it to the right ventricle. This is called Taussig-Bing anomaly. Blood flow across the aortic outflow is compromised, leading to the coarctation.

More valuable to the clinician is the timing of cyanosis in this group of lesions and the relative saturations in the upper and lower body. In simple transposition of the great arteries, there is little mixing of the systemic and pulmonary venous circulations after birth, just as in the normal newborn. Unlike the normal newborn, though, this separation of venous returns causes the desaturated systemic venous blood to cross the aortic valve to the ascending aorta, leading to significant, often intense, cyanosis, immediately after birth. The earlier and more severe the cyanosis, the more likely the neonate has transposition of the aorta rather than decreased pulmonary blood flow. In addition, the presence of a ductus arteriosus at birth and the shorter distance of the pulmonary valve to the ductus than the aortic valve usually leads to somewhat higher saturations in the lower body than in the upper body, which cannot happen in neonates either with decreased pulmonary blood flow or with persistent pulmonary hypertension (see Table 478-2).

Although neonates with simple transposition of the great arteries tend to present immediately after birth with severe cyanosis, neonates with complex lesions may not show clinical cyanosis for days or weeks. This is because those lesions are nearly always associated with a ventricular septal defect, which significantly increases pulmonary blood flow. Although the majority of the systolic ventricular shunt goes from the right ventricle to the left because systemic vascular resistance is higher than pulmonary vascular resistance, there can be a fairly large diastolic shunt from the left ventricle to the right because of the higher pulmonary venous return and left ventricular filling pressures, increasing right ventricular and thus aortic saturation to levels that may not be easily detected by the clinician. This is particularly true if there is also an atrial septal defect with a large left-to-right atrial shunt promoted by the large increase in pulmonary blood flow caused by the VSD shunt. The large amount of pulmonary venous return that crosses the atrial septal defect to the right atrium and right ventricle is preferentially ejected out the aorta, sometimes increasing aortic saturation to the mid-80s or higher. The use of screening pulse oximetry, however, has allowed for the early recognition of these lesions.

The therapy to stabilize these infants prior to surgical intervention is dependent on the fetal and postnatal physiology discussed above. In simple transposition of the great arteries, this means that the foramen ovale is likely to close at birth and that the ductus, while still patent, will likely shunt from the aorta into the lungs. Administration of PGE₁ maintains a ductal left-to-right shunt into the lungs, and a balloon atrial septostomy allows the highly saturated pulmonary venous blood to pass into the right atrium and out the aorta, until an arterial switch procedure is performed within a few days of birth.

If a neonate has a complex lesion, the associated abnormalities may require treatment. Aortic arch obstruction should also be treated with PGE₁ prior to surgical intervention. Ventricular septal defects can lead to very high pulmonary blood flow. That, in combination with mild hypoxemia causing pulmonary vasoconstriction, may lead to particularly high stresses on the pulmonary arterioles, and thus relatively earlier pulmonary vaso-occlusive disease, so that such shunts need to be treated and closed more aggressively than in patients only with a ventricular septal defect. The presence of pulmonary stenosis may protect the pulmonary vascular bed, but it may be so severe that a palliative procedure to increase pulmonary blood flow may be necessary.

INADEQUATE SYSTEMIC PERFUSION

Inadequate systemic perfusion, or hypoperfusion, is the second most common presentation of symptomatic heart disease in the neonate and represents the most common cause of mortality. Unlike cyanosis, hypoperfusion is commonly caused by noncardiac diseases, particularly sepsis, so that heart disease is not always considered in a timely manner. This is particularly true when no murmur is present, because many clinicians consider that its absence excludes congenital heart disease. Unfortunately, some of the most common and lethal forms of cardiac disease that present in the newborn and infant are not associated with murmurs.

Hemodynamic Categories

As with cyanosis, hypoperfusion on a cardiac basis can be divided into 2 pathophysiologic mechanisms that may overlap in an individual patient. Hypoperfusion may be caused by obstruction to the inflow of blood to or the outflow from the left side (pulmonary venous side) of the heart, or it may be caused by decreased left ventricular function without obstruction. Most causes of hypoperfusion that are not on a primary cardiac basis exert their effects on systemic perfusion by a decrease in left ventricular function, but some do so by other means, most notably by severely decreasing systemic vascular resistance. This causes pooling of blood in various vascular beds, diminishing the effective circulating volume to a critical level. Causes include vascular structures such as large teratomas and acute vasodilation crises such as occurs in some forms of sepsis. Only those causes of left ventricular dysfunction that are a form of congenital heart disease will be discussed in this section, although secondary causes are listed in Table 478-3.

Prior to discussing the individual congenital cardiac defects that cause hypoperfusion, a few important issues should be considered. First, the transitional circulation is different than the mature circulation in that the upper and lower body still may be perfused by different ventricles, while the ductus arteriosus is patent. Thus, evaluation of the neonate for signs of hypoperfusion must be performed rigorously, with the appreciation that demonstrating normal upper body perfusion does not exclude hypoperfusion of the lower body, and vice versa. Second, all patients with hypoperfusion present with moderate to severe respiratory distress due to elevation of pulmonary venous pressures. Whether the left side of the heart is obstructed or the left ventricle is dysfunctional, the inflow of blood is impaired, and pulmonary venous pressures increase, causing pulmonary edema. Thus, it is important to carefully evaluate every neonate with significant respiratory distress for hypoperfusion, which may be subtle and limited to only the upper or lower body. In that way, for example, a newborn with a coarctation of the aorta who presents with respiratory distress may be diagnosed and treated appropriately before cardiovascular collapse. Further details regarding the diagnosis and management of various lesions is provided in Chapter 479.

Left-Sided Obstruction

The left side of the heart may be obstructed at its inflow or outflow; many inflow lesions are associated with secondary outflow lesions because the reduced blood through the left heart structures in the fetus causes left-sided hypoplasia. The most proximal obstructive lesion is total anomalous pulmonary venous return with obstruction. The pulmonary venous confluence is not actually part of the primitive heart but is a coalescence of the pulmonary veins, arising from the primitive lung bud. The vessels coalesce with each other and the back of the primitive left atrium to form the posterior, pulmonary venous component of the left atrium. If they do not approach close enough to the left atrium, they connect to other vascular structures. Sometimes, they connect to the posterior cardinal veins and run inferiorly, below the diaphragm, and usually enter the portal sinus. After birth, as pulmonary flow increases dramatically and the ductus venosus closes, blood is trapped in the confluence, dramatically increasing pulmonary venous pressure and causing pulmonary edema and severe respiratory distress. More commonly, the veins connect to an ascending vein in the left mediastinum, part of the superior cardinal system, and drain into the innominate vein. This drainage may not be obstructed unless the vessel is trapped between the left pulmonary artery and the left bronchus, causing a “hemodynamic vise.” Other sites of drainage of the pulmonary veins, the CS, or the right SVC are obstructed less than 30% of the time.

Whether the pulmonary venous confluence is obstructed or not, the left side of the heart does not receive pulmonary venous return directly, but from the right atrium, via the foramen ovale. Thus, the left side is quite small, but systemic blood flow is usually not critically decreased. Thus, the symptoms of respiratory distress in total anomalous pulmonary venous return with obstruction far exceed the signs of hypoperfusion. Because of this and 2 other important facts—that the markedly elevated pulmonary venous pressures often cause secondary, severe pulmonary hypertension, and that there are no murmurs—this lesion is often misdiagnosed as pulmonary hypertension of the newborn. Every infant carrying the latter diagnosis must have a full cardiological evaluation, including echocardiography, to exclude this diagnosis.

When the pulmonary venous confluence does connect to the left atrium but perhaps just barely, the connection may be restrictive. Because the connection between the pulmonary venous confluence and the primitive atrium is small, the left atrium appears to be separated into 2, and thus the lesion is called cor triatriatum, or “heart with 3 atria.” This lesion may present in early infancy with similar findings to that of obstructive total anomalous venous connection, except that there is not significant systemic arterial desaturation, or the obstruction may be mild, presenting later with mild respiratory distress, with failure to thrive, or without symptoms.

Obstruction within the left atrium may occur just above the mitral valve (supravalvar mitral web) or at the valve (valvar mitral stenosis). When the valve is critically obstructed, just like in the right heart, there is severe hypoplasia of the left ventricle, often with secondary aortic valve atresia. This lesion, hypoplastic left heart syndrome, is the most common obstructive lesion that presents in the neonatal period. When the mitral valve is stenotic with only 1 papillary muscle rather than 2 (parachute mitral valve), there is often associated subvalvar aortic stenosis and coarctation of the aorta, called Shone complex.

Outflow obstruction at the subvalvar level can occur because of septal hypertrophy, often in the presence of maternal diabetes, or because of membranous or fibromuscular subaortic stenosis. At the aortic valve, critical obstruction can occur because of a bicuspid or unicuspid aortic valve. Supravalvar aortic stenosis can occur in Williams syndrome, although it rarely causes symptoms in infancy. Interrupted aortic arch, type B, is frequently associated with microdeletions of 22q11, usually with a posteriorly malaligned ventricular septal defect and, occasionally, with a right aortic arch. Coarctation of the aorta is a common cause of left-sided obstruction. It is usually associated with a bicuspid aortic valve and frequently with a ventricular septal defect.

Fetal flow patterns are quite different in this group of lesions, depending on the level of obstruction, and clinical presentation is also quite varied. When the obstruction is proximal to the foramen ovale, blood flow across the foramen is not altered, and thus, the left side of the heart should develop near normally, missing only the relatively small contribution of pulmonary venous return. Such is the situation of total anomalous pulmonary venous connection. At birth the left heart looks quite small, but it is always adequate for systemic output once the pulmonary veins are connected to the left atrium surgically. When the obstruction is distal, however, flow through the foramen ovale may decrease, possibly leading to hypoplasia of the chambers on the left side and associated downstream lesions, such as aortic valve hypoplasia or atresia, and coarctation of the aorta. Many left-sided obstructive lesions are therefore complex.

After birth, the left ventricle needs to increase its output nearly 3-fold, as it has to supply the lower body with blood flow and oxygen consumption increases dramatically due to the new demands of breathing, thermoregulation, and digestion. Thus, obstruction that is not significant in the fetus may become critical after birth. The level of the obstruction very much determines the timing and rapidity of progression of symptoms. The more proximal the obstruction, at equal levels of severity, the earlier is the onset. Thus, critical obstruction of the pulmonary veins presents within minutes or hours after birth, as blood rapidly accumulates in the pulmonary venous confluence and increases pulmonary venous pressures. Hypoplastic left heart syndrome, the most common of the obstructive lesions, usually presents within the first hours or days of life, as the ductus arteriosus begins to close. Systemic flow is entirely dependent on ductal size, so as it begins to constrict, blood to the body decreases, and signs of hypoperfusion manifest. In the uncommon situation when the foramen ovale is restrictive, blood returning from the lungs becomes obstructed, and these infants present like infants with total anomalous pulmonary venous connection with obstruction, within minutes or a few hours of life, with severe respiratory distress. Critical aortic stenosis and interrupted aortic arch present in a similar time frame to hypoplastic left heart syndrome, but perhaps slightly later, because the small amount of forward flow across the aortic valve supplements that crossing the ductus arteriosus. However, coarctation of the aorta may present significantly later. The coarctation usually occurs in the region of the aorta across from the ductus arteriosus, at the distal end of the aortic isthmus (Fig. 478-6). The ductus arteriosus, when patent, assists in blood supply to the lower body, maintaining adequate perfusion. It starts to constrict within the first hours of life and is fully closed in most infants within 24 hours. However, ductal closure begins in the middle of the ductus and progresses toward the ends. The ductal ampulla, the distal end of the ductus at the connection with the descending aorta, may remain relatively large for a few weeks, as the ductus undergoes full anatomic closure. During that time, the region around the coarctation may be of reasonable size so that symptoms of hypoperfusion do not manifest. In addition, it is thought that many infants develop coarctation because of the extension of ductal muscle posteriorly around the descending aorta. This is called a ductal sling. As the ductal sling constricts, a posterior indentation develops and the coarctation manifests.

Most infants with a severe coarctation of the aorta present with signs of hypoperfusion at about 7 to 10 days of age, although decreased pulses usually can be appreciated well before this time, and some present as late as 2 to 3 weeks of age. Thus, it is essential for the clinician to do a careful physical examination including upper and lower body pulses to exclude coarctation of the aorta through the first month of life and to consider obstructive heart disease when an infant presents with hypoperfusion during that time period.

The therapeutic approach to the infant with hypoperfusion and possible obstruction must be rapid and directed at the central problems of respiratory distress and decreased systemic blood flow. Early intubation and mechanical ventilation are essential. This not only drives the fluid from the alveoli, improving both oxygenation and ventilation, but also eliminates the metabolic demand of breathing, which, in the distressed infant, may represent up to 50% of oxygen consumption. The decrease in heart rate and catecholamine stimulation further decreases oxygen consumption, so that mechanical ventilation both dramatically increases oxygen uptake and decreases oxygen demand. Maintenance of a neutral thermal environment will aid in the decrease in oxygen consumption. Improvement in systemic blood flow is the next consideration. Filling pressures are usually high, even on the systemic venous side of the circulation, as evidenced by hepatomegaly, so that volume infusion is rarely beneficial, although it is often used. Inotropic support may be beneficial. Stabilization of the metabolic status of the infant in the presence of metabolic acidosis is generally undertaken, although it is not certain how beneficial this is. The newborn myocardium is quite resistant to the deleterious effects of acidosis on its function, and the volume load of the base may exacerbate the pulmonary edema. Prior to surgical or transcatheter relief of the obstruction of the lesion, PGE₁ will relieve the obstruction at the ductus arteriosus and should be initiated in all patients who have a presumptive diagnosis of left heart obstruction. In the past, the possibility of total anomalous pulmonary venous connection has led clinicians to hesitate using PGE₁ in the newborn presenting early with obstructive disease. However, many of these infants have suprasystemic pulmonary arterial pressures, so that the ductal shunt will be right to left, supplementing systemic flow, and it has been suggested that PGE₁ may dilate the ductus venosus, which would ameliorate the obstruction. Moreover, mechanical ventilation, if instituted immediately before PGE₁ infusion, should mitigate the problem of increasing pulmonary edema. The potential benefits of PGE₁ infusion in all patients with presumptive obstruction far outweigh the potential risks, as long as the clinician is aware of and rapidly responds to the vasodilatory effects of the drug.

Ventricular Dysfunction

Ventricular dysfunction without obstruction presents similarly to the obstructed heart and may be difficult to differentiate on clinical examination. It may be caused by processes that directly impair cardiac function, such as arrhythmias, coronary flow disturbances, or myocardial infections, or by indirect mechanisms, such as metabolic derangements, systemic infections, or severe anemia or polycythemia (Table 478-3). Each of these processes is discussed in other chapters and is not detailed here. Rarely, but importantly, patients may present with hypoperfusion despite the absence of obstruction. This occurs when blood from the left ventricle flows directly, in an obligatory manner, away from the systemic vascular bed. The most common and dramatic of the lesions is the vein of Galen aneurysm or other cerebral arteriovenous malformations. More rarely, hepatic arteriovenous malformations, or sacrococcygeal teratomas, may present with systemic hypoperfusion. There is an obligatory shunt through the low-resistance bed, and if the bed is large enough, the left ventricle cannot direct adequate volume to the normal systemic beds. Heart failure may present in the fetus as a form of nonimmune hydrops, but more commonly, the infant presents at birth with hypoperfusion. Likely this is because the demands for left ventricular output by the systemic circulation increase greatly at birth and because there is an addition of the low-resistance pulmonary vascular bed that the left ventricle sees in the hours after birth, due to patency of the ductus arteriosus during that time. The diagnosis of a cerebral arteriovenous malformation is obvious if the clinician auscultates the head for bruits, which, if it is a regular part of the newborn exam, will not be forgotten. Therapy is difficult because the bed is under low resistance and the shunt is obligatory. Intubation and mechanical ventilation are essential, for the reasons outlined above, and if an inotropic agent is used, it should also have vasodilatory actions so that blood is not further directed toward the malformation. Therefore, an agent such as milrinone is much more advantageous than dopamine, if ventricular dysfunction is present. However, the only way to resolve the hypoperfusion is to abolish the shunt. This is not offered in many patients because of the severe neurologic consequences of the malformation on the developing brain.

The second group of congenital malformations in which the left ventricle cannot maintain systemic blood flow despite the absence of obstruction includes those that cause severe left-sided atrioventricular valve insufficiency. There is no equivalent to Ebstein anomaly of the mitral valve except in congenitally-corrected transposition (so that the tricuspid valve connects to the systemic right ventricle), but severe mitral insufficiency occasionally occurs in the presence of very dysplastic valves. More commonly, the common atrioventricular valve in patients with complete atrioventricular canal defects may have severe insufficiency, particularly with the presence of a large left ventricle-to-right atrial shunt, such that the left ventricle fails to meet its obligation to supply the systemic circulation with adequate blood. As with arteriovenous malformations, these infants are commonly misdiagnosed as having hypoplastic left heart syndrome initially.

RESPIRATORY DISTRESS/FAILURE TO THRIVE

Newborns and infants with excessive pulmonary blood flow who are symptomatic present with respiratory distress or failure to thrive without overt cyanosis. This is the least common presentation of symptomatic heart disease in the neonatal period, but the most common in the subsequent months. The respiratory distress usually manifests during the period of the physiologic anemia of infancy, when cardiac output is highest. When pulmonary blood flow is very high, there may even be a pressure gradient between the pulmonary veins and the left atrium.

Hemodynamic Categories and Other Considerations

There is a very diverse group of congenital cardiac malformations that, despite their differences, have a common pathophysiologic process of increased pulmonary flow. The lesions can be divided into 2 hemodynamic groups, those lesions in which there is only a left-to-right shunt without a right-to-left shunt, and those lesions that have a large left-to-right shunt but in addition have a right-to-left shunt, so that the systemic arterial saturation is somewhat decreased, although rarely is there visible cyanosis (Fig. 478-7A and B). Lesions in the latter group are often labeled as forms of cyanotic heart disease, but this label does not take into account the pathophysiology that determines both the symptoms and the therapeutic approach. Thus, this categorization should be discouraged.

For example, truncus arteriosus is frequently labeled a form of cyanotic heart disease because pulse oximetry shows saturations in the 85% to 90% range. However, infants with saturations in that range are rarely appreciated as being cyanotic, and with normal systemic flow, this decrease in hemoglobin arterial oxygen saturation leads to only about an 8% to 10% decrease in systemic oxygen delivery. However, pulmonary flow is extremely high.

An infant with pulmonary flow that is increased to 3 times normal, with pulmonary arterial systolic and diastolic hypertension, equaling pressures in the systemic vascular bed, will produce large amounts of interstitial fluid and present with respiratory distress and failure to thrive. This is the same presentation as an acyanotic infant with a large ventricular septal defect. Thus, an infant with truncus arteriosus presents similarly to an infant with a large ventricular septal defect—without clinically appreciable or metabolically significant cyanosis, but breathing quickly and growing poorly. Thus, categorizing an infant with truncus arteriosus as having “cyanotic heart disease” rather than “respiratory distress/failure to thrive” makes no sense from a clinician’s standpoint. Infants with excessive pulmonary blood flow, whatever the lesion and whether they have normal or somewhat reduced systemic arterial saturation, should be considered together for diagnostic and therapeutic purposes.

An infant will develop excessive interstitial fluid due to increased pulmonary flow under increased arteriolar pressure. It is important to appreciate that most of the flow through the peripheral vessels occurs in diastole, so that infants with lesions associated with diastolic hypertension in the pulmonary vascular bed (eg, truncus arteriosus) are more likely to develop symptoms than those with only systolic hypertension (eg, ventricular septal defect), who in turn are more likely to develop symptoms earlier than infants with normal pulmonary arterial pressures (eg, atrial septal defect, which rarely presents symptomatically) with the same amount of pulmonary blood flow. Timing of the increased flow and fluid production is crucial to the development of symptoms as well. As the infant becomes older, the airways become less compliant and the respiratory muscles strengthen, so that it is much less likely that the increased flow and fluid production will be associated with symptoms. There is likely a critical period, in the first half year of life, when symptoms manifest. Thereafter, symptoms of the high flow become less likely, and concern for pulmonary vascular changes becomes the greater concern in patients with large shunts. The peak time to develop symptoms is around 1 to 3 months of age, when pulmonary vascular resistance is at its lowest and baseline flows are at their highest, because of the nadir in hemoglobin seen at this age.

Left-to-Right Shunt

As with the other hemodynamic categories, left-to-right shunts are best considered along lines of blood flow (Table 478-4). At the first level of venous return to the heart, pulmonary venous blood can be redirected to the lungs if there is connection of some of the pulmonary veins anomalously to the systemic veins or right atrium. This is called partial anomalous pulmonary venous connection. There is no right-to-left shunt because there is adequate flow via the other veins to the left atrium and ventricle to maintain normal systemic blood flow. In fact, if there is an associated atrial septal defect, as often occurs, the shunt across the atrial septal defect is left to right, further augmenting pulmonary blood flow. These infants are not symptomatic because the increase in pulmonary blood flow is not great, usually about 70% to 100%, and pressures are normal in the pulmonary arteries.

The next level of shunting occurs at the atrial septum. Shunting across atrial septal defects depends on the relative compliance of the 2 ventricles. At birth, the right ventricle is hypertrophied because it ejects at systemic pressure throughout fetal life. When the tricuspid and mitral valves open as venous blood returns to both atria, there is little difference in the compliance of the 2 ventricles, so that the atrial left-to-right shunt is small. Over the next few months, the right ventricle thins in the presence of low pulmonary vascular resistance, and the shunt increases. However, the pressure in the pulmonary arteries remains low, even with high pulmonary flows. Thus, normal infants with atrial septal defects rarely have symptoms and thus rarely need either early medical therapy or transcatheter or surgical closure.

The next level of shunt is at the atrioventricular level. Atrioventricular septal defects are variable in their extent, from primum atrial septal defects, or small inlet ventricular septal defects, to lesions in which there is almost no atrial or ventricular septum, with a common atrioventricular valve. A constant finding in this group of lesions is a defect in the atrioventricular septum, which lies between the left ventricle and right atrium. The absence of the atrioventricular septum can be appreciated on echocardiography by noting that the atrioventricular valves are lying at the same level. Normally, the mitral valve sits lower because of the atrioventricular septum. Infants are symptomatic usually when there is a “complete atrioventricular septal defect,” in which there are defects in all components, usually with a large ventricular defect. The majority of infants with complete atrioventricular septal defects have Down syndrome. Some patients have left atrial isomerism. Occasionally the defects are “unbalanced,” such that 1 or the other ventricle is hypoplastic, which then may be associated with secondary lesions such as coarctation of the aorta with a dominant right ventricle. As with ventricular septal defects, described below, the shunt occurs during ventricular systole, so that there is a lesser elevation in pulmonary arterial pressures in diastole. When symptomatic, infants usually present within a few weeks to months of age, as the shunt is dependent on the decrease in pulmonary vascular resistance and the increase in cardiac output secondary to the physiologic anemia.

The next level of shunt is at the ventricular level. There are many different types of ventricular septal defect, but, in the absence of malalignment of the outlet septum or other causes of obstruction of 1 or the other outflow, the presentation depends on the size of the defect, the downstream resistance, and systemic flow. Neonates with ventricular septal defect and no other problems are rarely symptomatic in the first days or weeks of life but usually present around 6 weeks to 3 months of age with respiratory distress and failure to thrive. There may, in fact, be no murmurs in the first days, if pulmonary vascular resistance falls slowly, but most infants, by the time of discharge after birth, have audible murmurs. Infants with large defects and symptoms usually undergo repair within 3 to 6 months of life to prevent the development of pulmonary vascular changes. If the defect is large and the infant does not show clinical findings associated with excessive pulmonary blood flow, the clinician should be more concerned, because this may indicate that pulmonary vascular resistance did not fall normally at birth, limiting the shunt, but increasing the likelihood of pulmonary vascular disease. Generally, a ventricular septal defect is closed early in infancy because of symptoms, and later in the absence of symptoms, if there is a concern of pulmonary vascular disease. The approach to children with ventricular septal defects beyond infancy is discussed later in this chapter.

The next level of shunt is at the aortopulmonary septum. An aortopulmonary window is a connection between the ascending aorta and main pulmonary artery but usually occurs in association with an interrupted aortic arch. An embryologically different but clinically similar lesion in the same location occurs when 1 or the other pulmonary artery arises from the ascending aorta. Both of these lesions present similarly to the next level lesion, a large patent ductus arteriosus.

Most infants with symptomatic patent ductus arteriosus are born prematurely, with immature lungs and low pulmonary vascular resistance, leading to symptomatic shunts at a very early age. This lesion is discussed in Chapter 479. Rarely, a term infant will present with a symptomatic ductus arteriosus. The ductus arteriosus in the term infant usually closes, at least partially, and is thus pressure restrictive. Thus, the infant is asymptomatic and undergoes elective transcatheter closure later in infancy. Occasionally, the ductus is widely patent, and the infant presents with symptoms. This happens most commonly in infants with lung disease, as discussed in infants with atrial septal defects. In patent ductus arteriosus, the shunt occurs primarily during diastole, so that it may be very large, and the high pulmonary arterial systolic and diastolic pressures lead to the production of symptoms at an early age. It also can lead to early development of pulmonary vascular disease, as in patients with aortopulmonary window or an isolated pulmonary artery from the ascending aorta, so in all of these conditions, early intervention is necessary.

The most distal left-to-right shunt is the arteriovenous malformation. Although it is not obvious, infants with arteriovenous malformation present with the same symptomatology as those with a ventricular septal defect, secondary to high pulmonary blood flow. The only caveat occurs when the malformation is so large that the obligatory shunt impairs systemic perfusion, as discussed above.

Bidirectional Shunting with Excessive Pulmonary Flow

Infants in whom there is a right-to-left shunt of systemic venous blood to the aorta have decreased systemic arterial saturation. However, if pulmonary blood flow is increased significantly and the great vessels are normally related (that is, the aorta is not transposed over the venous ventricle), the resultant systemic arterial oxygen saturation will only be mildly decreased and it will be neither clinically appreciable nor metabolically significant. The symptoms exhibited by these infants will be similar to those with normal arterial saturation and increased pulmonary blood flow (the “left-to-right shunt” group, discussed above), and thus should be considered as belonging to the same hemodynamic category rather than categorizing them as having “cyanotic heart disease.” Approaching such lesions along lines of blood flow, the first lesion to consider is total anomalous pulmonary venous connection.

Total anomalous pulmonary venous connection may occur immediately after birth, with pulmonary edema caused by severe obstruction to the egress of pulmonary venous blood that suddenly entered the lungs as pulmonary vascular resistance fell precipitously. Such infants have with severe respiratory distress and hypoxemia and may be misdiagnosed as having pulmonary hypertension of the newborn. If there is only moderate obstruction to the pulmonary venous return, the infants present over the first few days of life with respiratory distress and desaturation. However, some infants have no or minimal obstruction to pulmonary venous return. This occurs in some of the patients in whom the connection is above the diaphragm, particularly when it is to the CS. In such patients, pulmonary flow is very high so that systemic arterial saturation does not reach levels to cause visible cyanosis. Occasionally, these patients may reach adulthood without diagnosis; more commonly, they present in infancy with failure to thrive or recurrent pulmonary symptoms.

Intracardiac causes of bidirectional shunting with excessive pulmonary flow are myriad (examples are presented in Table 478-5), but all have a common physiology of mixing of pulmonary and systemic venous blood in association with unrestricted pulmonary blood flow. There may be a common atrioventricular valve, atresia of the mitral or tricuspid valve, or commitment of both valves to the left ventricle (double-inlet left ventricle). If there is no obstruction to either the pulmonary or aortic outflow, pulmonary and systemic flows will depend on their relative resistances. Soon after birth, the neonate may appear mildly cyanotic, as pulmonary vascular resistance falls. If not appreciated at that time, cyanosis may no longer be evident after the first few hours of life. Newborn pulse oximetry screening, however, would detect the decreased saturation.

The last level at which mixing can occur is at the outlet of the ventricles. Truncus arteriosus is a relatively common lesion that is highly associated with chromosome 22q11 microdeletion, particularly when there is a right or interrupted aortic arch. Incomplete migration of cardiac neural crest–derived cells is thought to lead to abnormalities in arch development, aortopulmonary septation, and septation of the truncus arteriosus into the aortic and pulmonary valves, which almost invariably also leads to absence of septation of the outlet ventricular septum (rare instances of truncus arteriosus without ventricular septal defect have been reported). As discussed previously, the initial presentation of an infant with truncus arteriosus may be cyanosis, but this is only apparent in the first hours of life. Because of the large left-to-right shunt that develops rapidly and the large runoff of blood into the pulmonary arteries in diastole, these infants present very early, within days or weeks of life, with respiratory distress and failure to thrive.

PHYSICAL EXAMINATION TO EXCLUDE SYMPTOMATIC HEART DISEASE

A neonate or young infant may have symptomatic heart disease if there is central cyanosis, hypoperfusion, respiratory distress, or failure to thrive. A systematic approach, evaluating the infant for one of these modes of presentation at each step in the examination, and, if present, placing the infant in 1 of the 2 hemodynamic categories, will immediately lead to recognition of the problem. The pediatrician does not need to diagnose the specific defect to understand the pathophysiologic problem and institute remedial therapy.

There are many ways to approach the physical examination of the young infant to exclude heart disease, but a straightforward and rapid approach is to evaluate the patient from general to specific, then distal to proximal. The general examination includes measuring vital signs and observing the infant, unclothed, in a radiant warmer. Pulse oximetry should be considered a vital sign in the newborn and should be measured at least once by 12 hours of life. The older infant should be plotted on a growth chart at each visit, to identify failure to thrive. Any postnatal decrease in weight percentiles compared to length and head circumference should raise the possibility of heart disease. The periphery, head, and neck should be observed for the dysmorphic features of syndromes associated with heart disease, such as 22q11 deletion (DiGeorge) syndrome and trisomy 21.

The first sign to assess on general observation is cyanosis. Peripheral cyanosis, or acrocyanosis, is common in newborn infants and reflects their normally variable peripheral vasomotor tone. Central cyanosis is indicative of systemic arterial oxygen desaturation, so that the clinician must evaluate vascular beds with little vasoconstrictor tone, such as the tongue, gums, and buccal mucosa. If pulse oximetry is not available, it is worthwhile to observe the infant during conditions such as feeding or crying, which are most likely to produce central cyanosis. If cyanosis is present, the clinician must be aware of the possibility that the upper and lower systemic circulations may be perfused via different great vessels, and perform pulse oximetry in the upper and lower bodies. If the right hand is used to measure upper body circulation oximetry and there is no difference with the lower measurements, it is of value to consider ear pulse oximetry, in the rare situation that the patient has a right aortic arch or an aberrant origin of the right subclavian artery from the descending aorta. If the patient demonstrates cyanosis or mildly decreased pulse oximetry without clinical cyanosis, an oxygen challenge test is occasionally of value, particularly if the infant is showing signs of respiratory distress or has an x-ray suggestive of parenchymal lung disease. The patient should be placed under a hood with 100% oxygen delivered under high flow to ensure that the inspired oxygen concentration is close to 100%. An arterial blood gas sample should be obtained from the right radial artery or a temporal artery to ensure that any decrease in partial pressure of oxygen (pO₂) is not caused by a right-to-left ductal shunt. If there is any question of saturation differential between the upper and lower body, blood gases can be measured both from the upper body and the umbilical artery to determine whether a small difference is clinically valid. With modestly low pulse oximetry values (mid-80s to low 90s), most patients with a respiratory problem should be able to increase pO₂ to 200 mm Hg or higher, whereas the infant with congenital heart disease causing an obligatory right-to-left shunt rarely reaches a level of 200 mm Hg.

The respiratory status should be carefully evaluated next. Infants who have cyanosis without increased pulmonary flow usually breathe more rapidly but without distress. If the respiratory distress is severe, particularly with grunting and intercostal retractions, elevated pulmonary venous pressures with edema are possible, so that evidence of hypoperfusion should be sought. If there is moderate distress without cyanosis, significant grunting, or severe retractions, particularly after the early neonatal period, concern for a cardiac lesion with excessive pulmonary blood flow should be raised. If oximetry had not been performed before this time, it should be now. Levels at about 95% or above would put the patient in the “left-to-right shunt” category, if the infant is found to have increased pulmonary blood flow as the cause of the distress.

Signs of hypoperfusion, including the temperature and color of the skin, blood pressure, peripheral pulses, and capillary refill in each extremity should be assessed next. Upper extremity pulses are best to feel in the axilla in an infant—the right axillary pulse should be examined, and if decreased, the carotid should then be palpated to exclude a coarctation of the aorta with an aberrant right subclavian artery or right aortic arch. Lower extremity pulses are more easily palpated in the feet rather than in the inguinal area. If the infant has a normal dorsalis pedis or posterior tibial pulse, then pulsatile blood flow to the lower extremity is not impaired. If the pulses are not normal, blood pressure should be measured in the lower extremity as well as the upper extremity. The left subclavian artery arises from the aortic isthmus and may be involved in a coarctation, so the left arm is not an appropriate location to measure upper body pressures unless an aberrant right subclavian artery is suspected. If not, blood pressures should be measured in the right arm and either leg, and simultaneously, if possible. Systolic, not mean pressures, should be compared, because blood flows through the aortic arch in systole.

At this point in the examination, the clinician knows whether the infant has cyanosis, hypoperfusion, respiratory distress, or failure to thrive. Examination of the abdomen, lungs, and heart is then directed to defining the hemodynamic category. The abdomen should be carefully evaluated because hepatomegaly is often a sign of right atrial hypertension or increased circulating volume from excessive pulmonary blood flow. Percussion, particularly if the infant is crying, more easily and accurately determines the size and location of the liver, and the location of the stomach, than does palpation. The liver and stomach are reversed in situs inversus. The liver may be midline in the heterotaxy syndromes, consisting of 2 anatomic right lobes in right atrial isomerism, or asplenia syndrome, or 2 left lobes in left atrial isomerism, or polysplenia syndrome.

The cardiac examination begins with palpation of the precordium. The normal newborn infant has a mild parasternal and subxiphoid impulse, because the sternum is thin and the right ventricle is thick walled. The parasternal and subxiphoid impulses are increased in most infants with cyanotic heart disease because the right ventricle is ejecting at systemic pressure or greater, if the patient has transposition of the great arteries or right ventricular outflow obstruction. A decreased right ventricular impulse in a cyanotic infant suggests inflow obstruction to the right ventricle, either tricuspid atresia or pulmonary atresia with a hypoplastic tricuspid valve and right ventricle. A parasternal thrill suggests the presence of a ventricular septal defect, but this occurs in only a minority of infants with ventricular septal defects. However, the presence of a parasternal thrill in a cyanotic infant is diagnostic of tricuspid atresia with ventricular septal defect, because only in this form of cyanotic heart disease is the ventricular shunt directed anteriorly, from the left to the right ventricle, rather than in the other direction.

The left ventricular apical impulse is not usually palpable in a normal neonate because the dominant right ventricle displaces the left ventricle posteriorly. A palpable left ventricular impulse usually indicates increased volume load as the ventricular cavity dilates and extends anteriorly and laterally. A suprasternal thrill is usually indicative of obstruction of the left ventricular outflow, either below, at, or above the aortic valve.

Auscultation should be performed in a systematic manner. The first heart sound is rarely helpful but may be louder than normal in the infant with a complete atrioventricular septal defect. The quality of the second heart sound provides important information. Although it is often difficult to appreciate splitting of the second heart sound because of the rapid heart rates in early infancy, the presence of a well-split second heart sound suggests markedly increased pulmonary flow. Most cyanotic infants have a single heart sound because the pulmonary valve is either diminutive or atretic or because it is malposed, posterior to the aorta. The presence of a widely split second heart sound in an infant with decreased oximeter saturations indicates that the patient likely has total anomalous pulmonary venous connection, because it is one of the few defects with desaturation in which pulmonary blood flow is markedly increased.

The presence of clicks and gallops should be evaluated next. Clicks may be difficult to hear, but when present, they usually indicate a bicuspid aortic valve or persistent truncus arteriosus. A click is not present in patients with severe aortic stenosis because valve mobility is greatly decreased. In contrast, truncus arteriosus can frequently be diagnosed in the patient with tachypnea and mild-moderate desaturation based on the presence of an ejection click caused by a dysplastic truncal valve. Midsystolic clicks are rarely heard but may be present in Ebstein anomaly. Gallop rhythms may be present in newborn infants with severe left ventricular dysfunction.

Lastly, heart murmurs should be evaluated. Murmurs occur in normal infants and may be absent in many infants with symptomatic cardiovascular disease. Thus, the presence of a murmur is of little predictive value for symptomatic heart disease. However, specific murmurs are much more likely to be appreciated if the clinician has a differential diagnosis in mind at the time that auscultation is performed. Conversely, the presence of a nonspecific murmur is of much less concern in an infant who has an otherwise normal examination. Specific diagnoses are based on unique features of the murmurs, such as pitch, location, and transmission. A murmur is best localized by determining the location of its highest frequency components, because high-frequency sounds transmit very short distances as compared to lower-frequency sounds. Conversely, loudness may be a poor indicator of the site of origin. Thus, a murmur with high-frequency components heard in the left axilla is extracardiac in origin and likely reflects physiologic peripheral pulmonary artery stenosis in a normal newborn infant. This concept also helps distinguish the presence of more than 1 systolic murmur. If a murmur of high pitch is heard, decreases in pitch as the stethoscope is moved in one direction, and the pitch then increases again, that increase in pitch indicates a different murmur.

The pitch of a murmur correlates directly with the pressure gradient where the murmur originates. A high-frequency murmur indicates a high-pressure gradient, and a low-frequency murmur indicates a low gradient. Mid-diastolic murmurs are difficult to appreciate and are often noticed as the absence of silence in diastole. Early diastolic murmurs caused by semilunar valve insufficiency are usually easy to hear but occur rarely. Their presence indicates specific lesions, such as absent pulmonary valve syndrome or aortic-left ventricular tunnel.

SUGGESTED READINGS

Congenital Heart Disease

INCIDENCE

Structural congenital heart diseases (left-to-right shunts, obstructive and regurgitant lesions, and right-to-left shunts) occur in 10 to 12 per 1000 live-born children; the incidence is higher in stillborn infants and in spontaneous abortuses. This figure excludes bicuspid aortic valves, patent ductus arteriosus in premature infants, and tiny muscular ventricular septal defects with respective incidences of 10 to 20, 4 to 5, and 30 to 40 per 1000 live-born children. Incidences are similar in all countries, and annually ~1,500,000 are born with congenital heart disease.

The distributions of various common types of congenital heart diseases at birth are given in Table 479-1.

ETIOLOGY

Congenital heart diseases result from interactions between genetic and environmental factors.

Genetic Factors

Single classic Mendelian mutant genes account for 3% of congenital heart diseases; 5% are caused by gross chromosomal aberrations, 3% by known environmental factors (eg, rubella, fetal alcohol syndrome), and the rest by multifactorial gene effects or single gene effects modulated by random events.

Environmental Factors

The environmental factors are listed in Table 479-2.

COUNSELING FAMILIES

The risk of occurrence of cardiac lesions in future children concerns parents. Chromosomal abnormalities have risks of recurrence that vary with the specific chromosomal change involved. Other forms of inheritance produce a much lower risk of recurrence (see Table 479-1). Furthermore, if 2 first-degree relatives have congenital heart disease, then the risk of heart disease in the next infant is about 3 times as high as the figures just cited. The risk of transmission of congenital heart disease to children if the parent, especially the mother, has congenital heart disease averages about 5% to 10%. If another child has congenital heart disease, it is most often similar in type (concordant) to that in the parent or sibling.

When a child has congenital heart disease, the parents frequently have severe feelings of guilt and are almost always worried about the risk of occurrence in future children. These issues should be discussed openly with the parents, who are often reticent about mentioning them. An explanation of what is known of the causes of congenital heart diseases and reassurance that the parents did not cause it by acts of omission or commission are arguments that might help allay guilty feelings. This approach must be correlated with all other aspects of giving continued support to parents with chronically ill children.

DIAGNOSIS

Institution of pulse oximetry screening has continued to expand through the United States. An original report from Sweden noted that left-sided obstructive lesions may be pulse oximetry negative and have either abnormal pulses or the presence of a murmur during the examination. Most patients are diagnosed by a careful history and physical examination, an electrocardiogram, and confirmation (if needed) by echocardiography. Some patients need additional imaging by magnetic resonance imaging or computed tomography or (much less commonly) nuclear imaging for regional ischemia. Cardiac catheterization is used to measure pressures and blood flows and to perform angiography.

LEFT-TO-RIGHT SHUNTS

A shunt from systemic to pulmonary circulation through an abnormal communication, termed a left-to-right shunt, recirculates oxygenated blood through the lungs. This shunt is wasted flow that adds to cardiac work without improving systemic delivery of oxygenated blood. A left-to-right shunt may be present alone or associated with right-to-left shunting (bidirectional shunting) or obstructive lesions.

Left-to-right shunts are classified anatomically by the level at which the systemic and pulmonary circulations communicate.

With defects that produce left-to-right shunts after birth, fetal somatic development is unaltered, and blood flow to the fetal organs and placenta is probably normal. However, alterations of flow patterns in the fetal heart and great vessels may affect their development. When some left ventricular output is shunted away from the ascending aorta, then decreased aortic isthmus flow may cause hypoplasia or even interruption of the aortic isthmus. Altered streaming patterns may change the composition of blood leaving the heart. Thus, with an atrioventricular (AV) septal cushion defect or large ventricular septal defect, the oxygen tension of blood leaving the right ventricle and perfusing the lungs may be higher than that in the normal fetus. This higher oxygen tension may alter the development of pulmonary resistance vessels.

Defects associated with left-to-right shunts are shown in Table 479-3. Four factors control the amount of left-to-right shunting postnatally: the size of and therefore the resistance to flow offered by the communication, the difference in pressures between the chambers or vessels, the relative distensibilities of the 2 ventricles, and the total outflow resistances (including peripheral resistances) of the chambers or vessels.

If the communication at any level is small, it offers a high resistance to flow through it so that the left-to-right shunt will be small, no matter what the pressures or resistances are. The latter 3 factors come into play only with medium-sized or big communications.

In pre-tricuspid (atrial-level) communications, atrial pressures are low and almost equal, and the amount and direction of shunting depend only on the distensibility of the left and right atria. Before and immediately after birth, systemic and pulmonary vascular resistances and pressures are high and equal, and both ventricles have similar wall thicknesses and distensibility. Therefore, diastolic inflow into each ventricle is similar, and even with a large atrial septal communication, there is little left-to-right atrial shunting. Over the next few weeks, systemic pressures and vascular resistances increase while pulmonary vascular resistances and pressures decrease and the left ventricular wall becomes thicker and the right ventricular wall remains relatively thin, so that diastolic distensibility becomes greater in the right than the left ventricle. Therefore, more blood flows from right atrium to right ventricle than from left atrium to left ventricle, so that a larger left-to-right shunt develops. (Think of the atria as a single chamber with 2 exits. More blood will enter the more distensible receiving chamber.) Note that the large left-to-right shunt can develop only after pulmonary arterial resistance and pressure have decreased greatly.

In a post-tricuspid shunt (ventricular septal defect or patent ductus arteriosus), when the communication is large, systolic pressures in the ventricles or great arteries are equal, and the magnitude and direction of shunting will be determined by the relative outflow resistance of each ventricle or great artery. If left-sided outflow resistance is much higher than that of the right side, there will be a large left-to-right shunt. If right-sided outflow resistance increases and approximates that of the left side, or if systemic resistance falls, the left-to-right shunt will be small or even disappear. If the outflow resistance is higher for the right than the left side, there will be a shunt from right to left. The outflow resistance may be at or below a semilunar valve orifice, in a great vessel, in peripheral resistance vessels, or any combination of these. In the absence of aortic or pulmonic stenosis, the relationship between pulmonary and systemic vascular resistances determines the magnitude of shunting. Because systemic vascular resistance is normally high and changes relatively little after birth, alteration in pulmonary vascular resistance is the major regulator of shunting through a large aortopulmonary or interventricular defect, particularly in the first months after birth, when the normal progressive fall in pulmonary vascular resistance occurs. This type of shunting, in which the ratio of pulmonary vascular resistance to systemic vascular resistance determines the shunt, is termed dependent shunting, and it applies to both pre- and post-tricuspid shunts (see Table 479-3).

Other left-to-right shunts have a communication between a high-pressure ventricle or artery and a low-pressure chamber or vein, such as a direct left ventricular to right atrial communication or a systemic arteriovenous fistula. The magnitude of the shunt depends on the size of the communication and the pressure difference between the chambers or vessels involved and not on the pulmonary vascular resistance; the shunt is termed obligatory.

GENERAL PATHOPHYSIOLOGY AND CLINICAL CORRELATES

The site of the defect determines some of its specific features; however, many features associated with left-to-right shunting are common to several defects. A small left-to-right shunt has little hemodynamic effect on the heart and presents only with specific murmurs related to turbulent flow across the defect. Larger shunts, however, have prominent effects that depend on the level at which shunting occurs, because this determines which part of the circulation receives the additional blood flow. In general, the murmur indicates the site of the communication but not its severity. Severity is determined by signs of a hyperactive circulation, by clinical and radiographic examination, and in the most severe instances, by congestive heart failure.

In an aortopulmonary left-to-right shunt, some of the left ventricular output leaves the systemic circulation and increases pulmonary flow by that amount. The greater pulmonary venous return to the left atrium and left ventricle increases left ventricular diastolic volume and increases left ventricular stroke volume and stroke work by the Frank-Starling mechanism. The left ventricle is enlarged and has a forceful, hyperactive apical impulse. Because of the increased left ventricular output, there may be a third heart sound caused by rapid left ventricular filling in early diastole and a fourth heart sound from left atrial hypertrophy or contraction against a noncompliant left ventricle. Also, when pulmonary venous return to the left atrium approximately doubles, there may be a low-frequency apical mid-diastolic rumbling murmur from turbulent diastolic flow across a normal mitral valve. Dilation of the left ventricle elevates left ventricular end-diastolic and left atrial pressures and, if marked, causes left heart failure and pulmonary venous congestion. Left atrial dilation may stretch the atrial septum, causing incompetence of the valve of the foramen ovale and a left-to-right atrial shunt that may be clinically significant. The right ventricle does not handle an extra volume load (unless there is an aorto-atrial shunt, as in a ruptured sinus of Valsalva aneurysm) but will have an increased pressure load if there is pulmonary hypertension. This produces a forceful heave felt at the lower left sternal border enlargement and a loud pulmonic valve closure sound (P₂).

Similar hemodynamic effects may follow a left-to-right shunt at the ventricular level, but the right ventricle will also have some volume overload, so that the right ventricular impulse also is hyperactive. Left-to-right shunts at the atrial level increase volume load only on the right atrium and ventricle, and if there is some outflow obstruction, a moderately increased right ventricular systolic pressure load may also occur. Therefore, a hyperactive impulse is felt over the right but not the left ventricle. An increase in right ventricular end-diastolic pressure with a subsequent increase in right atrial and systemic venous pressures is not usual in childhood because of the great capacity of the right atrium and systemic venous system, but it may occur when right ventricular performance decreases. With obligatory shunts, volume overloading of both ventricles occurs, and both right and left ventricular impulses are hyperactive. Persistently increased precordial activity with cardiac enlargement in infants and young children often produces anterior bulging of the left hemithorax.

The sympathetic-adrenal system and myocardial hypertrophy help to maintain adequate myocardial performance, normal systemic output, and adequate tissue oxygenation in the face of a large left-to-right shunt. There is increased catecholamine release from the adrenal glands and sympathetic nerve fibers within the myocardium, so that heart rate and the force of myocardial contraction increase. This increased sympathetic-adrenal activity also accounts for the excessive sweating seen in left ventricular failure, particularly in infants. These compensatory mechanisms are well developed in older children and adults but not fully developed in newborn, particularly premature, infants. In addition, because myocardial structure matures during fetal and neonatal development with consequently a lower proportion of contractile elements, premature infants are less capable of handling a volume overload than are mature or older infants. If the increased volume or pressure load on the ventricles persists, the muscle fibers hypertrophy, and the increased amount of contractile protein helps to handle the load without excessive ventricular dilation or sympathetic stimulation.

The increased workload and mass of the left ventricle increase myocardial oxygen requirements. Delivery of oxygen to the myocardium depends on coronary flow and the oxygen content of arterial blood. Coronary perfusion to the left ventricle, particularly the deep subendocardial muscle, occurs during diastole and depends on the systemic arterial–intramyocardial diastolic pressure difference as well as the duration of diastole. Therefore, a reduction in arterial diastolic pressure (as in an aortopulmonary communication with a large left-to-right shunt), an increase in left ventricular end-diastolic pressure and therefore subendocardial intramyocardial pressure (as with left ventricular failure), and a reduction in diastolic period (as with tachycardia) are all detrimental to myocardial perfusion and oxygen delivery. In the right ventricle, myocardial flow is unlikely to be compromised unless the right ventricle has a systemic systolic pressure and is hypertrophied.

Chest radiographs of post-tricuspid shunts show left ventricular and left atrial enlargement, and in aortopulmonary communications, the ascending aorta, which carries the increased flow, may be dilated. Increased pulmonary blood flow is manifested by prominent dilated main and branch pulmonary arteries extending into the lung fields. In pre-tricuspid shunts, the right ventricle and atrium are enlarged, and increased pulmonary blood flow is evident.

Electrocardiographic evidence of atrial and ventricular hypertrophy depends on the duration and magnitude of the shunt. Electrocardiographic features vary with the different types of atrial communication and are discussed later.

Echocardiographic findings depend on the magnitude of left-to-right shunting and the degree of heart failure as well as on the specific lesion.

EFFECTS ON PULMONARY CIRCULATION

With a large aortopulmonary or ventricular communication, systemic and pulmonary arterial pressures are similar, and because of the persistent high pulmonary arterial pressure, the medial muscle of the small pulmonary arteries does not regress as rapidly or as much as in normal individuals. Thus, although pulmonary vascular resistance falls rapidly immediately after birth because of the onset of ventilation, the subsequent decline in pulmonary vascular resistance is slower than normal. The lowest pulmonary vascular resistance reached is usually delayed 2 to 3 months and even then is higher than normal. Infants with large obligatory left-to-right shunts also have significantly increased pulmonary blood flow and therefore pulmonary arterial pressures that are higher than normal, because in early infancy the small pulmonary arteries are still thickened; this will also delay the medial smooth muscle regression. Regression of the medial muscular layer is also retarded by anything producing hypoxic pulmonary vasoconstriction in the newborn period, for example, high altitude, pulmonary disease, chronic upper airway obstruction, or obstruction of the major airways by dilated pulmonary arteries produced by a large left-to-right shunt. In patients with atrial communications, the pulmonary arterial pressure and pulmonary vascular resistance fall normally in the postnatal period, and small pulmonary arteries undergo the normal regression of medial smooth muscle.

PATENT DUCTUS ARTERIOSUS

The ductus arteriosus is closed postnatally by constriction of smooth muscle in its wall. In full-term infants, this functional closure normally occurs within 10 to 15 hours after birth; however, complete anatomic obliteration of the ductus arteriosus is slower and may not be complete until the third postnatal month. Because pulmonary vascular resistance falls as soon as the lungs expand, in the first 10 to 15 hours when the ductus arteriosus is still open, a left-to-right shunt through the ductus arteriosus may occur, and a murmur may be heard.

CAUSES OF PERSISTENT PATENCY

A clinically apparent patent ductus arteriosus occurs in 30% to 40% of premature infants with birth weights under 1750 g and about 80% with birth weights under 1000 g. The mechanisms responsible for continued patency are due to inability of the ductus arteriosus in immature infants to respond normally to an increased oxygen tension and to changes in prostaglandin concentrations. The incidence of persistent patency of the ductus arteriosus in full-term infants born at high altitude is significantly higher than in those born at sea level, probably because of the lower atmospheric oxygen tension. Persistent patency of the ductus arteriosus in full-term and occasional preterm infants at lower altitudes is generally related to a structural abnormality of the ductus arteriosus. Maternal rubella in the first trimester of pregnancy, however, is associated with a high incidence of persistent patency of the ductus arteriosus, and rubella virus has been cultured from ductal tissue.

CLINICAL MANIFESTATIONS IN MATURE INFANTS

The diagnosis of patent ductus arteriosus is easier in full-term infants or older children than in premature infants. Because of continuous runoff of blood from the aorta to the pulmonary artery through the ductus arteriosus, the murmur in older infants and children is continuous and has a rumbling, machinery-like or “train in a tunnel” quality, usually with late systolic accentuation of the murmur. It is heard best below the left clavicle. If the ductus arteriosus is small, this may be the only abnormal finding. If it is larger, the increase in left ventricular output is associated with an increase in stroke volume that causes a rapid rise in the aortic pulse pressure as a result of rapid left ventricular ejection and also causes left ventricular hyperactivity. The diastolic runoff through the aortopulmonary communication plus the peripheral vasodilation from baroreceptor stimulation account for the low diastolic pressure and the collapsing pulse. The increased volume load enlarges the left atrium and ventricle, with radiographic evidence of dilation and electrocardiographic evidence of hypertrophy. Because the ascending aorta receives the increased left ventricular output, it is dilated. On chest radiograph, the pulmonary vascular markings indicate increased pulmonary flow. If there is pulmonary hypertension, there may be signs of right ventricular pressure overload.

The echocardiogram shows the ductus arteriosus and may define its size, as well as assess the volume overload of the left ventricle.

DIFFERENTIAL DIAGNOSIS

In premature infants, particularly those < 1000 g birth weight, there is little chance that clinical findings suggestive of a patent ductus arteriosus are caused by some other congenital heart defect, because patency of a ductus arteriosus is so much more frequent than any other form of congenital heart disease. This does not mean that alternative diagnoses should be automatically excluded. However, in larger premature and full-term infants, sometimes a patent ductus arteriosus cannot be differentiated clinically from aortopulmonary window, truncus arteriosus, ventricular septal defect with aortic regurgitation, or arteriovenous fistula. A major problem may occur when there is severe heart failure with a markedly reduced cardiac output and sympathetic vasoconstriction; the peripheral pulses may not be bounding, the murmur may be soft and not continuous, and the precordium may not be hyperactive. After appropriate therapy for left ventricular failure, the classic physical findings reappear.

OUTCOME

In the full-term infant with a patent ductus arteriosus, spontaneous closure may occur, but much less commonly than in the premature infant. Medical management, if needed, should be instituted, and at a convenient time, surgical closure should be done. Even if there is no heart failure, there are 2 reasons to close a patent ductus arteriosus. If there is marked pulmonary hypertension as a result of a large communication, the danger of the development of pulmonary vascular disease necessitates closure, preferably before 6 to 8 months of age. In the older child with a small patent ductus arteriosus, closure is often advised in view of the risk of infective endarteritis, even though this risk is very low. Some cardiologists, however, believe that the risk of closing a small ductus is less than the risk of endarteritis. Transcatheter closure with a coil is satisfactory if the diameter of the ductus is below 3 mm, but larger ductuses can often be closed by devices such as the Amplatzer ductus occluder (St. Jude Medical). Some ductuses still need surgery, either because they are too large for a catheter-introduced device or, conversely, because an extremely premature infant has blood vessels that are too small to accept the large catheter needed to introduce coils or other devices. Surgery can be done safely by open thoracotomy or by thoracoscopy and may be a much shorter procedure than interventional catheterization. The surgical extrapleural approach to ligating the patent ductus arteriosus has been shown to be cost-effective in developing countries.

AORTOPULMONARY FENESTRATION

Aortopulmonary fenestration or window, caused by failure of formation of the base of the spiral septum, generally produces a large aortopulmonary communication just above the semilunar valves. The pulses are typically bounding or collapsing, like those of a large patent ductus arteriosus. However, the murmur more closely resembles that of a high ventricular septal defect; it is generally not continuous, has a rough, often crescendo-decrescendo character, and is heard maximally along the left sternal border in the third and fourth intercostal spaces. The diagnosis can be made by 2-dimensional echocardiography and confirmed (if need be) by cardiac catheterization and angiocardiography. Surgical closure during cardiopulmonary bypass is corrective. Occasionally a small opening can be closed by interventional catheterization.

ANOMALOUS ORIGIN OF LEFT CORONARY ARTERY

Anomalies of the coronary arteries are discussed in detail later in this chapter.

ANOMALOUS ORIGIN OF PULMONARY ARTERY BRANCH FROM ASCENDING AORTA AND LOBAR SEQUESTRATION

Anomalous origin of a pulmonary artery branch from the ascending aorta has been called hemitruncus arteriosus, but it is not related embryologically to persistent truncus arteriosus because the embryonic truncus arteriosus septates normally in the former defect, with the opposite pulmonary artery arising from a normal pulmonary valve and main pulmonary artery. Most often, the right pulmonary artery arises from the aorta. In lobar sequestration, a portion of the lung, usually a lobe or part of a lobe, gets its arterial blood supply from an abnormal artery arising from the aorta. The involved pulmonary artery does not communicate with the main pulmonary artery. Pulmonary vascular resistance and the resistance offered by the communicating vessel control the flow into the lung or portion of lung. The clinical presentation in children with these lesions also depends on the magnitude of the shunt and will be similar to that found with a patent ductus arteriosus, but congestive heart failure is more common in the anomalous pulmonary artery because it is equivalent to a large patent ductus arteriosus. However, the murmur, often continuous, may be better heard more laterally or even in the back.

Normally the systemic venous return is distributed between the 2 pulmonary arteries, but with an anomalous pulmonary artery, all the systemic venous return passes through the 1 normal pulmonary artery with about one-half of the total number of lung vessels. Pressure in the normally arising pulmonary artery is generally normal; therefore, the risks of subsequent pulmonary vascular disease are similar to those in children with atrial septal defects and a pulmonary blood flow about twice normal. However, with an associated left-to-right shunt, blood flow to the normal lung is more than doubled; thus, there may be pulmonary hypertension and subsequent pulmonary vascular disease. The lung supplied by the abnormally arising vessel is at risk not only from increased flow but also from increased pressure, because this lung is perfused at systemic pressure minus the pressure decrease offered by the channel. If the abnormally arising pulmonary artery is adequately developed, implantation into the main pulmonary artery can be done. If a significant portion of lung is involved in lobar sequestration, a lobectomy is indicated.

UNILATERAL PULMONARY ARTERY

Although this is not a lesion with a left-to-right shunt, it resembles an anomalous pulmonary artery from the ascending aorta. The right or the left pulmonary artery may be congenitally absent, either isolated or with other congenital cardiac defects, but most often the artery arose from a ductus arteriosus that subsequently closed. A unilateral pulmonary artery, either left or right, has the same incidence when these are isolated lesions and when they are associated with most cardiac defects; however, if there is a patent ductus arteriosus, then usually the right pulmonary artery is absent, and in the tetralogy of Fallot, the left pulmonary artery is almost always missing. The lung on the affected side is hypoplastic and supplied by bronchial arteries if the artery is truly absent, so that the chest radiograph shows a small hemithorax, no hilar pulmonary artery, and often a diffuse reticular pattern of bronchial collaterals. Because ventilation can still take place on that side, there is wasted ventilation and usually dyspnea on exertion.

The chief importance of the lesion is its tendency to produce pulmonary hypertension and pulmonary vascular disease in all except those with the tetralogy of Fallot. Because there is only 1 pulmonary artery, it receives the total right ventricular output, just as in the anomalous origin of the pulmonary artery from the ascending aorta. Therefore, even in the absence of other lesions, that lung receives twice its normal blood flow; if there are left-to-right shunts in addition, it gets more than this. In infancy, before pulmonary arterial muscle has regressed, this increased flow leads to hypertension and can eventually cause severe pulmonary vascular disease, which has been reported in 18% of patients with no other lesions and 88% of those with cardiac lesions.

The diagnosis is made by angiography, computed tomography, or magnetic resonance imaging. Treatment is directed at repairing the associated defects and avoiding anything that might affect the pulmonary vessels of the normal lung (eg, living at high altitude or taking oral contraceptives).

SINUS OF VALSALVA FISTULA

Rupture of a sinus of Valsalva into one of the cardiac chambers is secondary to an aneurysm due to a structural abnormality in the sinus. Most commonly these changes involve the anterior (right coronary) aortic valve sinus, and the rupture produces a communication from the right coronary sinus into the right ventricle or right atrium. Less commonly, rupture involves the noncoronary or the left coronary sinus; rupture into the left atrium or ventricle is discussed below in Aortic Regurgitation. The aneurysmal dilation of the sinus that precedes rupture is often associated with a ventricular septal defect, a combination particularly common in persons of Asian descent. Connective tissue disorders such as Marfan syndrome may also have associated aneurysmal dilation of the aortic sinuses, but these do not rupture. Small fistulas may occur after infective endocarditis, but more extensive rupture usually occurs after trauma or spontaneously with progressive weakening of the sinus. Acute rupture, although more common in young adults, does occur in children. At the time of rupture, there frequently is an episode of acute chest pain and dyspnea, with sudden onset of a murmur and congestive heart failure; however, a more insidious onset has been described. With rupture into the right ventricle, the physical signs resemble those of a patent ductus arteriosus, with a loud continuous superficial murmur along the left sternal border, but with the addition of an increased right ventricular volume load. With rupture into the right atrium, this lesion will behave like an obligatory shunt, and the features are those of a patent ductus arteriosus and an atrial shunt combined. The diagnosis can be made by 2-dimensional echocardiography, including Doppler and contrast echocardiography. Accurate differentiation from other lesions may require cardiac catheterization and angiocardiography. Surgical closure of the fistula can be done with cardiopulmonary bypass.

CONGENITAL CORONARY ARTERIOVENOUS FISTULA

In this lesion, a fistula usually passes from one of the coronary arteries directly into the right ventricle (the most common site) or into the right atrium (either directly or through the coronary sinus). Communications with the left ventricle, left atrium, or pulmonary artery are much less common, except for small coronary-pulmonary fistulas that are of little importance.

The most striking clinical feature is a continuous murmur superficial in character and heard best along the lower left sternal border. The murmur is generally maximal in diastole and has very high-pitched components. Ventricular hyperactivity and a mid-diastolic rumble depend on the magnitude of shunting, which is not usually great enough to cause congestive heart failure. A continuous thrill may be palpable. Occasionally the fistula causes a myocardial steal and ischemic symptoms. The diagnosis can be made by 2-dimensional echocardiography with Doppler and contrast echocardiography, but the specific diagnosis may require cardiac catheterization and angiocardiography. Treatment is usually performed by a catheter approach. Coils or occlusive devices can be placed relatively safely because most fistulas enter the right atrium or ventricle, so that embolization, if it occurs, is to the lungs, and the coil can easily be retrieved. Care needs to be directed toward not occluding normal coronary arteries. Surgery is occasionally necessary when the fistula is extremely large or proximal.

SYSTEMIC ARTERIOVENOUS FISTULA

Placental arteriovenous fistulas may produce a large increase in fetal cardiac output, particularly in descending aortic flow. Although the fistula is no longer present after birth, residual signs may remain in the neonate. These include peripheral edema, cardiomegaly, and a dilated descending aorta.

The most common sites for large arteriovenous communications in children are intracranial, hepatic, or in the extremities. However, fistulas have been described between internal mammary vessels or other major systemic arteries and their related veins, and with more frequent use of 2-dimensional echocardiography and color Doppler, these are being discovered more frequently. They may be seen as part of Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia). They can also be traumatic in origin, most commonly between renal vessels after needle biopsy of the kidney and in the femoral triangle after needling of the femoral vessels.

Because these lesions are obligatory left-to-right shunts, the hemodynamic and clinical features depend on the size of the communication and thus its resistance to flow. The majority of systemic arteriovenous fistulas are small and so do not produce major hemodynamic changes. The exceptions to this are hepatic or intracranial arteriovenous fistulas, particularly those that involve the great vein of Galen or its tributaries. Fistulas can be large and single, multiple, or even resemble cavernous hemangiomas.

Certain clinical features are common to all types of arteriovenous fistulas: a systolic or continuous murmur over the site of the fistula, occasionally a pulsatile mass, and distended and sometimes pulsatile veins draining the region of the fistula. Increased limb size and swelling may occur with peripheral arteriovenous fistulas. Hepatic arteriovenous fistulas generally do not involve one feeder vessel but are usually hemangiomatous.

Intracranial arteriovenous fistulas usually produce the most severe hemodynamic changes because they involve vessels of large caliber and the left-to-right shunt is often large. In early infancy, they may produce severe congestive heart failure, and they are among the few cardiovascular lesions that produce hydrops fetalis or severe congestive failure in the first days after birth. Clinically, there are continuous murmurs over either side of the skull and bounding carotid pulses and distended jugular veins. The superior vena cava is generally markedly dilated on chest radiograph, and there is significant right and left ventricular volume overload. Peripheral pulses are bounding and even collapsing, unless heart failure is so marked that all pulses except the carotids are feeble. If the shunt is not large, cardiovascular manifestations may be mild, and neurologic sequelae dominate the clinical picture. Contrast 2-dimensional echocardiography with Doppler is helpful in diagnosis, but the definitive diagnosis of these lesions may require cardiac catheterization and angiocardiography. Currently arterial embolization is the treatment of choice, but significant neurologic sequelae often remain.

Hepatic arteriovenous fistulas may present with congestive heart failure, but like most other hemangiomatous lesions, they tend to involute in the first year, especially after treatment with steroids. Conservative or medical management is appropriate for many of them, especially because the lesions may extend diffusely throughout the liver. If, however, patients have uncontrollable congestive heart failure, then the surgeon can either ligate the hepatic artery or, if the lesion is localized, perform a lobectomy.

VENTRICULAR SEPTAL DEFECT

Congenital defects of the interventricular septum are the most common of all congenital heart lesions, accounting for 30% to 60% of all full-term patients with congenital heart malformations; this percentage is equivalent to 3 to 6 of every 1000 live births. This excludes the 3% to 5% of neonates with tiny muscular ventricular septal defects that usually close within the first year. A ventricular septal defect usually occurs as an isolated abnormality but may be associated with other congenital cardiac malformations. In view of the pattern of flow in the heart and great vessels of a fetus with a ventricular septal defect, with diversion of blood from the aortic isthmus, narrowing of the aortic isthmus or true coarctation should always be considered when an infant with a ventricular septal defect has severe heart failure. Ventricular septal defects are also common in corrected transposition of the great arteries. They are always present in a truncus arteriosus communis and in a double-outlet right ventricle (DORV) that, in the absence of pulmonic stenosis, has the clinical features of an isolated ventricular septal defect.

An isolated ventricular septal defect may occur anywhere in the interventricular septum. At birth, about 90% of these defects occur in the muscular septum, but because these usually close spontaneously within 6 to 12 months of birth, the membranous septum becomes the most common site after infancy. Defects vary in size from minute openings to almost complete absence of the interventricular septum (a common ventricle). Most muscular (except multiple, “Swiss cheese”) and perimembranous defects have a high chance of spontaneous closure, unlike large inlet subtricuspid defects, subarterial outlet defects (subaortic as in tetralogy of Fallot), or large subpulmonic (as in “supracristal” defects) or doubly committed subarterial ventricular septal defects. Spontaneous partial closure of subpulmonic or doubly committed subarterial defects often involves prolapse of the aortic valve cusp into the defect with development of aortic regurgitation; this form of defect occurs in 5% of Caucasians but has a higher incidence in Hispanic children and occurs in about 35% of Japanese and Chinese. Spontaneous closure of perimembranous defects often is associated with ventricular septal pseudoaneurysm formation; early detection of such an aneurysm indicates a high likelihood of closure.

CLINICAL MANIFESTATIONS

The pathophysiology of left-to-right shunting through a ventricular septal defect involves left-sided volume overload.

The systolic murmur of a ventricular septal defect is generally harsh. With a small shunt, the murmur may be heard only in early systole; as the shunt increases, however, the murmur becomes full length and ends at the aortic component of the second sound. The murmur is always S₁ coincident and, therefore, holosystolic. The intensity of the murmur is not necessarily related to the size of the defect, and loud murmurs may be heard with hemodynamically insignificant defects (maladie de Roger). Loud murmurs are usually associated with systolic thrills. The murmur is generally heard best at the lower left sternal border, and it radiates throughout the precordium, but maximally toward the subxiphoid area. However, with a high subpulmonic ventricular septal defect, the maximal intensity may be at the middle to upper left sternal border, with radiation to the right of the sternum. Occasionally the murmur of a very small defect has a crescendo-decrescendo high-pitched almost whistling quality and must be distinguished from an innocent murmur. When the left-to-right shunt is large enough to produce a ratio of pulmonary flow to systemic flow greater than 2:1, a mid-diastolic rumbling murmur may be audible at the apex, and a third sound may appear. As the shunt increases, so does precordial activity. The peripheral arterial pulses give important information about shunt size. If there is a very large shunt that is well above the cardiac output, the left ventricle has to contract forcefully and rapidly to eject the increased stroke volume during a normal systolic interval. This is perceived in the radial and brachial arteries. Unlike in the patent ductus arteriosus, the volume of blood entering the aorta at each stroke is normal, and in diastole there is no rapid runoff through the ductus and less peripheral vasodilation because baroreceptors are not stimulated. Thus, the rapid fall to a low diastolic pressure is not seen with a ventricular septal defect, but the rapid rise of the pulse gives the impression of a collapsing pulse.

If the defect is small or medium in size, there is no pulmonary hypertension, and the pulmonic component of the second sound is either of normal or minimally increased intensity. If there is pulmonary hypertension, the pulmonic component of the second sound is accentuated with the pulmonary valve closure (P₂) happening earlier, close to the aortic valve closure sound (A₂). With a small or moderate-sized shunt, the chest radiograph shows no or a slight increase in left ventricular and left atrial size and pulmonary vascular markings. As the volume of shunting increases, cardiac enlargement and pulmonary vascularity also increase, and pulmonary edema may be seen. Because the shunt is at the ventricular level, the ascending aorta is not dilated. The electrocardiogram is normal if the defect is small; it shows increasing left ventricular hypertrophy as the left-to-right shunt increases, and when there is much right ventricular hypertension, right ventricular hypertrophy is added. A 2-dimensional echocardiogram can be used to show the size and position of the ventricular septal defect. Doppler with imaging techniques can localize the defect by detecting disturbed flow in the right ventricle, and color Doppler flow mapping can demonstrate single or even multiple defects. The Doppler measurement also allows measurement of the pressure gradient across the defect; the higher the gradient, the smaller the defect. In the most severe form of ventricular septal defect, single ventricle complex, magnetic resonance imaging may help to delineate the anatomy.

With a large left-to-right shunt, there are clinical signs and symptoms of volume overload and cardiac failure. In full-term infants, this occurs most commonly between 2 and 6 months of age, but it may occur earlier in premature infants. Although the left-to-right shunt should generally be greatest between 2 and 3 months of age, when pulmonary vascular resistance has dropped to its lowest level, congestive heart failure occasionally occurs in term infants under 1 month of age. In these infants, the ventricular septal defect is often associated with anemia, a significant left-to-right shunt at the atrial or ductus arteriosus levels, or coarctation of the aorta. In addition, infants who have DORV with ventricular septal defect are at risk of developing congestive failure earlier than expected. This is possibly because in fetal life the pulmonary vasculature is perfused with blood that has a higher oxygen tension than normal; thus, there may be unusually low pulmonary vascular resistance after birth.

MANAGEMENT

Isolated ventricular septal defects are the most common types of congenital heart disease, so all pediatricians need to know how they can be managed. The decision tree is shown in Figure 479-1, and the circled numbers in the table are as follows:

1. About 3% to 5% of all live-born babies have small muscular ventricular septal defects, most of which close spontaneously within the next 6 to 12 months. It is neither practical nor reasonable to obtain echocardiograms in all of them, provided that there appears to be nothing more than a small ventricular septal defect, the heart is quiet, and there are no symptoms. Note that a neonate with a large ventricular septal defect usually has no murmur in the newborn nursery; a large defect with a small shunt across it because of a high pulmonary vascular resistance produces little turbulence. In fact, a typical ventricular septal defect murmur heard in the newborn nursery is almost certainly caused by a small defect.

2. Because defects in the perimembranous or muscular portions of the septum have a high incidence of spontaneous closure, it is appropriate to treat them medically for up to 1 year in the hope that surgery can be averted. Several different mechanisms may be responsible for spontaneous closure of a ventricular septal defect. These include growth and hypertrophy of the muscular portion of the defect, formation of a membranous diaphragm (from intimal proliferation), apposition of the septal leaflet of the tricuspid valve against the defect, or prolapse of the aortic valve cusp, which can lead to aortic regurgitation. When the defect is getting smaller, the systolic murmur may first increase in intensity, but with a progressive decrease in size, the murmur becomes softer, and when the defect is extremely small, the murmur becomes shorter and acquires a crescendo-decrescendo high-pitched whistling quality that often portends complete closure. Spontaneous closure may eventually occur in up to 70% of patients, and many of these closures occur by 3 years of age. In a further 25%, the defect becomes smaller but may not close completely; however, the hemodynamic effects are significantly reduced. Because of these statistics, if the defect seems to be becoming smaller, surgical correction should be delayed in the hope of spontaneous closure.

   Figure 479-1 also shows reasons for considering early surgery without waiting for the defect to close spontaneously.

3. Some patients respond well enough to medical treatment to go home, but return a week or so later in more severe congestive heart failure. Treatment regimens and doses are adjusted, they improve, and they go home, but the cycle is repeated. These children should be regarded as treatment failures, and they require closure of the defect. Children with trisomy 21 appear to get early pulmonary vascular disease, so their surgery should not be deferred if the defect remains large.

4. Severe social problems are rare reasons for early surgery. These include inability of the parents to bring the child for frequent medical supervision because of distance from the doctor or negligence. In addition, some of these infants are very difficult to manage. They require 2-hourly feeds and consume so much attention that other children in the family are neglected; marriages may even be threatened.

5. Although all infants with large ventricular septal defects grow poorly, with weights usually below the fifth percentile and heights below the 10th percentile, catch-up growth usually occurs once the defect is closed (spontaneously or after surgery). In most of these infants, the growth of head circumference is normal, but in a few, head growth falls off rapidly by 3 or 4 months of age. Head growth will return to normal if the defect is closed at this time but can fail to catch up if surgery is delayed more than 1 to 2 years.

6. If the patient does not need early surgery for one of the reasons mentioned above, it is appropriate to wait for about 12 months in the hope that the defect will close or become smaller.

7. If the shunt remains large after 1 year of age, there has to be a reason for not closing a large ventricular septal defect because of the increasing risk of irreversible pulmonary vascular disease. By 2 years of age, about 33% of these children have irreversible pulmonary vascular disease.

8. If the left-to-right shunt becomes smaller, there will be clinical improvement, manifested by decreasing cardiac hyperactivity and heart size, diminishing intensity and eventual disappearance of the mid-diastolic murmur, decreasing intensity and changing character of the systolic murmur, lessening and then disappearance of tachypnea, improved appetite and growth, and lessening demand for drug therapy. It is crucial not to be misled into thinking that this improvement necessarily indicates a smaller VSD, because it might also reflect the development of pulmonary vascular disease or, less often, infundibular stenosis. Echocardiography and perhaps cardiac catheterization are mandatory to make decisions about future management at this stage.

9. In most patients with a ventricular septal defect, severe pulmonary vascular disease does not occur until after 1 year of age. However, it can occur earlier, and this will be indicated by a decrease in the left-to-right shunt, a finding that indicates the need for further studies. If obstructive pulmonary vascular disease occurs, there is often little or no left-to-right shunting and no significant right-to-left shunting for several years. However, generally by 5 to 6 years of age, there is increasing cyanosis, particularly during exercise (Eisenmenger syndrome). As severe pulmonary hypertension develops, the main pulmonary artery segment becomes markedly dilated, and the peripheral pulmonary vascular markings on the chest radiograph decrease. Obstructive pulmonary vascular disease may progress rapidly in some infants and become irreversible by the age of 12 to 18 months; this should never be allowed to occur. Any doubt as to the cause of any change in clinical status should be investigated by 2-dimensional echocardiography with Doppler or, if necessary, by cardiac catheterization, and there is rationale to consider routinely recatheterizing children with large ventricular septal defects at 9 to 12 months of age to detect early pulmonary vascular disease that is not clinically apparent. Once irreversible pulmonary hypertension occurs, treatment with prostaglandin analogs (eg, Flolan), endothelin receptor blockers (eg, bosentan), or phosphodiesterase inhibitors (eg, sildenafil) may ameliorate the disease, but hemoptysis and congestive heart failure eventually cause death, usually in the third or fourth decades. The only definitive treatment is lung transplantation.

10. Infundibular hypertrophy generally develops fairly rapidly, and there may be only a short period in which the left-to-right shunting is present. Soon thereafter, there will be cyanosis, initially on exercise only but then persistently, and the features of the tetralogy of Fallot can develop. In those infants who develop right ventricular outflow obstruction, the incidence of spontaneous closure of a ventricular septal defect is low; a right-to-left shunt can be further complicated by cerebral thrombosis, embolism, or abscess, and the development of infundibular hypertrophy leads to more difficult surgical repair, so that closure of the defect and infundibular resection, if necessary, should be considered early.

11. A patient with a clinically small VSD can be followed providing an echocardiogram has excluded a subpulmonic or doubly committed VSD. One should also consider an echocardiogram to exclude the presence of a supracristal VSD. These defects are usually large but partly occluded by a prolapsed aortic valve leaflet so that the shunt is small. In time, the prolapse tends to increase and cause aortic regurgitation, so that preventive closure is recommended.

Primary surgical closure of the defects can be done with very low mortality. If primary closure is not feasible because of multiple muscular defects or other complicating factors, then banding the pulmonary artery will decrease the left-to-right shunt, reduce pulmonary flow and pressure, and relieve congestive heart failure. Banding has its own complications, and removal of the band when the defect is closed later adds to the morbidity of the procedure.

Muscular defects, especially if multiple, can be difficult to close surgically. From a right ventriculotomy, the masses of hypertrophied trabeculae are daunting and make the defect(s) difficult to find. Although a left ventriculotomy simplifies surgery, a large incision in the systemic ventricle should be avoided. Some surgeons cut away all the right ventricular trabeculae to make closing the defect easier, and others suture all the trabeculae together to close the exit holes. Because of the difficult surgery, closing the muscular defect by catheter introduction of an Amplatzer device is being used more often. Some catheterization procedures are very lengthy, and an alternative is to use a hybrid method in which a surgeon performs a small thoracotomy and the Amplatzer device is inserted more directly through a trocar. Some cardiologists have even used similar devices for nonsurgical closure of perimembranous ventricular septal defects, but this procedure has more risk of producing complete AV block and of damaging the aortic valve.

CONSEQUENCE AND COMPLICATIONS

In some infants with significant reductions in left-to-right shunts caused by spontaneous closing of the ventricular septal defects, mid to late systolic clicks have become audible. In these children, aneurysmal dilation of the thin membranous septum or tricuspid valve tissue that has grown to close the defect has occurred, with bulging of pseudoaneurysm into the right ventricle. A small opening often present at the apex of the pseudoaneurysm allows a small left-to-right shunt. Normally, the defect closes, and the pseudoaneurysm slowly shrinks, but rarely it may enlarge progressively. These pseudoaneurysms can be demonstrated by echocardiography.

A number of infants have developed progressive aortic insufficiency associated with ventricular septal defect, particularly if it is subarterial. There is prolapse of an aortic valve leaflet with dilation of the aortic valve sinus, and distortion or even rupture of the aortic sinus or cusp may occur. The development of aortic insufficiency has been attributed to stress on the unsupported aortic cusp and perhaps suction on it by the jet of the shunt passing through the defect. Even with a small ventricular septal defect, or one showing evidence of closure, aortic insufficiency requires surgical closure of the defect to prevent further prolapse. It may in fact be prudent to close subarterial ventricular septal defects even before evidence of aortic valve cusp involvement is apparent.

Infective endocarditis can occur even after spontaneous closure of the defect. If infective endocarditis involves the tricuspid leaflet sealing the ventricular septal defect, rupture may occur and produce a direct left-ventricular-to-right-atrial communication. Previously, antibiotic prophylaxis for infective endocarditis had been recommended for children with even small defects. Recently, however, the guidelines have been changed and prophylaxis is not recommended except for special circumstances, as discussed in Chapter 484.

CONGENITALLY CORRECTED TRANSPOSITION

The anatomic left ventricle is on the right side and connects the right atrium to the pulmonary artery. The anatomic right ventricle on the left side receives oxygenated blood from the left atrium and ejects into an anteriorly placed left-sided aorta. The combination of discordant AV and discordant ventriculoarterial connections allows normal flow of venous blood to the lungs and arterial blood to the body; hence, the designation (physiologically) corrected transposition of the great arteries.

If there are no other lesions, people with this anomaly may live normal lives, but almost all have ventricular septal defects, many have pulmonic stenosis, some have an Ebstein-like malformation of the left-sided systemic tricuspid valve that produces left-sided AV regurgitation, and many have defects of AV conduction (particularly complete AV block). Those with normal conduction at birth develop complete heart block at a rate of 1% to 2% per year. The symptoms and signs depend on the severity and nature of these associated lesions.

In addition to the murmurs of ventricular septal defects or pulmonic stenosis, these patients characteristically have a loud second heart sound, often single, best heard at the upper left sternal border because of the high left anterior position of the aortic valve. The electrocardiogram may show AV conduction defects and will show right- or left-sided hypertrophy as appropriate for associated lesions. In about 80% of these patients, the electrocardiogram shows Q waves in right chest leads and no Q waves on the left, with the pattern reflecting the activation of the septum from right to left.

Frequently, the chest radiograph indicates the diagnosis because the levoposed aorta produces a straight shoulder on the left heart border. Echocardiograms disclose the abnormal position of the great arteries, the morphology of the right- and left-sided ventricles, as well as another typical anatomic feature, the anteroposterior orientation of the ventricular septum.

Surgical correction of these lesions is more hazardous than correction of similar lesions without ventricular inversion. The abnormal conduction system increases the risk of surgically produced complete AV block when a ventricular septal defect is closed. Large coronary arteries often run across the outflow tract of the pulmonic ventricle, where an incision would have to be made. The pulmonary artery is very posterior, so that correcting pulmonic stenosis is difficult, particularly because the obstruction is seldom a valvar stenosis but more often a subpulmonic fibromuscular narrowing or else a mass of accessory tissue from the adjacent mitral valve. For these reasons, surgery is not advised if patients are doing well. If they deteriorate, then the pulmonary artery may be banded for a large left-to-right shunt, or else an aortopulmonary shunt is done to palliate severe cyanosis. Complete correction should be attempted only by a skilled surgeon and only after the risks have been fully assessed. Correction of the intracardiac and outflow tract defects can be done, but many patients eventually develop right ventricular failure and AV valvar regurgitation. The alternative is to perform an anatomic correction. In this procedure, not only are intracardiac defects corrected, but an arterial switch connects aorta and pulmonary artery to their correct ventricles and then an atrial baffle is performed to make pulmonary venous return enter the left ventricle. These procedures are surgically formidable, and although short- and mid-term results are quite good, the long-term outcome is unknown.

ATRIAL SEPTAL DEFECTS

Interference with the development of the atrial septum at its lower margin, associated with abnormal development of the endocardial cushions, produces an ostium primum atrial septal defect. This lesion is generally associated with abnormalities of the mitral and tricuspid valves (which form from the endocardial cushions) as well as defective formation of the upper portion of the interventricular septum.

A second type of atrial septal defect is the ostium secundum defect. This is a defect in the central portion of the septum in relation to the foramen ovale; it results from inadequate closure of the central hole in the septum primum by the septum secundum and is more appropriately termed a fossa ovalis defect.

A third type of atrial septal defect is the sinus venosus defect—that is, in the superior portion of the atrial septum—and generally extends into the superior vena cava.

INCOMPETENT (PATENT) FORAMEN OVALE

With the onset of ventilation after birth, pulmonary venous return increases markedly, and left atrial pressure rises. The foramen ovale is therefore normally functionally closed by the membranous valve of the foramen ovale, apposed to the crista dividens and the lower portion of the septum secundum. Although typically functionally closed shortly after birth, the foramen ovale remains probe-patent or larger in 30% of people. When pulmonary vascular resistance does not fall normally after birth, the resultant pulmonary hypertension and increased right ventricular end-diastolic pressure and right atrial pressure often cause right-to-left shunting across the foramen ovale and systemic hypoxemia.

In some infants, although the normal atrial pressure relationships occur after birth, the valve of the foramen ovale does not completely cover the foramen, either because the valve is too short or because the foramen ovale has become enlarged and stretched in infants in whom left atrial pressure and volume are increased, as with patent ductus arteriosus, ventricular septal defect, or left ventricular outflow obstruction secondary to aortic stenosis or coarctation. Significant left-to-right shunting may occur through an incompetent foramen ovale when left atrial pressure is high. If the cause of the increased left atrial pressure is relieved, atrial shunting generally decreases or disappears. In some congenital heart defects, survival after birth depends on persistent patency of the foramen ovale. These defects include tricuspid, aortic, and mitral atresia and total anomalous pulmonary venous connection. In aortopulmonary transposition, a patent foramen ovale may be the only communication between the systemic and pulmonary circulations. Right-to-left shunting across the foramen ovale is also associated with right ventricular obstructive lesions, such as pulmonic stenosis, and with pulmonary hypertension, particularly in newborns.

OSTIUM SECUNDUM ATRIAL SEPTAL DEFECT

Ostium secundum defects vary in size from a small defect to one in which only a rim of atrial tissue separates the defect from the AV valves. Usually ostium secundum defects are isolated lesions, but some may be associated with partial anomalous pulmonary venous connection (usually draining the right lung) or pulmonic stenosis.

Small atrial communications are associated with small shunts. Such small defects are common at birth. Defects under 3 mm in diameter almost all close spontaneously, as do a high percentage of those from 3 to 6 mm diameter. Some defects become larger.

Large defects are associated with large left-to-right shunts if there is a low inflow resistance of the right ventricle and a low pulmonary resistance. The effect of a large shunt at the atrial level is a marked increase in flow through the right atrium and right ventricle. This extra volume load is tolerated well by the right ventricle because it is handling the increased volume at a low pressure. Therefore, cardiac failure is unusual in infancy and, when it occurs, is generally precipitated by either a combination of defects, associated cardiomyopathy, or some other complication such as severe anemia.

Children with large atrial septal defects are generally asymptomatic. However, when there is pulmonary hypertension because of congenital or acquired lung disease, especially in preterm infants, the atrial septal defect may contribute to the symptoms as well as to right-to-left intracardiac shunting. The increased right ventricular volume load causes precordial hyperactivity along the left sternal border. The first heart sound is normal, and the second heart sound is characteristically widely split, with absence of the normal respiratory variation in the width of splitting. Both components of the second sound are of normal intensity. Although fixed splitting of the second sound is characteristic in older children, this sign is occasionally absent, especially in infants or when the communication is not large.

Flow across the atrial septal defect is not associated with a murmur; however, a long systolic ejection murmur that is crescendo-decrescendo (ejection) in type is generally heard at the upper left sternal border as a result of increased flow across the right ventricular outflow tract and pulmonic valve. The murmur associated with atrial septal defects can usually be differentiated from an innocent pulmonary flow murmur, which is usually shorter, by the response to the Valsalva maneuver. When intrathoracic pressure is increased, systemic venous return is immediately reduced, right ventricular stroke volume decreases immediately, and the intensity of an innocent pulmonary flow murmur suddenly decreases. However, with a large atrial septal defect, the left-to-right shunt across the atrial communication maintains right ventricular stroke volume for several beats despite the decrease of systemic venous return; thus, there is little, if any, change in the intensity of the murmur in the first 3 to 4 beats. If the left-to-right shunt is fairly large, there is often a low-frequency, rumbling, early or mid-diastolic murmur caused by increased flow across the tricuspid valve and heard best at the lower left sternal border. A prominent third heart sound is often heard at the lower left sternal border.

The chest radiograph shows enlargement of the right atrium and ventricle and sometimes the outflow region of the right ventricle. The main pulmonary artery is dilated, and pulmonary vascular markings are increased. However, the relationship between prominence of the pulmonary vascularity and the magnitude of the left-to-right shunt is unreliable. The electrocardiogram generally shows right axis deviation with normal atrial complexes and normal conduction. There is right ventricular hypertrophy with a typical rsR or rSR pattern in the right precordial leads, and the S wave in the inferior leads is usually notched.

Two-dimensional echocardiography shows an increase in diastolic size of the right ventricle together with paradoxic motion of the interventricular septum. Other similar hemodynamic disturbances, such as partial anomalous pulmonary venous return and pulmonary or tricuspid regurgitation, may give similar findings. Septal dropout is often seen, indicating the site of the atrial septal defect, and color Doppler clearly demonstrates the flow patterns and often the defect. A negative shadow in the right atrium during contrast echocardiography can delineate the defect.

Persistent right-to-left shunting is unusual in ostium secundum defects, but transient right-to-left shunting is common after any Valsalva-like maneuver. However, with sinus venosus defects there may be right-to-left shunting from the superior vena cava into the left atrium because of deficiency in the upper part of the septum where it normally meets the superior vena cava, and slight arterial oxygen desaturation may be found. Infective endocarditis is rare in uncomplicated secundum atrial septal defects. Obstructive pulmonary vascular disease may occur, but not usually before the late second decade or third decade. This becomes evident by a decrease in the physical findings associated with the left-to-right shunt and later by right-to-left shunting. It is concern about the possible development of pulmonary vascular disease that generally leads to surgical closure of the communication. Atrial arrhythmias, especially atrial fibrillation or flutter (probably caused by atrial enlargement), congestive heart failure, mitral regurgitation, and strokes from paradoxic embolization may occur in adult life, and these are added reasons for considering closure of atrial defects in children. However, several years after simple surgical closure, atrial arrhythmias still can develop. Nonsurgical closure using an umbrella-like device (Amplatzer, Helex, and others) manipulated into the defect by means of a large catheter are currently favored over surgical closure for all but the largest defects or those with an inadequate rim of tissue (see Chapter 490).

OSTIUM PRIMUM DEFECTS AND ATRIOVENTRICULAR SEPTAL (ENDOCARDIAL CUSHION) DEFECTS

Ostium primum and AV septal defects result from arrested or abnormal development of the endocardial cushions in the primitive AV canal; they range in severity from a small ostium primum atrial septal defect to a complete AV canal. The severity and type of anatomic defect depend on which endocardial cushions are involved and the stage of developmental failure. Because the cushions are involved in the development of both atrial and ventricular septa, as well as mitral and tricuspid valves, many different combinations of abnormalities in this region are found. They may occur as isolated lesions in otherwise normal infants; however, they may be associated with other congenital heart lesions (eg, tetralogy of Fallot, single ventricle) or other congenital abnormalities such as trisomy 21 (Down), asplenia or polysplenia, and Ellis-van Creveld syndrome.

Fetal somatic development is essentially normal; however, there is a high incidence of secondary hemodynamic alterations in the aorta in this group of lesions. Subaortic outflow obstruction, although often of only minor severity, is common; when associated with the potential obligatory shunt in utero, it may result in significant alterations in the patterns of blood flow during fetal life. Therefore, aortic isthmus narrowing and juxtaductal coarctation are found in many infants with this defect.

OSTIUM PRIMUM DEFECT

Ostium primum defect (partial AV canal defect) is the most benign form of endocardial cushion defect. The central portion of the atrial septum in the region of the mitral and tricuspid valve rings is absent, and the defect is usually large. The anterior (or septal) mitral valve leaflet is displaced and usually cleft. The tricuspid valve is generally not involved but may also have a small cleft in the septal leaflet. The magnitude of the left-to-right shunt is controlled by the same mechanisms in ostium primum as in secundum atrial septal defects. The clinical features are similar and include right ventricular hyperactivity, increased pulmonary flow, and a widely split second sound. In addition to the right ventricular outflow murmur and the tricuspid mid-diastolic flow murmur, murmurs of mitral or tricuspid regurgitation, or both, may be present. The electrocardiogram characteristically shows left axis deviation, generally in the 20° to 60° range, and right ventricular hypertrophy with an rsR′ pattern in right precordial leads. Chest radiographic findings depend on the magnitude of left-to-right shunting. Two-dimensional echocardiography and color Doppler flow mapping usually clearly delineate the anatomy. Congestive heart failure and arrhythmias occur, usually in late teenage or early adult life.

Surgical closure of the primum defect and repair of the cleft mitral valve has low risk and high effectiveness, but postoperative subaortic stenosis is common. Some patients develop severe hemolysis from red cell trauma if a small deficiency in the mitral valve leaflet directs a high-pressure jet at the atrial patch. At times, hemolysis improves, but some patients require reoperation to abolish the hemolysis.

COMPLETE AV CANAL DEFECT

Complete AV canal defects involve failure of development of separate tricuspid and mitral valve rings. In addition to the ostium primum defect, there is a ventricular septal defect in the posterior portion of the interventricular septum and clefts in the septal leaflets of both the tricuspid and mitral valves. The anterior and posterior segments of each septal leaflet are not separated (as in normal development) but join each other through the defect, so that in the most severe form there is a large common anterior mitral-tricuspid valve leaflet as well as a smaller common posterior mitral-tricuspid valve leaflet. The chordae tendineae attach these common valves to the crest of the ventricular septum, the right side of the septum, or occasionally the right ventricular free wall. The earlier the stage of arrested development of the endocardial cushions has occurred, the larger the ventricular septal defect and the more primitive the development of the AV valves. Although the most severe form may occur as an isolated defect, it may be associated with other complex anomalies such as asplenia or polysplenia syndromes and single ventricle.

In general, the more severe or primitive the defect, the more marked are the clinical manifestations. The ventricular septal defect behaves like any other ventricular septal defect in producing a left ventricular volume load and, if it is large, pulmonary hypertension and a right ventricular pressure load. The characteristic murmur of a ventricular septal defect will be present, as will a mid-diastolic rumble caused by increased pulmonary venous return with increased diastolic flow across the mitral valve. If the cleft in the mitral valve is significant, mitral regurgitation may be present, and an apical pansystolic blowing murmur may be heard. The mid-diastolic rumble will then be further accentuated by the even larger flow across the mitral valve, and left ventricular enlargement will be more prominent. The ostium primum defect portion of the complete canal will present with physical findings similar to those in an isolated atrial septal defect; these include right ventricular volume overload, a tricuspid diastolic flow rumble, and a right ventricular outflow murmur. Should tricuspid regurgitation be present, a pansystolic blowing murmur in the tricuspid area and systolic pulsation of the jugular veins may be evident, and the increased flow across the tricuspid valve will accentuate the mid-diastolic murmur. Both the atrial and ventricular shunts are dependent. However, often the cleft in the misplaced mitral valve allows ventricular blood to pass through it and the ostium primum defect to enter the right atrium, so that there is an obligatory shunt from left ventricle to right atrium. There may at times be minor right-to-left shunting and mild cyanosis.

Heart failure often occurs by 2 months after birth. However, symptoms may develop very early in infancy if there is an obligatory large left-ventricle-to-right-atrium shunt or with significant AV valve dysfunction; an additional defect, such as a patent ductus arteriosus, may also lead to early symptoms. These symptoms are primarily related to severe congestive heart failure and include tachypnea, sweating, and difficulty with feeding. Systemic cardiac output is generally low, and the infant then has poor pulses, tachycardia, hepatomegaly, and peripheral pallor. Marked cardiomegaly is common.

The electrocardiogram shows left axis deviation (superior axis in the range of 60°–150°). The P-R interval is often prolonged. Ventricular and atrial hypertrophy depend on the level of maximal shunting and the amount of AV valve regurgitation. The left-axis deviation is not pathognomonic of an AV septal defect; it may also be found with DORV, with tricuspid or pulmonary atresia, or even in normal children. The absence of left-axis deviation does not exclude the diagnosis of an AV septal defect but suggests strongly against it. Chest radiographic findings depend on the level of shunting and the amount of AV valve regurgitation. Two-dimensional echocardiography and Doppler color flow mapping yield specific anatomic information and permit detection of differences between incomplete and complete forms of this defect. Magnetic resonance imaging may contribute to anatomic detail.

Untreated infants with this defect either die from congestive heart failure or are at high risk of developing obstructive pulmonary vascular disease from the severe pulmonary hypertension and large left-to-right shunt, so that early surgery is advisable. Many infants have poor responses to vigorous medical management, although this may buy a little time. Complete surgical repair of these lesions can be done in infancy with a low mortality rate providing the 2 ventricles are about of equal size. Infants with Down syndrome tend to have a more favorable anatomy for correction but are at higher risk for pulmonary vascular disease.

The availability of transesophageal echocardiography during surgery adds to the effectiveness of surgery, particularly when mitral regurgitation is a major component. If the ventricles are unbalanced, then some form of single ventricle repair can be done. Postoperative hemolysis is a rare complication.

If for some reason complete correction is not appropriate, intractable cardiac failure may be improved by pulmonary artery banding, which will increase the outflow resistance of the right ventricle and so decrease the amount of dependent shunting. However, in most infants with complete AV canal defects, the large left-ventricle-to-right-atrium shunt or AV valve regurgitation will be unaffected by pulmonary artery banding.

PARTIAL ANOMALOUS PULMONARY VENOUS CONNECTION

Partial anomalous pulmonary venous connection may occur without an associated atrial septal defect. The anomalous pulmonary veins almost always drain either the complete right lung or a portion of it, and they may connect with the superior vena cava or directly with the right atrium. In addition, there is a specific entity (scimitar syndrome) in which the pulmonary veins from the lower lobe and sometimes the middle lobe of the right lung drain by a common channel into the inferior vena cava. Associated with this is underdevelopment as well as lobar sequestration of that portion of the lung. The chest radiograph in scimitar syndrome is typical, and the anomalous vessel is generally seen easily. The clinical presentation of these lesions resembles that of secundum atrial septal defects, except that the second heart sound is generally normally split. Partial anomalous pulmonary venous connection, when associated with an atrial septal defect, does not generally contribute any specific clinical features. If the right side of the heart is dilated, surgical baffling of the anomalous veins into the left atrium achieves excellent results.

REGURGITANT LESIONS

Each of the cardiac valves may be affected pathologically so that the valve orifice is incompetent, and blood regurgitates across it from the higher-pressure to the lower-pressure region. In each condition associated with regurgitation of the left or right side of the heart, the left or right ventricle is dilated proportionally to the degree of regurgitation.

The severity of the lesion can be evaluated by assessing the effect of the regurgitant volume on the cardiac chamber or great artery on either side of the regurgitant valve. This can be done simply by the history, physical examination, electrocardiogram, chest radiograph, and echocardiography.

The possible etiologic factors and anatomic cause of the particular valvar abnormality leading to regurgitation must be sought.

With echocardiography, more precise assessment of hemodynamics and anatomy can be obtained. This diagnostic technique, however, is often unnecessary at each subsequent visit if the physician can apply less expensive basic clinical skills and diagnostic techniques.

AORTIC REGURGITATION

The primary finding is a high-pitched, early diastolic murmur that starts at the aortic component of the second heart sound. The length and loudness of the murmur increase with the severity of regurgitation.

Most children with this condition are asymptomatic, but if it is at least moderately severe, they have fatigue on exercise. Those with either significant chronic regurgitation or acutely developing regurgitation may develop congestive heart failure. With acute onset of aortic regurgitation, as from ruptured sinus of Valsalva (discussed below), symptoms develop abruptly.

With moderate or severe aortic regurgitation, the pulse pressure is widened, the systolic pressure being elevated by the augmented left ventricular stroke volume (cardiac output plus regurgitant volume), and the diastolic pressure is lowered because of “runoff” into the left ventricle as well as baroreceptor-induced peripheral vascular vasodilation. On auscultation, an aortic systolic ejection murmur is frequently present from the augmented forward flow across the aortic valve or structural abnormality of the valve. There may be at the apex a low-pitched, mid-diastolic murmur (Austin Flint murmur) attributed to the regurgitant aortic jet striking the anterior leaflet of the mitral valve, making it vibrate.

An electrocardiogram may show tall R waves in the left precordial leads from left ventricular dilation. T waves become flat or inverted in these leads if coronary perfusion is impaired by low aortic diastolic pressure.

Chest radiographs are normal if regurgitation is mild but show cardiac enlargement with a left ventricular contour when moderate or severe regurgitation is present. The ascending aorta may appear prominent along the upper right side of the mediastinum from either the large stroke volume or anatomic features secondary to the condition causing the regurgitation, such as Marfan syndrome or aortic stenosis.

The echocardiogram is very helpful in assessing the hemodynamics and anatomic causes of this regurgitation. The regurgitant jet can be identified and assessed by color echo Doppler; the breadth and extent of the jet correlate with the degree of regurgitation. In addition, measurement of left ventricular dimensions can assess the regurgitant volume, and the ejection or shortening fraction assesses the ventricular response to the volume overload. The appearance of the aortic valve, surrounding structures, and ascending aorta is critical to determine the underlying cardiac abnormality or etiologic factor.

Regurgitation from the aorta into the left ventricle results from a variety of congenital or acquired cardiac conditions, which occasionally coexist.

Congenital aortic stenosis usually occurs secondary to a bicuspid valve that during childhood may develop minimal aortic regurgitation, recognizable only as a soft murmur and minimal regurgitation on echo Doppler. The usual treatment of moderate or severe aortic stenosis is by valvotomy or valvoplasty. After either procedure, the degree of regurgitation increases, but rarely enough to result in symptoms or more than minimal hemodynamic disturbance, except in an occasional patient following balloon valvoplasty.

In membranous subaortic stenosis, the jet through the membrane, which is located slightly below the aortic valve, strikes one of the aortic valve cusps, distorting and thickening it, so it may become mildly regurgitant.

Sinus of Valsalva aneurysm results from separation between the aortic media and the heart at the level of the annulus fibrosis, as the aneurysm is below the level of the valve. The aneurysm can occur in any of the 3 aortic sinuses and may rupture into the adjacent cardiac chamber (see Sinus of Valsalva Fistula above). With progressive prolapse, aortic regurgitation develops. If the aneurysm ruptures, congestive cardiac failure and a murmur of aortic regurgitation develop abruptly.

Aortico–left ventricular tunnel is a rare condition in which a vascular-like structure arises above the aortic valve and passes through the ventricular septum to the left ventricle. This results in findings resembling significant aortic valve regurgitation. Rarely, the tunnel connects the aorta to the right ventricle.

With a ventricular septal defect adjacent to the aortic annulus, usually a subpulmonary or supracristal ventricular septal defect, the support of the adjacent aortic cusp is weakened. The cusp tends to sag into the left ventricle, and the left-to-right shunt through the ventricular septal defect exerts force on the cusp through the defect. The cusp in the ventricular septal defect tends to narrow it, while the aortic regurgitation worsens. The findings are those of a ventricular septal defect plus aortic insufficiency. Repair of the defect may buttress the aortic cusp sufficiently to reduce the aortic regurgitation and obviate surgery on the aortic valve.

Marfan syndrome is associated with dilated sinuses of Valsalva and ascending aorta. Aortic regurgitation that may be severe can result. The echocardiographic findings are diagnostic, showing greatly dilated aortic sinuses, symmetric enlargement of the ascending aorta, and often mitral valve prolapse. The diagnosis is made by characteristic features involving a number of organ systems because of abnormalities in connective tissue caused by defective fibrillin. Establishing a diagnosis of Marfan syndrome is critical because of the potential danger of aortic dissection when the ascending aorta becomes excessively dilated (> 5 cm in diameter in adults). Serial echocardiograms are used to monitor progression of ascending aortic aneurysm formation.

Rheumatic fever is a major cause of aortic incompetence worldwide but is uncommon in the United States.

Finally, infective endocarditis can occur on a malformed aortic valve. Staphylococcal endocarditis in particular can destroy the valve, leading to significant aortic regurgitation.

MANAGEMENT

Most patients can be managed conservatively without treatment. In those with more significant regurgitation, periodic echocardiograms to assess left ventricular size and function should be performed to help guide decisions about surgery. Afterload reduction has been used with moderate or severe aortic regurgitation in an attempt to lessen the regurgitant volume. Operations that involve valve replacement are reserved for those patients with chronic regurgitation who are symptomatic and have developed significant left ventricular dilation and/or dysfunction, or those patients who have developed aortic regurgitation acutely and are in congestive heart failure. Surgical repair of the valves has become more common in recent years.

MITRAL REGURGITATION

The primary feature is an apical high-pitched systolic murmur that, if moderately loud, radiates to the left axilla and left posterior thorax. Typically, it begins with the first heart sound and may continue throughout systole (pansystolic) and so occupies both the isovolumetric contraction and ejection phases of systole. In mitral valve prolapse (discussed below), the murmur begins later in systole because of the anatomic features of the valve.

When the regurgitant volume equals or exceeds the cardiac output, the first heart sound becomes loud, and a third heart sound is heard at the apex. A low-pitched, mid-diastolic murmur is heard at the cardiac apex. Arterial pulses are normal with mild regurgitation, but with massive regurgitation manifest a small collapsing pulse, as described for a large ventricular septal defect. Large R waves are found in the left precordial leads. On chest radiograph, there may be cardiac enlargement from left ventricular dilation and left atrial enlargement, evident as elevation of the left mainstem bronchus or, if severe, as an enlarged left atrial appendage along the upper left cardiac border.

Once the regurgitant volume is twice the cardiac output, so that left ventricular volume is 3 times normal, the degree of left ventricular dilation is excessive. Then cardiac failure with its associated symptoms and signs appears.

The echocardiogram allows assessment of hemodynamics and anatomic features of the mitral valve. Mitral regurgitation can develop secondary to both acquired and congenital anomalies of the mitral valve that are reviewed below. Internationally, the most common cause is rheumatic fever, whereas in the United States, it is usually secondary to mitral valve prolapse (up to 5% of the population).

Mitral regurgitation can occur secondary to primary anomalies of the mitral valve, which include cleft in the anterior leaflet and double orifice. Only the echocardiogram diagnoses these conditions. Papillary muscle dysfunction from anomalous left coronary artery or conditions with left ventricular hypertrophy can result in mitral regurgitation. In the former, the electrocardiogram is typical; in the latter, the cause of left ventricular hypertrophy can typically be found on clinical examination, electrocardiograms, or echocardiograms. In adults, mitral regurgitation may be due to spontaneous rupture of chordae tendineae, but in children, such rupture is rare and usually follows chest trauma.

In some patients, mitral regurgitation improves following medical or surgical treatment of the underlying condition (eg, left atrial myxoma, endocardial cushion defect, anomalous left coronary artery, severe aortic stenosis, hypertrophic cardiomyopathy, rheumatic fever). In these patients, improvement occurs without direct treatment of the mitral valve. Mitral regurgitation secondary to neonatal asphyxia or hypoglycemia generally improves spontaneously during the first year of life, as the ischemic left ventricular myocardium recovers. Many patients require no treatment, but in those who become symptomatic or have moderate regurgitation, afterload reduction may lessen the regurgitant volume and delay valve replacement.

A cleft mitral valve may be repaired directly, but other forms of mitral regurgitation generally require valvoplasty or valve replacement. Replacement is reserved for those with symptoms or deteriorating left ventricular function when a conservative operation is not possible. Recently, transcatheter clipping of the valve leaflets in adults has lessened the degree of regurgitation, but the role of this procedure has not been established.

MITRAL VALVE PROLAPSE

Either leaflet of the mitral valve may prolapse into the left atrium. The reasons for prolapse are unknown. Mitral valve prolapse occurs in increased frequency in patients with connective tissue disorders of Marfan or Ehlers-Danlos syndromes and also with mucopolysaccharidoses, ruptured chordae (perhaps from bacterial endocarditis), and certain cardiac anomalies (such as atrial septal defect) associated with reduced left ventricular volume. Because the leaflets of the mitral valve are tethered by the chordae tendineae to the left ventricular papillary muscles, the extent and duration of the prolapse depend on the left ventricular volume. Left ventricular volume is larger when the patient reclines and is smaller when the patient sits or stands. Thus, in the former state, the mitral valve prolapses less and for a shorter period of time than in the latter positions.

Mitral valve prolapse can be recognized by typical auscultatory findings that are usually diagnostic. At the apex, a late systolic crescendo murmur is heard, often initiated by a click. When the patient sits or stands, the murmur is louder and longer, and when the patient squats or reclines, it becomes softer, shorter, and later in systole. Most patients are asymptomatic, but some have chest pain or palpitations of unknown cause. There are no typical electrocardiographic or radiographic findings, but the echocardiogram, if performed, demonstrates the anatomic and hemodynamic features. There is an association with thoracic anomalies, such as pectus excavatum, scoliosis, or straight back syndrome.

Mitral valve prolapse is common in Marfan syndrome because of the elongated chordae tendineae. The resultant mitral regurgitation can become significant, causing major left atrial enlargement to such a degree that atrial fibrillation may develop.

PULMONARY REGURGITATION

The primary finding is an early decrescendo diastolic murmur beginning with the pulmonary component of the second heart sound. The murmur is usually low pitched, unlike a murmur of aortic regurgitation, because of the low pulmonary artery diastolic pressure. The murmur is high pitched when pulmonary hypertension is present, as in a neonate or a patient with pulmonary vascular disease in whom pulmonary regurgitation develops.

Pulmonary regurgitation is usually well tolerated because of the low pulmonary artery diastolic pressure and shape of the right ventricle. Thus, children are asymptomatic with this condition and have a near-normal exercise tolerance. Congestive heart failure is uncommon unless there is pulmonary hypertension or abnormal right ventricular function, but it may appear after many years of marked regurgitation.

If the regurgitant volume exceeds twice normal, a soft pulmonary systolic ejection murmur may be heard, accompanied by widened, but variable, splitting of the second heart sound. Because of the increased anterograde flow into the pulmonary trunk and proximal pulmonary arteries, the pulmonary arterial pulse pressure is increased, and the pulmonary arteries are pulsatile, as shown by imaging techniques. On a chest radiograph, the pulmonary trunk and proximal pulmonary arteries may be dilated. With increasing volumes of blood in the right ventricle, the right ventricle dilates, leading to cardiomegaly on a chest radiograph and an rSR in the right precordial electrocardiographic leads.

The most common cause of pulmonary regurgitation is postoperatively after relief of pulmonary stenosis, either isolated or combined with a ventricular communication (most frequently tetralogy of Fallot). After either a surgical or a balloon valvoplasty for valvar pulmonary stenosis, the degree of regurgitation and the hemodynamic alterations are usually minimal. In patients in whom pulmonary stenosis has been relieved by a transannular patch or in whom a ventriculotomy is done for an intracardiac repair, fatigue or heart failure may develop, cardiomegaly is found, and the electrocardiogram shows complete right bundle branch block. These patients may develop exercise fatigue from inability of the right ventricle to increase cardiac output during exercise and eventually right heart failure.

Congenital pulmonary regurgitation is rare and may be associated with either an intact ventricular septum or a ventricular septal defect.

MANAGEMENT

Most patients with pulmonary regurgitation after valvoplasty, valvotomy, or transannular patch do not require treatment but should be followed periodically. If there are symptoms or evidence of significantly decreased right ventricular function, valve replacement should be performed. In many patients, prosthetic pulmonary valves can be inserted by catheter.

In infants with coexistent ventricular septal defect and absent pulmonary valve, an operation to close the ventricular septal defect and plicate the main pulmonary arteries should be done. Various degrees of tracheobronchomalacia may be present.

TRICUSPID REGURGITATION

The primary finding is a pansystolic murmur along the lower left sternal border; the murmur may radiate toward the right. The murmur is usually low pitched because of the low right ventricular systolic pressures but is higher pitched if associated with a high right ventricular systolic pressure.

Because of the increased right atrial volume, the right lower cardiac border of the chest radiograph may be rounded and prominent, and the electrocardiogram shows tall and slightly broadened P waves of right atrial enlargement. If significant, the jugular veins are distended, and the liver is enlarged.

Because of the increased antegrade flow, a low-pitched mid-diastolic murmur is present in the tricuspid area. Once the right ventricular volume exceeds twice normal, cardiomegaly and an rSR (lead V₁) may be found.

Because of the low right ventricular systolic pressure, compliant right ventricle, and right ventricular shape, this condition is usually well tolerated and unassociated with congestive heart failure unless right ventricular dysfunction coexists.

Tricuspid regurgitation is common, secondary to congenital or acquired conditions associated with right ventricular dilation, although the degree is often mild and detectable only by color Doppler interrogation of the tricuspid valve. Two particularly critical conditions causing tricuspid regurgitation can present in the neonatal period.

TRANSIENT TRICUSPID INSUFFICIENCY OF THE NEONATE

In some neonates with severe perinatal stress, marked tricuspid regurgitation may develop secondary to right ventricular myocardial ischemia. Affected neonates often have acidosis and hypoglycemia. Myocardial enzyme levels (creatine kinase MB band) and troponin are elevated. Pulmonary hypertension frequently coexists and accentuates the degree of regurgitation.

Cardiac failure may be present, accentuated by the elevated pulmonary vascular resistance and myocardial dysfunction. There are no distinguishing features other than the perinatal history and frequently ST-segment and T-wave changes on an electrocardiogram. Treatment is supportive with inotropes to improve myocardial function, ventilator support to reduce oxygen consumption, and nitric oxide.

The tricuspid regurgitation generally resolves during infancy as pulmonary resistance declines and the right ventricular myocardium recovers. Usually by 6 months of age, there are no abnormal findings.

EBSTEIN MALFORMATION

This congenital cardiac anomaly must be considered in the differential diagnosis of tricuspid insufficiency and is discussed below.

SECONDARY TO RIGHT VENTRICULAR DYSFUNCTION

Tricuspid regurgitation may develop secondary to right ventricular dysfunction. The 2 common situations in which this occurs in childhood are right ventricular failure and severe pulmonary stenosis. The former is found late in the postoperative course of children following atrial baffle procedures for complete transposition or right ventriculotomy (plus conduit placement), as in tetralogy of Fallot.

In those patients following atrial baffle procedures, because the right ventricle is connected to the aorta, systemic afterload reduction reduces the degree of regurgitation. Among those who have significant postoperative pulmonary regurgitation following repair of tetralogy of Fallot, repair of this problem often reduces right ventricular volume and lessens the tricuspid regurgitation. In children with severe pulmonary stenosis, tricuspid regurgitation may develop from either coexistent structural anomalies of the tricuspid valve or right ventricular dysfunction. In these patients, the regurgitation is accentuated by the elevated right ventricular systolic pressure. Relief of the pulmonary stenosis is generally sufficient to diminish the tricuspid regurgitation. Many patients with hypoplastic left heart syndrome who have undergone various stages of surgical palliation have significant tricuspid insufficiency because the right ventricle dilates under the increased afterload of the systemic circulation.

Rare causes of tricuspid regurgitation include endocarditis, which occurs on a normal valve following intravenous injection of contaminated drugs, and carcinoid disease. Other primary congenital anomalies of the tricuspid valve are also rare and include isolated cleft of the septal leaflet, abnormal chordae tendineae, or structural abnormalities of the leaflets.

OBSTRUCTIVE LESIONS

Obstruction of flow because of a congenital abnormality may occur in any part of the pulmonary and systemic vascular systems, but the outflow tracts of each ventricle are most often affected. The obstruction may be so mild as to produce no significant hemodynamic effects or so severe as to cause total obstruction of flow. Mild, moderate, or severe obstruction is called stenosis, whereas complete obstruction is termed atresia. Atresia may occur at an AV valve, at a semilunar valve, or in the aortic arch. With atresia, blood is diverted from its normal pattern of flow and is directed through abnormal pathways to maintain systemic or pulmonary blood flow. Most of these complex lesions involve complete admixture of pulmonary and systemic venous returns and thus produce both right-to-left and left-to-right shunting; they are considered below. When the obstruction is incomplete, blood flow is largely maintained through normal pathways, and the basic anatomy is unaltered. However, to maintain a normal output through the stenosis, an unusually high pressure proximal to the obstruction is required, causing an increased pressure load proximal to the obstruction. For example, narrowing of the aorta increases left ventricular systolic pressure; with severe obstruction, left ventricular end-diastolic pressure rises. Left atrial and pulmonary venous pressures then increase, and pulmonary edema may occur. This causes pulmonary hypertension and eventually right ventricular failure, with an increase in systemic venous pressure. In association with the increased pressure, the chamber of the heart involved dilates and eventually hypertrophies in order to maintain the pressure load. If this cannot be accomplished, cardiac failure occurs, and cardiac output and arterial blood pressure fall. It is important to remember that although the foramen ovale is functionally closed soon after birth, it may allow shunting between the 2 circulations in either direction if there is an obstruction distal to it.

A general pathologic effect of an obstruction is to cause hypertrophy of the chamber(s) proximal to the obstruction. This will cause electrocardiographic changes of hypertrophy of the involved chamber(s). Because hypertrophy from obstruction merely thickens the chamber wall by a few millimeters, the chest radiograph usually does not show an enlarged heart (unless there is also dilatation), although shape changes of the chambers are sometimes visible.

LEFT HEART OBSTRUCTION

PULMONARY VENOUS OBSTRUCTION

Obstruction to pulmonary venous return is generally associated with abnormal connection of the pulmonary veins, either below or above the diaphragm (see Total Anomalous Pulmonary Venous Connection, below), and may occur for the first time after surgical repair of these anomalous veins. Obstruction of normally connected pulmonary veins does occur occasionally as a result of external compression by a posterior mediastinal mass, fibrosis, or an intrinsic abnormality in the pulmonary veins; single or multiple pulmonary veins may be involved. Intrinsic narrowing may be caused by diffuse hypoplasia, a localized diaphragm, or narrowing of the pulmonary veins as they enter the left atrium.

Pulmonary venous pressure increases with an anatomic obstruction to pulmonary venous return. The rise in pulmonary venous pressure causes increased transudation of fluid through the capillary walls into the interstitial lung spaces, from where it passes into alveoli or lymphatics. The fluid accumulation makes the lungs stiff and is clinically apparent as respiratory distress, retractions, and rales, as well as by interference with gas exchange, particularly of carbon dioxide, leading to increasing arterial blood carbon dioxide tension. As fluid accumulates, there is lymphatic engorgement that on chest radiograph is associated with Kerley B lines, fluid in the major fissures, and eventually pleural effusion. In some infants in whom congenital lymphangiectasia has been diagnosed, subsequent autopsy examination has revealed pulmonary venous obstruction, usually associated with total anomalous pulmonary venous connection.

Frequently increased pulmonary venous pressure is associated with an increased pulmonary vascular resistance. The suggested mechanisms that produce this effect include a decrease in oxygen tension to which the resistance vessels are exposed, with resultant pulmonary vascular constriction, and compression of the resistance vessels by edema fluid. Reflex vasoconstriction has been postulated but never proved. With the increase in pulmonary vascular resistance, pulmonary arterial pressure rises, causing a pressure overload on the right ventricle.

The clinical presentation includes the signs and symptoms of pulmonary edema and pulmonary hypertension. It can be difficult to differentiate certain forms of chronic pulmonary disease from pulmonary venous obstruction.

Treatment of pulmonary venous obstruction is surgical repair. Anomalous veins are attached to the left atrium; intrinsically stenotic veins are enlarged with a patch. Recurrence of stenosis with the need for multiple surgeries is common. Newer methods in which the stenotic regions are excised and suturing of the veins is avoided by suturing the pericardium around the vein seem to reduce recurrences. Nonsurgical catheter-based treatment, including balloon dilation, alone or with stent placement, has been used. Although immediate improvement is common, recurrence of stenosis is frequent, and therefore this therapy has limited use. Lung transplantation remains an option for patients who have failed repeated conventional surgeries.

OBSTRUCTION WITHIN THE LEFT ATRIUM

Cor triatriatum is a membrane in the midportion of the left atrium; the membrane obstructs flow from the pulmonary veins to the mitral valve. Failure of resorption of the common pulmonary vein results in division of the left atrium into upper and lower chambers during development. The pulmonary veins drain into the proximal chamber that communicates through an obstructive opening with the distal portion of the atrium, which in turn is connected to the atrial appendage and the mitral valve. The physiologic effects and clinical presentation are the same as in pulmonary venous obstruction. The diagnosis is made by echocardiography or magnetic resonance imaging. Cardiac catheterization with angiography is rarely needed. Definitive treatment consists of surgical excision of the obstructing membrane.

An equally uncommon lesion producing obstruction within the left atrium is a supravalvar mitral ring, often associated with a parachute mitral valve, subaortic stenosis, and coarctation of the aorta (Shone syndrome). The supravalvar mitral ring is a membrane that develops in the left atrium adjacent to the mitral valve and restricts leaflet motion, causing obstruction. A tumor within the left atrium, usually a myxoma, can also produce obstruction within the left atrial chamber, and it generally mimics mitral stenosis; however, because such a tumor is often on a pedicle, the obstruction to the mitral valve orifice (and hence the clinical features) may be intermittent. Treatment of supravalvar mitral ring and myxoma is by surgical resection, which is curative.

MITRAL VALVE OBSTRUCTION

Outflow from the left atrium can be obstructed by either abnormalities of the mitral valve apparatus or left ventricular failure and results in increased atrial pressure. The left atrium dilates and hypertrophies. Left atrial hypertension may be inferred clinically on hearing a well-marked fourth heart sound that suggests more forceful contraction by the hypertrophied atrium. Electrocardiographically there may be a widely notched P wave in lead II and in leads V₅ and V₆, and the P wave in V₁ may be enlarged with a prominent negative or biphasic component suggesting left atrial enlargement. On a chest radiograph, the typical signs of left atrial dilation, prominent left upper heart silhouette, and superiorly deviated left bronchus may be seen. An increased pulmonary venous pressure is manifested by tachypnea.

The most severe form of mitral valve obstruction is mitral atresia, discussed below in Hypoplastic Left Heart Syndrome. Congenital mitral stenosis may be an isolated defect or may be associated with other abnormalities such as an atrial or ventricular septal defect, aortic stenosis, coarctation of the aorta, or endocardial fibroelastosis. Congenital malformations of the mitral valve may produce grossly abnormal valve cusps or a valve that appears normal but has fused commissures or else fusion of chordae tendineae below the valve ring. Parachute mitral valve, in which the chordae tendineae are all attached to a single papillary muscle, also obstructs flow at the mitral valve level. This may occur as an isolated lesion, but it is more commonly part of a complex group of left heart obstructions, known as Shone syndrome.

The congenital forms of mitral stenosis are generally severe and present in early infancy with symptoms and physical findings of pulmonary edema; if pulmonary hypertension occurs, severe congestive heart failure may supervene. Various degrees of mitral regurgitation may be associated with the stenosis, and there may be an apical blowing murmur. An opening snap of the mitral valve may be heard, but this is not common because the valve is very thick and immobile. Tricuspid regurgitation may occur if there is severe pulmonary hypertension with right ventricular dilation. On the electrocardiogram, the P waves are broad and notched, suggesting left atrial enlargement, and right ventricular hypertrophy may be present. The chest radiograph shows only moderate enlargement of the cardiac silhouette caused by left atrial and possibly right ventricular enlargement. The pulmonary vascular markings depend on the severity of obstruction. In severe mitral stenosis in older children and adults, the increased pulmonary venous pressure dilates the veins near the lung apex (erect position), but dependent edema in the lower parts of the lungs constricts them, the reverse of the normal radiographic pattern. In infants who spend much of their time supine, this sign is usually absent.

The specific diagnosis may be made by echocardiography and rarely needs confirmation by cardiac catheterization and angiography.

Medical treatment of severe congenital mitral stenosis with intractable heart failure in infancy and early childhood is usually unsuccessful. Surgical management, because of the marked thickening and deformity of the mitral valve, generally involves inserting a prosthetic valve; however, in older patients, valve repair may be tried. The prosthetic valve has a limited effective life, and surgical replacement with a larger prosthetic valve is needed to accommodate growth. In addition, children with a prosthetic mitral valve must be given anticoagulants to prevent thrombosis of the valve. Recently dilation of the stenotic valve with a balloon catheter has shown promise, particularly in older patients (see Chapter 490). If the left ventricle is hypoplastic, then repair of the mitral valve may not be appropriate, and a single ventricle–type surgical repair may be needed.

LEFT VENTRICULAR OUTFLOW OBSTRUCTION

Most left ventricular obstructive lesions do not occur rapidly, and compensatory myocardial hypertrophy occurs in response to the increased systolic pressure in the chamber. The increased muscle mass allows increased cardiac work to be performed with little ventricular dilation and without greatly increased end-diastolic pressures. As an additional response to stress, increased sympathetic activity occurs and produces greater contractile force and rate of ejection, thus shortening systole and lowering end-diastolic pressure. However, with severe obstruction, even these compensatory mechanisms may fail, and the left ventricle dilates and end-diastolic pressure increases.

The oxygen requirements of the left ventricular myocardium are related to the systolic wall tension generated within the ventricle, the thickness of the wall, the diameter of the cavity, and the degree of sympathetic stimulation. The amount of oxygen supplied to the myocardium is related to the aortic diastolic pressure, the left ventricular diastolic pressure, the duration of diastole, and the oxygen-carrying capacity of blood perfusing the myocardium. Therefore, with severe obstruction, oxygen requirements are significantly increased, but the supply of oxygen may be compromised if there is left ventricular failure with an increase in ventricular end-diastolic pressure and a shortened diastolic duration because of the compensatory tachycardia. If the ventricle is both hypertrophied and dilated, the increased wall tension increases myocardial oxygen demand still further and adds to the risk of subendocardial ischemia.

The left ventricular response to obstruction is manifested by left ventricular hypertrophy, inferred from a slow forceful heave of the left ventricular apex. Hypertrophy alone does not significantly enlarge the external heart dimensions, for the increased wall thickness may be only a few millimeters, but if there is associated dilation, the left ventricular apex is displaced downward and to the left. The heart may or may not show enlargement on a chest radiograph; even if it is not enlarged, there may be a slightly more rounded left ventricular contour than typically seen. There are no specific changes in the first or second heart sounds, but a third heart sound may appear; if there is systemic hypertension, aortic closure is loud. Electrocardiography shows increased left inferior and posterior forces. The mean frontal-plane QRS axis is normal with pure left ventricular hypertrophy because an inferiorly placed ventricle with a normal sequence of depolarization does not produce the left superior axis, termed left-axis deviation.

Several congenital cardiovascular malformations obstruct ejection of blood from the left ventricle. The most common of these is obstruction of the aortic valve cusps; however, the left ventricular outflow tract may be obstructed by an abnormally situated mitral valve leaflet or papillary muscle, by muscular hypertrophy of the ventricular septum, by a subvalvar fibrous ring, by a thin subvalvar membrane with a small orifice, or by supravalvar aortic narrowing. Because valvar aortic stenosis is the most common form of aortic stenosis, it is described in detail, and differences associated with other forms of left ventricular outflow tract obstruction are identified.

VALVAR AORTIC STENOSIS

About 85% of congenitally stenotic aortic valves are bicuspid, with 1 small and 1 large cusp and an eccentric fish-mouth orifice between them. Another 14% have no obvious separation into leaflets, so that there is a thick monocusp with an eccentric orifice shaped like a teardrop. The obstruction results in part from the small orifice left by commissural fusion and in part from thickening and lack of mobility of the valve. In the neonate, some of these abnormal valves have myxomatous thickening.

Somatic development is usually normal at the time of birth. If the stenosis was severe in utero, then blood will have been diverted from the left ventricle, so that it and the ascending aorta are hypoplastic. Because of the high left ventricular pressure, there may be marked endocardial thickening (secondary endocardial fibroelastosis) that further impairs left ventricular performance. Subendocardial flow may be inadequate and cause subendocardial ischemia. In moderately severe aortic stenosis with mean pressure gradient across the valve of 30 to 50 mm Hg, exercise may cause anginal pain and ST depression or T-wave inversion in the left ventricular electrocardiographic leads. Ischemia or ischemic damage may also be responsible for the occasional sudden death, due to ventricular fibrillation. Failure of exercise to cause angina does not exclude severe stenosis. One other symptom of severe aortic stenosis is syncope, usually following exertion or prolonged standing. Lesser degrees of stenosis cause left ventricular hypertrophy with no evidence of ischemia at rest or exercise, and the mildest stenotic lesions produce only a systolic ejection murmur with no left ventricular hypertrophy.

After birth, in an infant with severe aortic stenosis, if the foramen ovale is competent, left atrial pressure rises, and left ventricular output is well maintained, but at the expense of pulmonary edema. If, however, the foramen ovale is incompetent and allows a large left-to-right shunt, left atrial pressure may not rise as much, so there may be less pulmonary edema but at the expense of a lower cardiac output. In either circumstance, left ventricular dilation may be marked, and left ventricular failure occurs. Infants with less severe aortic stenosis are generally capable of maintaining cardiac output and of developing adequate hypertrophy to overcome the obstruction.

Congenital aortic stenosis is usually progressive. As the child grows and cardiac output increases, the valve orifice may not grow to keep pace with increased cardiac output requirements; thus, the obstruction becomes more severe, and the pressure difference between the aorta and left ventricle increases. Rapid changes in the severity of aortic stenosis may occur with rapid growth spurts.

CLINICAL FEATURES

Severe aortic stenosis generally presents in the immediate postnatal period. The physical findings are those of a systolic murmur of variable intensity, depending on the left ventricular output. This systolic murmur is often best heard at the middle left sternal border in infants; it can be confused with the murmur of ventricular septal defect. An early systolic ejection click is common. Peripheral perfusion and pulses depend on the degree of failure, but they are generally decreased; these infants can be misdiagnosed as having septic shock. Evidence of significant atrial left-to-right shunting with right ventricular hyperactivity is often present. Mitral regurgitation can be severe due to papillary muscle ischemia. Chest radiographs show marked cardiomegaly with severe pulmonary venous congestion. The electrocardiogram often shows increased right ventricular forces; increased left ventricular forces are rarely present in the neonate. An echocardiogram may show the abnormal aortic valve and usually demonstrates a dilated, poorly contractile left ventricle, sometimes with bright subendocardial echos that indicate secondary fibroelastosis.

In older children with aortic stenosis, the murmur usually draws attention to the defect. Chest or epigastric pain or syncopal episodes are generally associated with severe stenosis and are uncommon presenting symptoms. They may develop in a child known to have aortic stenosis, indicating progression in severity of the stenosis. Many of the physical findings of aortic stenosis correlate roughly with the severity of the stenosis. If there has been long-standing severe obstruction from infancy, a left precordial bulge and an apical impulse in the left anterior axillary line may be evident. In children with moderately severe stenosis, the systemic arterial pulse is usually normal. In adults, as the stenosis becomes more severe, the upstroke of the pulse is slowed, and pulse volume is decreased; this sign is uncommon in children, even those with moderately severe stenosis. The first heart sound may be normal or soft in severe stenosis. Commonly, an early systolic ejection click is heard along the left sternal border and is usually transmitted toward the apex of the heart.

A prominent apical third sound is frequently heard, and in severe stenosis, a fourth sound may also be present. A loud crescendo-decrescendo systolic murmur, often grade 4 to 5 in intensity and associated with a suprasternal notch thrill, is characteristic of significant aortic stenosis. The murmur starts with the first sound and reaches peak intensity early in systole in mild stenosis and later in systole in more severe stenosis.

The electrocardiogram may show left ventricular hypertrophy, but this is a poor index of the severity of the stenosis. T-wave flattening or inversion and ST-segment depression in left ventricular precordial leads indicate left ventricular strain from severe aortic outflow obstruction and indicate the need for treatment. These changes may not be present at rest but may be brought out by graded exercise. The chest radiograph occasionally shows left ventricular enlargement, but more often the only abnormal finding is poststenotic dilation of the ascending aorta.

It is important to realize that symptoms, physical findings, chest radiographs, and electrocardiograms are unreliable in predicting the severity of aortic stenosis. It is for this reason, and because sudden death may occur in children with stenosis and relatively minor physical findings, that the pressure difference between aorta and left ventricle and the hemodynamic status should be evaluated carefully by Doppler examination or cardiac catheterization.

Echocardiography with Doppler examination is essential for any child with aortic stenosis with or without symptoms. If there is no evidence of myocardial ischemia at rest, an exercise test may help to determine the adequacy of myocardial perfusion. Any suggestion that the stenosis is severe should lead to referral for treatment. In most centers, cardiac catheterization is performed when there are doubts about the echocardiographic findings or the stenosis is severe enough to warrant treatment. If valvotomy is not needed, these patients should be followed at least yearly with electrocardiograms at rest and during exercise and by echocardiogram-Doppler study because of the tendency of this lesion to become more severe.

TREATMENT

Symptoms of chest pain or syncope warrant immediate evaluation and treatment, as does evidence of ischemia on electrocardiogram. A pressure gradient of greater than 70 mm Hg (or a mean gradient of 50 mm Hg) measured with echo Doppler velocity generally indicates the need for treatment in an asymptomatic patient. This most often correlates with a valve area of less than 0.65 cm²/m² body surface area, with normal being greater than 2 cm²/m². Treatment historically had been surgical valvotomy, but balloon valvoplasty has become the treatment of choice (see Chapter 490). Both forms of valvotomy are only palliative, but palliation is lifesaving and may produce a good functional result that lasts for many years. However, there is a high incidence of recurrence of stenosis, often associated with calcification, and 40% of patients require repeat treatment within 10 years. Most patients with severe stenosis will eventually require surgical treatment. If possible, surgical treatment should be deferred until the patient is fully grown to avoid repeat surgical procedures. Surgical options include moving the pulmonary valve ring with the intact valve into the aortic annulus, implanting the coronary arteries into the new aortic root, and placing a homograft aortic valve into the right ventricular outflow tract (Ross procedure), or doing an aortic homograft (new pulmonary valve) that will usually require replacement every 10 to 15 years.

BICUSPID AORTIC VALVE

Bicuspid aortic valve is present in 1% to 2% of the population. There is an asymmetric orifice, and the valve may not open fully in systole, but there need not be any obstruction to left ventricular ejection. Bicuspid valves are found in 50% of patients with coarctation of the aorta but more often are isolated anomalies. Sometimes they are associated with a grade 1 to 2/6 systolic ejection murmur and click at the right upper sternal border, but often they are not clinically apparent. The diagnosis is best made by 2-dimensional echocardiography.

The importance of bicuspid aortic valves is that they may produce aortic stenosis in later life; middle-aged adults with calcific aortic stenosis usually have congenitally bicuspid aortic valves. The likelihood of late development of calcific aortic stenosis or less often aortic regurgitation is ~75%. Occasionally, bicuspid aortic valves are the seat of infective endocarditis; however, if bicuspid aortic valves are diagnosed, prophylaxis against infective endocarditis is no longer officially recommended.

Poststenotic dilation of the aorta is common, and the aortic wall is often abnormal, sometimes showing cystic medial necrosis. Dissection of the ascending aorta may occur but is very rare under 40 years of age.

DISCRETE SUBVALVAR AORTIC STENOSIS

Subvalvar aortic stenosis may be caused by either a thin membranous diaphragm or a thick fibromuscular obstruction. The aortic valve may be thickened and distorted by the high-velocity jet stream passing through the subaortic obstruction and may be regurgitant. The clinical features are similar to those observed with valvar aortic stenosis, and there are no reliable clinical criteria to differentiate valvar from subvalvar obstruction. The 2-dimensional echocardiogram may be used to define more accurately the type, thickness, and site of obstruction present. In addition to the subaortic obstruction, there may be hypoplasia of the aortic annulus.

Subaortic stenosis may be isolated or may be associated with Shone syndrome, ventricular septal defect, or other forms of congenital heart disease. Unlike most other forms of congenital heart disease, subaortic stenosis may not be present at birth but develops later. It may increase in severity with time.

Differentiation between valvar and subvalvar aortic stenosis by echocardiography is important because a subvalvar diaphragm is readily removed at surgery with good results and because even mild subvalvar obstruction may cause progressive aortic valve damage and regurgitation. Unfortunately, recurrence of obstruction is common. Some children may have subvalvar obstruction from an abnormally placed papillary muscle and displaced mitral valve. This is much more difficult to alleviate surgically, and it may be complicated by mitral regurgitation.

DIFFUSE SUBAORTIC STENOSIS

Diffuse subaortic left ventricular outflow stenosis may be associated with any cause of diffuse hypertrophy of the left ventricle. It occurs with valvar aortic stenosis and with certain types of cardiomyopathy, such as glycogen storage disease. Infants born to diabetic mothers have a high incidence of a mild form of diffuse hypertrophic cardiomyopathy, although a few may have severe asymmetric septal hypertrophy. The abnormalities are temporary and generally resolve within several months. Some children with Noonan syndrome have a specific form of eccentric subaortic stenosis. Tumors, such as rhabdomyomas, may also cause outflow obstruction. In premature infants with chronic lung disease treated with steroids, a diffuse symmetric hypertrophy may develop. This regresses spontaneously once steroid treatment is discontinued.

The most common form of diffuse subaortic stenosis is idiopathic. This entity has been called idiopathic hypertrophic subaortic stenosis (IHSS), hypertrophic obstructive cardiomyopathy (HOCM), hypertrophic cardiomyopathy (HCM), or asymmetric septal hypertrophy (ASH). The disease is transmitted as a Mendelian dominant trait with variable expression and is usually seen in more than 1 member of a family. In some families, there is a tendency to have ventricular arrhythmias and less severe outflow tract obstruction, whereas in others, there is severe obstruction. About 50% of patients have mutations that map to the myosin heavy chain on chromosome 14; many different mutations are now known. Other mutations affect cardiac troponin T and α-tropomyosin. Linkage studies have also suggested mutations on chromosomes 1, 11, and 15.

Many of the physical findings are similar to those in valvar aortic stenosis, but certain features usually distinguish them. A double or triple apical impulse, described as a precordial ripple, can be seen or palpated. The first heart sound may be normal or soft; systolic clicks are rarely heard. The suprasternal notch thrill is absent. A delayed-onset crescendo-decrescendo systolic murmur, usually of grade 2 to 4/6 intensity, may be heard best at the middle left to upper right sternal border, and a systolic thrill may be palpable over the precordium. If the patient squats, thereby increasing venous return and peripheral vascular resistance, the murmur decreases in intensity as a result of left ventricular dilation. All these maneuvers tend to produce opposite effects in valvar aortic stenosis. The chest radiograph shows left ventricular enlargement without dilation of the ascending aorta. The electrocardiogram is variable, but with severe or moderately severe hypertrophy, there are markedly increased left ventricular forces often associated with ST-segment depression and T-wave flattening or inversion in the left precordial leads. Deep Q waves in the left precordial leads indicative of septal hypertrophy are more evident than in valvar aortic stenosis.

The 2-dimensional echocardiogram is of great help in diagnosing this lesion. It demonstrates the asymmetric septal hypertrophy, and during systole it usually shows anterior movement of the mitral valve (SAM), which touches the septum and in part causes the outflow tract obstruction. SAM is not always demonstrated but usually can be provoked by maneuvers that precipitate outflow obstruction, such as amyl nitrite inhalation (through decreasing afterload) or the Valsalva maneuver (through decreasing preload).

Children with this disease are more likely to die from arrhythmias than from obstruction and heart failure. The results of treatment of this lesion are variable. Some children respond fairly well to β-adrenergic receptor blockers. Calcium channel blockers are useful, particularly when the major problem is decreased diastolic ventricular distensibility. Disopyramide has also been shown to reduce left ventricular outflow tract obstruction in HCM. Inotropes must be avoided. Surgical excision of the hypertrophied muscle has produced marked improvement in some children. Unfortunately, death from arrhythmia can occur even without any obstruction, and some patients require an implantable cardioverter-defibrillator.

SUPRAVALVAR AORTIC STENOSIS

Supravalvar aortic stenosis is a localized or diffuse narrowing just above the level of the coronary arteries and the superior annular margin of the sinuses of Valsalva. The coronary arteries usually arise proximal to the obstruction and are often tortuous, with thickened medial and intimal layers. Coronary perfusion may be compromised by involvement of the coronary ostia in fibrous tissue. Although supravalvar aortic stenosis may occur as an isolated lesion, it is often associated with Williams syndrome. On auscultation, the aortic closure sound is frequently accentuated; an ejection click is unusual, and the systolic murmur is best heard at the base and toward the neck. If peripheral pulmonic stenosis is associated, a long systolic or continuous murmur may be heard laterally in the chest. Characteristically, blood pressure is about 15 mm Hg higher in the right than the left arm. The chest radiograph does not show poststenotic dilation of the ascending aorta. The electrocardiogram shows left ventricular hypertrophy as well as T-wave inversion in left chest leads if there is severe stenosis. Magnetic resonance imaging and echocardiography demonstrate the supravalvar narrowing, and Doppler study can assess the pressure gradient. Cardiac catheterization and angiography are done to confirm the severity of the supravalvar obstruction and associated peripheral pulmonic stenosis and to assess the coronary arteries. If obstruction is severe, the diffuse supravalvar narrowing can be relieved surgically with excellent long-term results. If severe peripheral pulmonary artery stenosis is associated with the supravalvar obstruction, cardiac catheterization with balloon dilation of the branch pulmonary stenoses is performed before surgical repair in some centers. However, unlike most other stenoses, peripheral pulmonary artery stenoses in Williams syndrome often decrease in severity spontaneously.

AORTIC OBSTRUCTIONS

Obstructive lesions of the aorta may be subdivided into diffuse narrowing (hypoplasia) or interruption of a portion of the aortic arch, discrete narrowing (thoracic coarctation) closely related to the attachment of the ductus arteriosus with the aorta, pseudocoarctation, and abdominal coarctation. The discrete thoracic coarctation is the most common lesion and is usually associated with a normally developed aortic arch.

HYPOPLASIA OR INTERRUPTION

In normal fetal life, the aortic isthmus (the portion of aorta between the origin of the left subclavian artery and the ductus attachment) conducts only about 10% to 12% of the combined output of both the left and right ventricles. This probably explains why in healthy full-term infants the diameter of the aortic isthmus is about three-fourths that of the descending aorta; this difference usually disappears by about 6 months of age.

Pathologic hypoplasia of the aortic arch is noted most commonly in the aortic isthmus but may occur in other parts of the aortic arch. The most severe form of this lesion is complete interruption of the aortic arch. With rare exceptions, infants with aortic arch interruption or hypoplasia have associated major congenital cardiac defects, such as a large ventricular septal defect, DORV, Taussig-Bing anomaly, tricuspid atresia with aortopulmonary transposition, truncus arteriosus, or AV septal defect. During the newborn period, the ductus arteriosus is invariably patent. The reason for these associations is that aortic outflow obstruction associated with these intracardiac lesions may divert flow during fetal life, with a consequent reduction in the growth of the aortic arch. The clinical course of infants with these lesions is dictated by the intracardiac lesions (usually a ventricular septal defect with or without other complicating defects), by the magnitude of right-to-left flow across the ductus arteriosus, and by the degree of obstruction of the aorta.

With complete interruption, descending aortic flow is provided only by right-to-left flow through the ductus arteriosus. In hypoplasia of the arch, some of the descending aortic blood flow will pass through the aortic arch, with the amount depending on the severity of the obstruction and the ability of the left ventricle to overcome the increased afterload. Because there is generally a significant left-to-right shunt across a ventricular septal defect, the increased pulmonary blood flow and pressure usually delay the normal postnatal fall in pulmonary vascular resistance. The elevated pulmonary vascular resistance promotes right-to-left shunting into the descending aorta through the patent ductus arteriosus and maintains lower body flow. Initially, while the ductus arteriosus is dilated, there may be no arterial blood pressure difference between the upper and lower body. There may be cyanosis of the toes and feet with normal color of the fingers and hands because of the right-to-left shunt at the ductus arteriosus level. However, with progressive constriction of the ductus arteriosus, the lower body arterial blood pressure falls, and its pulse pressure narrows. The progressive fall in pulmonary vascular resistance after birth further interferes with the flow of blood across the ductus arteriosus because flow will preferentially go through the pulmonary circulation rather than to the lower body. Left ventricular myocardial performance, already affected by the increased afterload, is further stressed by this volume load so that there may be severe left ventricular failure. The time course of these changes varies. As perfusion to the lower body further decreases, metabolic acidemia develops, and there may be oliguria or anuria related to inadequate renal blood flow.

In many infants, the clinical presentation of these lesions is that of a large left-to-right intracardiac shunt with left-sided failure. In some of these, the hypoplasia is not severe, and the arch anomaly is only of secondary importance, but in others, the arch may be severely hypoplastic or even interrupted. Two-dimensional echocardiography defines clearly the intracardiac abnormalities associated with aortic arch interruption. Clear definition of the arch itself, however, is not always possible with echocardiography alone and may require cardiac magnetic resonance imaging or catheterization with angiography.

Infants with aortic arch narrowing and an associated intracardiac lesion may respond to medical management, with prostaglandin E1 infusion to restore ductal patency being the most important medication. After dilation of the ductus arteriosus, lower body perfusion is often restored, renal function returns, and the infants clear acidemia. This temporizing measure then allows stabilization before surgery. Surgical repair should be done, even in premature infants, if the narrowing is severe or the arch is interrupted. At the time of correction of the aortic arch anomaly, surgical measures to correct or palliate the intracardiac lesion may be necessary.

LOCALIZED JUXTADUCTAL COARCTATION OF AORTA

Several terms, such as postductal or adult-type coarctation, have been applied to this lesion. However, localized narrowing of the aorta (coarctation of the aorta) is always closely related to the insertion of the ductus arteriosus into the aorta; in fact, the posterolateral shelf that forms the localized narrowing is generally directly opposite to the ductus arteriosus. For this reason, the term juxtaductal aortic coarctation is more appropriate. With closure of the ductus arteriosus and growth of the child, the usual concentric obstruction seen in older children and young adults develops. Unlike hypoplastic aortic arches, major intracardiac anomalies are not commonly found with isolated coarctation of the aorta; however, there is a high association of this lesion with Turner syndrome and with bicuspid aortic valve. Other associated abnormalities include aberrant origins of the subclavian arteries, ventricular septal defect, persistent patency of ductus arteriosus, and the group of defects associated with parachute mitral valve.

Because the ductus arteriosus is wide during fetal life, localized juxtaductal coarctation is unlikely to produce significant alteration in the distribution of blood flow during fetal life, and fetal development is normal. After birth, the ductus arteriosus constricts at its pulmonary artery end first, so that although the ductus is functionally closed, an aortic ampulla of the ductus arteriosus persists for several days to several months. There is generally a progressive reduction in the size of the ampulla as the ductus arteriosus constricts toward its aortic end. If there is a juxtaductal aortic coarctation directly opposite the aortic end of the ductus arteriosus and the aortic ampulla remains moderately large, the posterolateral shelf does not impede flow from the ascending aorta to the descending aorta, so there will be no clinical evidence of the coarctation. However, as the aortic end of the ductus arteriosus constricts, blood flow becomes obstructed; obstruction is facilitated by constriction of an extension of ductus smooth muscle that forms a sling around the posterior shelf. If the posterolateral shelf is large and obstruction develops rapidly, a sudden increase in afterload to the left ventricle causes left ventricular failure.

CLINICAL FEATURES

The clinical presentation is often similar to that of severe aortic stenosis in the neonatal period and mimics the circulatory collapse associated with overwhelming sepsis. Significant left-to-right atrial shunting may occur through a stretched foramen ovale, and when there is severe left ventricular failure, all pulses may be weak. However, with improvement in left ventricular function, a significant pressure difference (usually > 20 mm Hg) develops between the arms and the legs. Because there has been no obstruction during fetal life and heart failure has occurred rapidly, collateral circulation is not usually well developed in the newborn. Specific murmurs are not a feature of this lesion in infancy; however, if the ductus arteriosus is still patent, a continuous murmur may be heard at the upper left sternal border. As with aortic stenosis in infancy, the electrocardiogram typically shows right-axis deviation and right ventricular hypertrophy. The chest radiograph shows marked generalized cardiomegaly with pulmonary venous congestion secondary to left ventricular failure. Two-dimensional echocardiography can usually define the anatomy of the coarctation and, together with evaluation of the Doppler velocity signals in both the ascending and descending aorta, can assess the severity of the obstruction. If the anatomy is not clarified by echocardiography, then magnetic resonance imaging or aortography should be done. In general, infants who have rapidly developed severe congestive heart failure from a coarctation in the neonatal period respond poorly to medical treatment, and surgical excision of the coarctation should be performed as soon as the patient is stable. If left ventricular function is severely depressed, inotropic support should be given. Infusion of prostaglandin E₁ (PGE₁) is essential in preparation for surgery, as it usually relaxes the ductus arteriosus muscle, permitting blood to flow around the constricting shelf and relieve the acute aortic obstruction.

If the aortic shelf is not prominent, or the ampulla of the ductus arteriosus occludes gradually, aortic obstruction develops slowly over several weeks or months. Rapid left ventricular failure is less likely because compensatory mechanisms such as myocardial hypertrophy and development of collateral circulation have time to occur. Collateral anastomoses generally involve the periscapular, intercostal, transverse cervical, and internal mammary arteries. If there are large collateral vessels, only minor pressure differences may be apparent between the ascending and descending aorta at rest; larger differences may be brought out by exercise. Heart failure may appear at 3 to 6 months as the coarctation becomes more severe. However, if heart failure does not occur by 6 months of age, it is rare until adult life. In older children, the presenting symptoms may be headaches related to hypertension in the ascending aorta or to intermittent claudication due to decreased blood flow to the legs during exercise. Cerebrovascular accidents associated with hypertension are rare before the age of 7 years and may be associated with rupture of berry aneurysms. Hypertension above and below the coarctation has been described, but the mechanism is unclear. Intimal thickening of the coronary arteries may occur. Infective endocarditis is also seen with coarctation and usually involves the aortic wall in the dilated poststenotic segment, but it may occur on the bicuspid aortic valve.

The clinical findings in a child with coarctation of the aorta can include palpable collateral arteries above the clavicle and over the lateral and inferior scapular margins. The arm pulses are strong, but femoral pulses are decreased and delayed relative to the arm pulses. Because there is a high association of abnormality of one of the subclavian arteries, palpation of both subclavian arteries as well as carotid arteries should be routine. An aberrant right subclavian artery arising below the coarctation gives a low blood pressure in the right arm; the left subclavian artery arises normally but may be hypoplastic, so that left arm pressures also may be low. Blood pressure measurements in the arm and leg confirm the palpated differences. Depending on the severity of the coarctation, the heart may or may not be enlarged, and an increased left ventricular impulse palpable. The heart sounds are generally normal; however, with hypertension or an associated bicuspid aortic valve, an ejection systolic click and a third heart sound may be heard. Soft high-frequency continuous murmurs are often audible over the large collateral vessels. A short, soft ejection systolic murmur may be heard at the upper sternal area or posteriorly to the left of the spine.

The chest radiograph has several classic features. Cardiac enlargement and left ventricular enlargement depend on the severity of the stenosis. The ascending aorta is often dilated and displaces the superior vena cava to the right. On the left border of the aortic arch and descending aortic shadow, the area of poststenotic dilation below the coarctation and the dilated aortic segment just above the coarctation may be seen as the “3” sign. Notching of the lower margin of the ribs at about the junction of the middle and medial thirds, caused by erosion of the bone by large intercostal arteries, may be seen after 1 year of age in half the patients. The electrocardiogram demonstrates left ventricular hypertrophy from the obstruction. Older children may have ST depression and T-wave flattening or inversion in left chest leads, but these changes are uncommon. Two-dimensional echocardiography and color Doppler flow mapping are valuable in assessing the anatomy of the coarctation and the adjacent aorta and vessels; Doppler evaluation can estimate the pressure difference across the coarctation but usually exaggerates the severity as compared to upper to lower extremity blood pressure measurements. Magnetic resonance imaging can accurately define the anatomy and should be performed if the echocardiogram is unclear.

TREATMENT

If the coarctation is not treated, there may be persistent hypertension, rupture of a berry aneurysm of the circle of Willis, congestive heart failure, infective endocarditis, hypertensive encephalopathy, or rupture of the aorta; the latter has been reported only in adults. For these reasons, treatment is recommended at the time of diagnosis. Surgery remains the treatment of choice in infants and young children. Excision with direct anastomosis is the surgical technique of choice whenever possible; however, widening of the aorta with a patch or part of the subclavian artery to reduce the chances of recoarctation is sometimes necessary. Some surgeons mobilize the descending aorta and then pull it up to anastomose with the underside of the arch that has been opened. This method not only eliminates the coarctation but also repairs a hypoplastic arch at the same time. Recurrent obstruction is uncommon after this procedure. Surgery has become very safe and effective, even for neonates. Recoarctation is more common if surgery is done before 2 years of age; however, its incidence is decreasing with improved surgical techniques. There is evidence that the earlier the repair, the less likely there is to be persistent “essential” hypertension that sometimes follows coarctation surgery. Balloon angioplasty for older children and angioplasty with stent placement for adolescents and adults are excellent less invasive therapeutic alternatives to surgery. This treatment requires minimal hospitalization with return to full activities within 2 days. Balloon angioplasty of both native (unoperated) coarctation and postoperative recoarctation is effective in 80% of patients and has become the treatment of choice for all recoarctation patients. Angioplasty with stent placement is effective in over 95% of patients but has been reserved for older children and adults because of the limitations of stent size on vessel growth.

POSTCOARCTECTOMY SYNDROME

Fever, abdominal pain of varying degree, abdominal distension, nausea, and vomiting may commence 1 to 3 days after surgical repair of aortic coarctation and last for several days. Systemic hypertension is always present, and renin levels are very high. In the most severe forms, infarction of segments of bowel has occurred, but in most children the syndrome is mild. This complication may be secondary to arteritis in thin mesenteric and renal arteries suddenly perfused with pulsatile flow at pressures higher than those to which they have previously been exposed. The mainstay of treatment is to lower blood pressure with antihypertensive agents. Other therapy includes fluid and electrolyte maintenance and, if necessary, abdominal decompression by nasogastric suction. Rarely, resection of an infarcted area of bowel becomes necessary.

PSEUDOCOARCTATION

Increased length of the aortic arch occurs occasionally and is probably due to retention of the third rather than the fourth cervical arch. The high arch position causes kinking of the descending thoracic aorta. Murmurs caused by turbulent flow across the arch, as well as minor pressure differences between the arms and the legs, may lead one to suspect a true coarctation of the aorta. The diagnosis is made by either cardiac catheterization with angiocardiography or magnetic resonance imaging; the distal portion of the aortic arch is generally angled anteriorly, and there is no posterolateral shelf. Usually, no specific treatment is required, although rarely, aortic dissection has been reported in adults.

ABDOMINAL COARCTATION

Obstruction of the lower thoracic or abdominal aorta by an intrinsic narrowing (middle aortic syndrome) is considerably less common than the usual form of coarctation of the aorta. Rather than the short segment of constriction seen in juxtaductal coarctation, a long narrow segment is usually present, and 1 or several major branch arteries of the abdominal aorta are usually involved. The lesions may be congenital or due to some inflammatory change as seen in giant cell arteritis or Takayasu syndrome. The diagnosis is generally suspected when there is a difference between the upper- and lower-limb pulse volumes and arterial blood pressures without any indication of thoracic collateral arterial circulation or a murmur in the chest. A systolic or continuous murmur is frequently heard over the abdomen and is best heard posteriorly. The diagnosis is confirmed by 2-dimensional echocardiography with Doppler, computed tomography, magnetic resonance imaging, or cardiac catheterization and angiocardiography. Treatment involves surgical removal of the obstructed segment, which may be difficult because arterial branches to vital organs may be involved in the coarcted segment. If the area is not adjacent to major abdominal aortic branches, angioplasty with stent placement can be effective in the older patient.

RIGHT HEART OBSTRUCTION

Right heart obstruction can occur in the pulmonary capillary bed, pulmonary arteries, pulmonary valve, right ventricular outflow tract, tricuspid valve, and systemic veins. The responses of the right ventricle to an increased afterload are similar to those described for the left ventricle. Right ventricular hypertrophy produces a forceful slow lift felt best along the left sternal border and behind the sternum. If there is pulmonary hypertension, the pulmonary artery may be felt in systole in the third interspace at the left sternal border, the pulmonic component of the second heart sound is accentuated, and there may be an ejection systolic click at the base. The ventricle appears enlarged on chest radiograph only if dilated; even if the heart is not enlarged, the apex may be tipped up. If there is pulmonary hypertension, the main pulmonary artery may be enlarged. The electrocardiogram shows right-axis deviation, tall R waves, or a qR complex in the right precordial leads, and there may be upright T waves at an age when they should be inverted or deep inversion of the right precordial T waves, described as a strain pattern.

When right atrial pressure rises, systemic venous return is obstructed, and systemic venous pressure rises. Should the systemic venous pressure be elevated, characteristic enlargement of liver and spleen and distention of the jugular veins occur. Peripheral edema of the soft tissues is a late finding, very uncommon in younger children.

Right atrial pressure elevation is usually the result of right ventricular failure. Right ventricular pressure elevation is frequently the result of pulmonary hypertension caused by a raised pulmonary venous pressure, which in turn follows left ventricular failure. Because left ventricular pressure overload, as in coarctation of the aorta, can cause a right ventricular pressure overload via a raised pulmonary venous pressure and vascular resistance, it is possible for the clinical picture of left heart obstruction to be dominated by the right ventricular signs.

SYSTEMIC VENOUS OBSTRUCTION

Obstruction to superior or inferior vena caval return may result from an extrinsic lesion such as a mediastinal mass or an intrinsic lesion such as thrombosis, or it may occur secondarily to intracardiac surgical procedures such as an atrial baffle procedure for transposition of the great arteries. Acute obstruction may present with venous distension and edema of that portion of the body drained by the obstructed vein. Peripheral organs, particularly the liver and spleen, become congested and enlarged, and peripheral edema may result. Increased systemic venous pressure in the intestine may result in bowel edema and, eventually, ascites, leading to poor food absorption, nausea, vomiting, and abdominal pain. However, collateral venous channels generally form rapidly, and these signs soon diminish. Venous collateral channels may be evident superficially. If symptoms persist, treatment by either surgical patch or balloon angioplasty with stent placement can be effective. Congenital interruption of the inferior vena cava occurs commonly with cardiac and visceral malposition; polysplenia is commonly associated. Venous drainage takes place through an enlarged azygous system, and there is usually no venous obstruction.

OBSTRUCTION IN THE RIGHT ATRIUM

A tumor in the right atrium, generally a myxoma but occasionally an extension of a Wilms tumor or a hepatic tumor, may obstruct venous return. The clinical presentation usually mimics that of tricuspid stenosis, with intermittent obstruction when there is a myxoma. Right atrial myxomas are far less common than those in the left atrium. Thrombus formation in the right atrium may also produce venous obstruction; this is rare in children but may complicate indwelling caval or atrial catheters.

TRICUSPID VALVE OBSTRUCTION

The most severe form of tricuspid valve obstruction is tricuspid atresia (see Tricuspid Atresia below). Isolated congenital tricuspid stenosis is rare, and more often underdevelopment of the tricuspid valve and its annulus is associated with underdevelopment of the whole right ventricle. Underdevelopment of the right ventricle (hypoplastic right ventricle) is usually associated with either severe pulmonic stenosis or pulmonary atresia. Whether or not the ventricular septum is intact, a hypoplastic right ventricle generally presents in infancy with severe cyanosis as a result of right-to-left shunting at the atrial level.

If the interatrial septum is intact, the physical findings of tricuspid stenosis include those of venous obstruction. On auscultation, there is usually a mid-diastolic rumbling murmur at the lower left sternal border as well as a prominent third sound, and in severe stenosis, there is an audible fourth sound. The electrocardiogram may show tall peaked P waves indicative of right atrial enlargement, and the latter may be seen also on the chest radiograph.

Treatment of tricuspid stenosis often depends on the associated right heart abnormalities. Isolated valve stenosis can be repaired surgically with an annuloplasty. Associated right ventricular hypoplasia may ultimately require a palliative approach with placement of a Glenn shunt (superior vena cava to right pulmonary artery), thereby requiring the small right ventricle to pump only the lower body blood flow.

RIGHT VENTRICULAR OUTFLOW OBSTRUCTION

As with left ventricular outflow obstruction, right ventricular outflow obstruction may occur at the level of the pulmonic valve or above or below the valve leaflets. Valvar pulmonic stenosis is the most common form of right ventricular outflow obstruction. Complete obstruction, pulmonary atresia, is discussed below in Pulmonary Atresia.

VALVAR PULMONIC STENOSIS

In valvar pulmonic stenosis, the valve annulus is usually normally formed, but there are abnormalities of the valve leaflets. In less severe forms, there are 3 normally formed cusps, but the raphae are partly fused, so that the leaflet movement is restricted. In more severe forms, there is less clear separation of the cusps, which are thickened to varying degrees and form a dome in systole. Right ventricular hypertrophy occurs in response to the valve obstruction, with significant infundibular (subvalvar) stenosis developing in more severe forms of valvar pulmonic stenosis; this tends to be progressive, producing a secondary outflow obstruction. With the more severe forms of valvar pulmonic stenosis, the valve annulus and even the entire main and major branch pulmonary arteries may be underdeveloped (hypoplastic). In children with Noonan syndrome, there is a high incidence of valvar pulmonic stenosis with thick myxomatous cusps.

Somatic development is usually normal at the time of birth in infants with pulmonic stenosis. Although the right ventricle is normally the dominant ventricle in the fetus and ejects 55% to 65% of the combined ventricular output, total fetal cardiac output is probably normal in the face of right ventricular outflow obstruction. Systemic venous return is probably diverted across the foramen ovale and ejected by the left ventricle, which assumes dominance. The wider-than-normal ascending aorta and aortic isthmus found in infants with severe pulmonic stenosis or pulmonary atresia supports this thesis.

With valvar pulmonic stenosis, development of the right ventricle and tricuspid valve in the fetus probably depends on the stage of gestation at which the stenosis occurs. If stenosis develops early in gestation, venous return is likely to be diverted across the foramen ovale, with subsequent underdevelopment of the right ventricle and the tricuspid valve and even eventual development of pulmonary atresia. However, if the stenosis occurs later, right ventricular development is more likely to be normal.

CLINICAL FEATURES

Severe pulmonic stenosis presents in the immediate postnatal period and resembles pulmonary atresia with severe cyanosis and cardiovascular collapse as the ductus closes. In moderately severe pulmonic stenosis during infancy, mild cyanosis may be present if the foramen ovale remains patent. However, if the foramen ovale becomes sealed, the cyanosis disappears. Right ventricular failure may become evident after about 6 months, but if it does not occur at that time, it is generally delayed until adulthood. Right ventricular failure will be evidenced by rapid onset of hepatomegaly, prominent pulsatile neck veins (large a waves), and a low-output state.

Most children have mild or moderate pulmonic stenosis, are asymptomatic, and are detected because of a murmur. Many of the physical findings of pulmonic stenosis correlate roughly with the severity of the stenosis. When right ventricular enlargement is produced, a fairly diffuse forceful parasternal impulse along the lower left border of the sternum may be palpable. A systolic thrill is often palpable at the upper left sternal border. The first heart sound is usually normal but may be accentuated. A systolic ejection click is often heard along the entire left sternal border and is softer in patients with severe stenosis.

The murmur of pulmonic stenosis is an ejection systolic murmur of the crescendo-decrescendo type best heard at the upper left sternal border, with radiation to the left infraclavicular area. The frequency of the murmur correlates with the severity of stenosis, with higher frequencies heard with severe stenosis and low to medium frequencies heard with mild stenosis. During the Valsalva maneuver, as intrathoracic pressure is increased and systemic venous return and right ventricular stroke volume are reduced, the murmur of pulmonic stenosis decreases immediately unless there is congestive heart failure or severe infundibular hypertrophy.

The electrocardiogram shows right atrial hypertrophy with peaked P waves. There will also be right ventricular hypertrophy and right-axis deviation, with the degree depending on the severity of the stenosis. The right precordial leads show tall R waves, and with severe stenosis, they may also show T-wave inversion and ST-segment depression.

The chest radiograph shows right ventricular prominence with an upturned apex. The magnitude of enlargement depends on the severity of the stenosis and subsequent development of right ventricular hypertrophy. The main and left pulmonary arteries are prominent because of poststenotic dilation. The pulmonary vascular markings are generally normal but may be slightly diminished. Valve cusp thickening, annular narrowing, right ventricular free wall thickening, and pulmonary arterial enlargement are seen on 2-dimensional echocardiography. Doppler examination reliably indicates the severity of the obstruction.

TREATMENT

Some children with moderate stenosis show little or no change in right ventricular systolic pressure over many years, indicating that the valve orifice has enlarged with growth. However, other children have a marked increase in right ventricular systolic pressure, suggesting either inadequate growth of the pulmonic valve orifice, development of infundibular stenosis, or both. If this should occur, right ventricular end-diastolic pressure eventually rises, and right heart failure may develop. In general, mild stenosis over 2 years of age indicates the ability of the valve orifice to grow to keep pace with the increase in stroke volume. These children are unlikely to get more severe stenosis. However, in a child seen early in infancy, the growth potential of the valve is unknown, and a mild stenosis at 3 months may occasionally become a severe stenosis by a year of age. Therefore follow-up in infancy needs to be more frequent than in older children.

Mild valvar pulmonic stenosis with a small increase in right ventricular systolic pressure may not affect right ventricular output or the right ventricular myocardium significantly. In many instances, with growth of the child, there is little or no increase in right ventricular systolic pressure, and minimal right ventricular hypertrophy may occur. The long-term outcome for mild right ventricular pressure elevation is excellent, with minimal impact on cardiac function until late adult years, if ever.

Children with severe stenosis (right ventricular systolic pressure greater than systemic) should undergo immediate pulmonary balloon valvoplasty or, if this cannot be done, surgical valvotomy. The majority of children with severe valvar pulmonic stenosis also have infundibular hypertrophy; however, this regresses once the valvar stenosis is relieved. All symptomatic patients with exercise intolerance or fatigue and those with significant right ventricular hypertrophy should be treated, even if the measured gradient is relatively mild. Without symptoms or hypertrophy, a right ventricular systolic pressure of over 50 mm Hg in children warrants treatment because over a prolonged period such pressure elevation may lead to myocardial fibrosis. Balloon valvoplasty done at cardiac catheterization is the treatment of choice in most patients, even infants; it can be performed as an outpatient procedure using sedation alone. The relief of obstruction is excellent with minimal short- or long-term complications (see Chapter 490).

SUBVALVAR PULMONIC STENOSIS

Isolated diffuse infundibular pulmonic stenosis with a normal pulmonic valve is rare. It is more likely to be associated with a ventricular septal defect. The most common type is tetralogy of Fallot, where the aorta overrides a large outlet VSD and the right ventricular outflow tract is displaced medially, causing subvalvar pulmonic obstruction (see Tetralogy of Fallot below). Double-chambered right ventricle, also quite common, is caused by large aberrant muscular bands that divide the right ventricular cavity into 2 separate chambers and obstruct flow through the subpulmonic infundibular area. This anomaly is usually but not always associated with a ventricular septal defect, is often progressive, and should be treated if significant obstruction is present or there is evidence of right ventricular hypertrophy. Treatment by surgical resection of the aberrant muscle bundles with closure of the ventricular septal defect is usually curative.

Diffuse interventricular septal hypertrophy secondary to marked left ventricular hypertrophy may bulge into the right ventricle or outflow tract and thereby produce obstruction (Bernheim effect). Myocardial tumors, particularly those involving the interventricular septum, may also produce right ventricular outflow obstruction.

The clinical features of these lesions are similar to those of valvar pulmonic stenosis. An ejection click is less commonly heard, however, and poststenotic dilation of the pulmonary artery is less prominent or absent. The systolic murmur is usually maximal at the third or fourth interspace along the left sternal border. These findings lead one to suspect subvalvar stenosis, and the diagnosis can be confirmed by echocardiography. If the anatomy or the degree of obstruction is not well defined by echocardiography, then cardiac catheterization or magnetic resonance imaging is needed before surgical repair can be done.

SUPRAVALVAR PULMONIC STENOSIS

Stenosis of the major pulmonary arteries may occur anywhere along the entire length of the pulmonary arterial tree. Obstruction may be single or multiple and may be by a diaphragm, localized narrowing, or more diffuse constrictions. Often there are long hypoplastic segments as well as multiple areas of discrete stenosis. There is often an association with intrahepatic cholestasis (Alagille syndrome).

STENOSIS OF MAIN PULMONARY ARTERY

In stenosis of the main pulmonary artery, a constricting ring is usually present in the main pulmonary artery, either at or shortly beyond the tips of the pulmonic valve leaflets. This type of stenosis is commonly associated with rubella syndrome and presents as a thick fibrous ring. In addition, children with peculiar facies and associated supravalvar stenosis without a history of rubella have been reported, and in them, a thin supravalvar diaphragm is present. The clinical findings in this lesion are similar to those of valvar pulmonic stenosis, but the second heart sound is usually normal. The diagnosis can be made at cardiac catheterization or by echocardiography. Although balloon dilation has been tried, results are poor. Optimal treatment is surgical patch repair. Immediate results are excellent, although there is a small incidence of restenosis at the patch site because of poor growth or scar tissue formation.

PERIPHERAL BRANCH STENOSIS

In the newborn period a physiologic branch pulmonary arterial stenosis is present, and it accounts for innocent murmurs in many infants up to 6 to 12 months of age. True peripheral pulmonary arterial branch stenosis or hypoplasia may occur as an isolated defect or may be associated with underdevelopment of part or all of 1 lung or with underdevelopment of the right heart. Peripheral pulmonary arterial stenosis is frequently noted in infants with rubella syndrome, often in association with patent ductus arteriosus. Peripheral branch pulmonary arterial stenosis may also be found with other intracardiac congenital heart diseases, especially tetralogy of Fallot, and with Alagille syndrome.

The clinical features vary and may mimic either valvar pulmonic stenosis or a patent ductus arteriosus. The murmur is generally harsh and systolic and suggestive of pulmonic stenosis, but it usually has wider radiation into the infraclavicular regions (particularly toward the right) and the axillae; occasionally the murmur is continuous. The murmur is heard better in the axillae than at the base. The second heart sound is not consistently altered, and an ejection click is unusual. The electrocardiogram shows right ventricular hypertrophy in the more severe lesions; in rubella syndrome, left-axis deviation is common. The chest radiograph may show right ventricular enlargement and occasionally shows multiple dilated pulmonary artery segments caused by poststenotic dilation. If the peripheral stenosis involves only 1 lung or 1 segment of lung, undervascularization of that segment may be evident. Central stenoses may be shown by 2-dimensional echocardiography, but peripheral stenoses are often less well-defined. Echocardiography is useful at estimating the right ventricular pressure. In addition, radionuclide pulmonary flow scans can demonstrate the presence and physiologic significance of peripheral pulmonary artery stenoses. To define the location and anatomy of these defects, magnetic resonance imaging or cardiac catheterization with angiography is often necessary. Treatment depends on the severity and the number of stenoses; multiple peripheral lesions in the parenchyma of the lung can be treated with interventional catheterization techniques (see Chapter 490), whereas more central lesions may be better relieved surgically. Transvascular placement of stents has markedly improved the ability to dilate branch pulmonary arteries and to maintain dilation even of tortuous or kinked vessels; multiple as well as more peripheral stenoses are also manageable by this approach.

RIGHT-TO-LEFT SHUNTS

In the normal circulation, all the systemic venous return of desaturated or right-sided blood is directed via the right atrium and ventricle to the pulmonary arteries for oxygenation, and the fully saturated pulmonary venous blood is returned via the left atrium and ventricle to the aorta to provide oxygen for the body. Many congenital heart lesions are associated with redirection of some of the right-sided blood to the aorta, thus causing systemic arterial hypoxemia that leads to cyanosis. This pathophysiologic process is called a right-to-left shunt. (Diversion of some of the oxygenated blood back into the lungs is termed a left-to-right shunt.) The pathophysiology and initial of congenital heart defects presenting in infancy with right-to-left shunts are discussed in detail in Chapter 478. Specific lesions are further described below.

PATHOPHYSIOLOGIC CLASSIFICATION

Three pathophysiologic groups are associated with right-to-left shunts. Each group has fairly reproducible pathophysiologic processes that dictate the clinical presentation. The first group has a right-to-left shunt only. Because systemic blood flow is normal in these patients, the right-to-left shunt must necessarily decrease pulmonary blood flow—the less the pulmonary blood flow, the more the cyanosis. The second group has normal to increased pulmonary blood flow but is associated with cyanosis because the aorta is transposed over the ventricular septum. Thus, the aorta primarily receives systemic venous return, and the patient usually presents with severe cyanosis. The third group of defects not only has a right-to-left shunt and thus some systemic arterial desaturation but also has a left-to-right shunt. Frequently the blood is fully mixed in the heart, and the degree of cyanosis depends on the relative pulmonary and systemic blood flows. If neither circulation is obstructed, much more blood tends to be delivered to the lungs because, even at birth, pulmonary vascular resistance is less than systemic. The elevated pulmonary blood flow in these patients limits the degree of cyanosis, and their symptoms usually are related to the elevated pulmonary blood flow, which frequently causes respiratory symptoms and failure to thrive.

PURE RIGHT-TO-LEFT SHUNT (DECREASED PULMONARY BLOOD FLOW)

GENERAL

Pure right-to-left shunts occur when the inflow or outflow of the right side of the heart is redirected or obstructed or when one of the right-sided valves is regurgitant. It is best to think of this group of lesions along lines of blood flow (Table 479-4). For example, the first level of redirection of flow is at the level of the systemic veins, some of which can flow directly into the left atrium, as occurs in an unroofed coronary sinus. The first level of obstruction or regurgitation within the heart is at the tricuspid valve. Obstruction may be caused either by complete absence of the valve (tricuspid atresia) or stenosis (hypoplastic right heart syndrome). Tricuspid regurgitation may be secondary to perinatal asphyxia, causing transient papillary muscle dysfunction, or may be secondary to a primary valve abnormality, as in Ebstein malformation. Whatever the cause, right atrial pressure is elevated, and thus systemic venous blood is directed across the atrial septum to the left side of the heart and causes cyanosis. Obstruction of the outflow of the right ventricle can occur with a ventricular septal defect (tetralogy of Fallot) or without it (critical pulmonary stenosis or pulmonary atresia with intact ventricular septum). Pulmonary arterial stenoses usually occur in association with tetralogy of Fallot but can be isolated, as in Williams syndrome. Last, pulmonary arterial blood flow can be redirected just before it is about to reach the capillary bed for oxygenation, as occurs in pulmonary arteriovenous malformations.

INITIAL PRESENTATION

The degree of cyanosis is determined by the amount of pulmonary flow in these patients. In neonates with critical obstruction or insufficiency, systemic arterial oxygen tension falls rapidly over the first hours or days of life, and PGE₁ infusion is essential to maintain adequate pulmonary blood flow via the ductus arteriosus. In any newborn with significant cyanosis in the first hours of birth, infusion of PGE₁ should be started immediately on the assumption that pulmonary blood flow is compromised. Oxygen therapy is of very limited value because pulmonary blood flow is decreased and pulmonary venous blood is nearly fully saturated, but it may increase oxygen content in the blood slightly by adding oxygen dissolved in the blood. If hemoglobin concentrations are low, blood transfusions can increase oxygen uptake in the lung by increasing the amount of hemoglobin to which the oxygen can bind.

Metabolic acidemia is rarely present unless the cyanosis is extremely severe (usually < 65%). Prostaglandin E₁ will usually rapidly increase pulmonary blood flow and lead to resolution of the acidosis, but if acidosis is moderately severe, intravenous infusions of sodium bicarbonate can be given. The infant should also be kept at an optimal temperature (skin temperature about 36.5°C) to minimize oxygen needs. In the very sick infant, tracheal intubation, muscle paralysis with neuromuscular blocking agents, and mechanical ventilation may conserve energy and ensure the best possible ventilation. These very sick infants often have acute gastric dilation, and removal of stomach contents and limitation of oral intake may be necessary to prevent aspiration. In some patients, inhaled nitric oxide 20 ppm can be attempted as saturations stabilize.

Hypoglycemia is common because anaerobic metabolism accelerates glycolysis. Blood glucose levels should be checked early, and glucose infusions should be given if the levels are low. Hypocalcemia may occur and also should be treated.

Definitive diagnosis is usually made by echocardiography. Cardiac catheterization is rarely indicated except for those in whom the catheterization may be therapeutic (such as balloon pulmonary valvoplasty in infants with critical pulmonary stenosis or coil embolization of pulmonary arteriovenous malformations). Unlike patients with transposition of the great vessels, the atrial communication is usually large, and thus balloon atrial septostomy is rarely indicated. This is because the obstruction is present in utero, and thus a much larger amount of blood than the typical 35% to 45% of combined venous return crosses the foramen ovale to the left atrium and ventricle. The increased blood flow across the foramen ovale is thought to increase the size of the foramen ovale and lead to true secundum atrial septal defects in many infants. Diagnostic catheterization is generally reserved for patients with pulmonary arterial abnormalities (eg, patients with pulmonary atresia, ventricular septal defect, and major aortopulmonary collaterals), because echocardiography does not afford a good view of the peripheral pulmonary vascular bed.

LONG-TERM MEDICAL THERAPY

Although most patients with cyanotic heart disease due to right-to-left shunting now undergo definitive or at least palliative procedures at a very early age to increase pulmonary blood flow and systemic arterial oxygen saturation to acceptable levels, some patients either do not present to medical care or are not amenable to corrective procedures. These patients have sequelae of chronic cyanosis. The most common group of patients with chronic, persistent cyanosis are those with severe tetralogy of Fallot (with or without pulmonary valve atresia) who have extremely abnormal pulmonary vascular beds that are unable to accept normal amounts of blood flow, so that the ventricular septal defect cannot be closed. Patients with inflow obstruction to the right side of the heart tend to progress to Fontan procedures at about 2 to 4 years so that cyanosis is resolved.

Polycythemia with increased hemoglobin and hematocrit is an important consequence of arterial oxygen desaturation; it is a hematopoietic adaptation to the hypoxic stimulus. The increased oxygen content achieved by this compensatory mechanism is advantageous until the hematocrit exceeds about 55%, when the effects of the high blood viscosity begin to outweigh the advantages of the increased circulating oxyhemoglobin. It is important that hypochromic microcytic anemia be recognized in the severely cyanotic patient with high erythrocyte counts but relatively normal hemoglobin and hematocrit levels; this anemia can easily be corrected by oral iron administration.

The increased blood viscosity in severe cyanotic polycythemia may cause cerebral, mesenteric, renal, or pulmonary thromboses. Dehydration increases the danger of thrombosis, and adequate fluid intake should be maintained, particularly during febrile illnesses and hot weather. Anemia (hypochromic microcytic) in association with hypoxemia has also been implicated, particularly in infants, as one mechanism for cerebrovascular accidents.

Brain abscesses may occur in patients with right-to-left shunts because bacteria usually filtered out in the pulmonary circulation may be shunted directly into the systemic circulation.

Cyanotic patients with long-standing severe polycythemia may have thrombocytopenia and abnormalities of the soluble coagulation system, particularly in the older patient; caution is advised in regard to excessive postoperative bleeding.

The prolonged and severe hypoxemia of cyanotic congenital heart disease often results in retarded physical growth that is most striking in the musculature. Preschool children with cyanotic heart disease, as a group, may have slightly lower IQ scores and may perform less well with perceptual motor tasks than do children with acyanotic heart disease.

SPECIFIC LESIONS

Although there are a large number of congenital heart defects associated with decreased pulmonary blood flow, the most prevalent and representative of specific groups of lesions are presented below, based on levels of blood flow.

ABNORMAL SYSTEMIC VENOUS DRAINAGE

Abnormal systemic venous connections are sometimes associated with complex cyanotic malformations, but isolated abnormal systemic venous connections to the heart are rare and relatively occult causes of cyanotic congenital heart disease without any other abnormal clinical signs or findings. These abnormal connections include termination of the right or left superior vena cava, the inferior vena cava, or hepatic vein in the left atrium. A left superior vena cava usually drains into the heart via the coronary sinus, so that the drainage of left superior vena caval blood into the left atrium is often referred to as unroofed coronary sinus. Rarely, a large persistent eustachian valve directs blood from a normally connected inferior vena cava through the foramen ovale. Diagnosis may at times be suspected with careful 2-dimensional Doppler and color echocardiographic examination and 2-dimensional echocardiographic contrast studies, but appropriate venous angiography may be necessary to define operative possibilities.

TRICUSPID ATRESIA

Tricuspid atresia constitutes 1% of all congenital heart disease in the first year of life. There is agenesis of the tricuspid orifice with no opening from the right atrium to the right ventricle, and the only outlet from the right atrium for systemic venous return is an interatrial communication, usually a widely patent foramen ovale. Mixing of the entire pulmonary venous return and systemic venous return occurs in the left atrium; consequently, systemic arterial oxygen desaturation depends on pulmonary blood flow. Left ventricular output is then distributed directly to the aorta and indirectly through a ventricular septal defect or patent ductus arteriosus to the pulmonary vascular bed. Pulmonary blood flow is usually severely diminished in tricuspid atresia because of the small, restrictive ventricular septal defect and the underdeveloped stenotic right ventricular outflow tract. Occasionally, the ventricular septal defect and the right ventricular outflow are widely patent, resulting in unrestricted pulmonary blood flow. Less often, if there is no ventricular septal defect, pulmonary atresia and an extremely hypoplastic right ventricle may be present; pulmonary blood flow must then come from the aorta via a patent ductus arteriosus or aortopulmonary collateral vessels. Increased pulmonary blood flow is uncommon in tricuspid atresia but may occur when the ventricular septal defect is large and the pulmonary outflow tract from the right ventricle is well developed, or when transposition of the great arteries is present and the pulmonary artery arises directly from the left ventricle.

CLINICAL FEATURES

Intense cyanosis usually occurs within hours to days after birth as the ductus arteriosus begins to close, unless the ventricular septal defect and right ventricular outflow tract are widely patent. Right heart failure, manifested by hepatomegaly and occasionally by presystolic hepatic pulsations, is rarely present but will occur if right-to-left shunting is obstructed at the patent foramen ovale. The precordium is quiet. This is an important clinical finding and distinguishes tricuspid atresia from almost all other common forms of cyanotic congenital heart disease except for hypoplastic right heart syndrome. Neonates within this group with outflow obstruction, or neonates with transposition of the great arteries or bidirectional shunts, have either pressure or volume loading of the right ventricle and thus present with either normal or increased right ventricular impulses. There is usually a harsh systolic murmur along the left sternal border caused by flow through the ventricular septal defect and right ventricular infundibular stenosis. The second heart sound is narrowly split, with a soft pulmonary component. If the ventricular septum is intact, there may be no significant murmur or only the very faint continuous bruit of a small patent ductus arteriosus, and the second heart sound is single.

Chest Radiograph

The radiographic findings in the usual infant with tricuspid atresia and small ventricular septal defect include diminished pulmonary vasculature and a small heart with a distinctive rounded or apple configuration resulting from deficiency of the right ventricular and pulmonary artery segments.

Electrocardiography

The electrocardiographic findings of left superior axis deviation and left ventricular hypertrophy are helpful clues because the 2 most prevalent cyanotic heart lesions, tetralogy of Fallot with diminished pulmonary blood flow and complete transposition of the great arteries with increased pulmonary blood flow, usually manifest right-axis deviation and prominent right ventricular forces (both normal for a newborn). Right atrial hypertrophy with prominent peaked P waves in limb lead II is also common, and the P-R interval is often abnormally short. In tricuspid atresia with transposition of the great arteries, the QRS axis is usually in the left lower quadrant, but this is still relatively leftward as compared to a healthy newborn.

Echocardiography

The 2-dimensional echocardiogram readily establishes the absence of a tricuspid orifice and valve leaflet apparatus. Few infants survive beyond 6 months of age without surgical palliation, but for those who do, clubbing, polycythemia, and poor physical development may be apparent.

In contrast, infants with tricuspid atresia and large ventricular septal defect (often with transposition of the great arteries) present with increased pulmonary blood flow and show only minimal cyanosis after the newborn period. Congestive heart failure, with tachypnea, dyspnea, excessive perspiration, hepatomegaly, and pulmonary rales, appears by 3 to 6 weeks of age. In addition, they may present with significantly decreased systemic output due to the underdevelopment or hypoplasia of the aortic arch. The findings in these infants are those of a large left-to-right shunt: precordial hyperactivity, a long harsh pansystolic murmur along the left sternal border, and a prominent mid-diastolic rumbling murmur at the apex. Radiographic findings show increased pulmonary markings and a large cardiac silhouette because of left ventricular enlargement. There is an enlarged left ventricle and usually a hypoplastic right ventricular outflow tract. Tricuspid atresia variants with large ventricular septal defect or with transposition of the great arteries can easily be distinguished, as can more complex tricuspid (right- or left-sided AV valve) atresia malformations with ventricular and great artery inversion.

Cardiac catheterization is rarely indicated in the newborn period because the pulmonary arteries are normally developed and the foramen ovale is usually widely patent. Catheterization is generally reserved for the patient following palliative surgical procedures in anticipation of further surgery.

TREATMENT

Treatment of infants with tricuspid atresia and diminished pulmonary blood flow is surgical and often urgent. After the initial presentation of cyanosis and the subsequent institution of PGE₁, the patient usually undergoes a palliative systemic-pulmonary shunt, a modified Blalock-Taussig anastomosis (with Gore-Tex conduit interposition). The operative survival is excellent (~95%) and with stable and prolonged augmentation of the pulmonary blood flow. In the older infant or young child, the shunt is replaced by a cavopulmonary connection that decreases the amount of blood returning to the left ventricle and thus its work. The typical procedure connects the superior vena cava directly to the main pulmonary artery, which is either banded or completely disconnected from the right ventricle (bidirectional Glenn procedure). A late complication reported with the Glenn shunt has been the occurrence of intrapulmonary arteriovenous shunts in dependent portions of the lungs or large superior-to-inferior vena caval collaterals, both with a resultant increase in cyanosis.

The young child, however, becomes more cyanotic over the next 2 to 4 years of life, as the lower body grows faster than the upper body. The modified Fontan-Kreuzer operation is the final palliative procedure in these children. It diverts the inferior vena caval return directly to the pulmonary arteries, either using an external conduit or a lateral tunnel within the right atrium. After this procedure, all systemic venous blood (except the relatively small coronary circulation, which returns directly to the heart via the coronary sinus) goes directly to the lungs so that the patients are no longer cyanotic. Success of the Fontan operation depends on appropriate selection of patients with adequate-sized pulmonary arteries, low pulmonary artery pressure and vascular resistance, and good left ventricular function without significant mitral regurgitation. The results can be very satisfactory, although there is concern about deterioration 15 years or more after the surgery. Heart failure and atrial arrhythmias are the most common late complications, and there is a significant late mortality secondary to these developments.

Neonates with tricuspid atresia and large ventricular defects, with or without transposition of the great arteries, present with markedly increased pulmonary blood flow and usually have early surgical palliation with pulmonary artery banding to restrict the pulmonary blood flow in order to prevent pulmonary vascular disease. Subsequent medical and surgical approaches to these patients are similar to those for the usual patient with tricuspid atresia. Recently, some institutions have advocated for a palliative arterial switch operation for this anatomy.

EBSTEIN MALFORMATION

This is a rare malformation in which the posterior and septal leaflets of the tricuspid valve are displaced downward and attached anomalously to the right ventricular wall. The abnormally placed tricuspid valve divides the right ventricle into a proximal “atrialized” segment and a distal functional ventricle. The atrialized ventricular segment and the right atrium together are usually enormously dilated, and there is severe tricuspid regurgitation. Hemodynamic abnormalities are related to the extent of the tricuspid regurgitation, to the small size of the remaining functional right ventricle and its outflow (which may be severely obstructed), and to the subsequent degree of right-to-left shunting through a patent foramen ovale.

CLINICAL FEATURES

Wide variations in hemodynamic derangements cause the clinical symptoms to vary widely. In the most extreme lesions, severe tricuspid regurgitation presents in utero, and death occurs secondary to hydrops fetalis. Many neonates present with severe cyanosis. Although this decreases dramatically in the first few days of life because of the rapid perinatal decrease in the pulmonary vascular resistance, some have persistent severe cyanosis that requires placement of a systemic-pulmonary shunt. Those infants usually have severely hypoplastic ventricles and obstructed outflow tracts. The long-term approach for these patients is similar to that of tricuspid atresia or regurgitation, with a modified Fontan circulation being the final palliative procedure. In most patients, cyanosis resolves in the first few days of life and does not recur, if at all, until later childhood or young adulthood. Although there frequently is little limitation to activities during childhood, exercise tolerance eventually deteriorates. Episodes of paroxysmal supraventricular tachycardia occur in 20% to 25% of patients.

On auscultation a characteristic triple or quadruple heart sound rhythm overrides a soft high-pitched systolic murmur (due to elevated pulmonary arterial pressures) of tricuspid regurgitation. There is also a characteristic soft scratchy mid-diastolic murmur at the left sternal border and apex. The second heart sound is usually widely split with little respiratory variation. The radiographic findings include moderate or marked cardiomegaly with striking enlargement of the right atrium and usually diminished pulmonary vascular markings. The electrocardiogram may also be characteristic, usually showing right atrial hypertrophy, prolonged P-R interval, and incomplete or complete right bundle branch block patterns. Preexcitation patterns (Wolff-Parkinson-White syndrome) occur in about 10% to 15%. The 2-dimensional echocardiogram is diagnostic and shows a large tricuspid orifice with apical displacement of the septal leaflet of the tricuspid valve.

TREATMENT

Dysrhythmias can usually be controlled pharmacologically or sometimes by ablating accessory pathways. Surgical treatment is seldom necessary in infancy or childhood. When major tricuspid regurgitation is associated with progressive congestive heart failure, surgical maneuvers directed at realigning the tricuspid valve leaflets to their true annulus, resecting redundant atrialized tissue, or placing a prosthetic tricuspid valve have been done with reasonably satisfactory functional results.

The life expectancy of the patient with Ebstein malformation varies widely, depending on the severity. Because the pathologic substratum is so variable, management of these patients must be individualized. The usual cause of death is congestive heart failure in the second or third decade of life. In the child or young adult, the more severe the cyanosis the poorer is the prognosis; the onset of florid congestive heart failure is usually followed by death within a few years.

PULMONARY ATRESIA WITH INTACT VENTRICULAR SEPTUM

Two percent of infants who present with severe congenital heart disease in the first year after birth have pulmonary atresia or critical pulmonary valve stenosis with intact ventricular septum. The majority have a hypoplastic but thick-walled right ventricle with a markedly hypoplastic tricuspid orifice and valve. About 15% have a right ventricle of normal or large volume, with tricuspid valve incompetence, and these often have critical stenosis rather than atresia. Intermediate forms occur. In all of the patients there is little or no blood flow across the pulmonary valve; rather, systemic venous return crosses the atrial septum to the left heart and the aorta. The pulmonary circulation is sustained primarily through a patent ductus arteriosus.

CLINICAL MANIFESTATIONS

Cyanosis occurs early in the neonatal period, and these infants usually deteriorate rapidly and die unless PGE₁ is started. Gross cardiac failure occurs rarely, and only if there is severe tricuspid incompetence. Similar to tricuspid atresia, the precordium is quiet unless there is marked tricuspid incompetence. If murmurs are heard, they are usually faint. A soft systolic blowing murmur, representing insufficiency of the hypoplastic tricuspid valve, may be heard along the lower left and right sternal borders; a soft continuous bruit of a small patent ductus arteriosus may be heard at the upper left sternal border. The second heart sound at the pulmonary area is single, reflecting only aortic valve closure. On chest radiograph, the infant with a markedly hypoplastic tricuspid orifice shows a small heart; diminished pulmonary vascular markings are the rule, except rarely with a large persistent patent ductus arteriosus or with an infusion of PGE₁. Even with high pulmonary blood flow, however, the central arteries are not large, so the pulmonary vascular markings may appear diminished. Infants with marked tricuspid insufficiency and large right ventricular and atrial volumes have gross cardiomegaly. On the electrocardiogram, left ventricular hypertrophy is common in the first days or weeks of life, but right ventricular hypertrophy becomes evident as the right ventricular muscle hypertrophies further. In contrast to tricuspid atresia, where there is continuing left ventricular hypertrophy and usually a superior left QRS axis deviation, the infant with pulmonary atresia shows an inferior QRS axis, right atrial enlargement, and right ventricular hypertrophy. A 2-dimensional echocardiogram shows the small right ventricle, hypoplastic tricuspid valve, pulmonary valve atresia, and intact ventricular septum. Doppler interrogation sometimes documents retrograde right ventricular coronary sinusoid-to-coronary artery blood flow in systole and may demonstrate flow across the pulmonary valve if there is critical pulmonary stenosis rather than atresia. In contrast to many other lesions, cardiac catheterization is indicated in most patients with pulmonary atresia/critical pulmonary stenosis for both diagnosis and therapeutic reasons. Catheterization shows right atrial hypertension, a massive right-to-left interatrial shunt, and right ventricular hypertension, often with peak systolic pressures far greater than systemic. A right ventricular selective angiogram establishes the diagnosis by demonstrating the obstruction between the right ventricle and the pulmonary artery, and the extent of hypoplasia of the ventricular cavity and tricuspid orifices. In ventricular systole, intramyocardial sinusoids may fill from the dead-end right ventricular cavity and drain retrograde into the coronary arterial system.

Occasionally, there is no connection between some of these coronary arteries and the aorta; this is called a right ventricular dependent coronary circulation. Although the prognosis for pulmonary atresia in general is poor, with midterm survival in the 60% to 80% range, the prognosis for infants with a right ventricular dependent coronary circulation is particularly poor, so it should be sought out in every patient. The pulmonary artery will be seen to fill through a tortuous ductus arteriosus. Pulmonary valvoplasty is attempted in most of these patients, even with atretic valves, as discussed below.

TREATMENT

Immediate intravenous infusion of PGE₁ on diagnosis has greatly improved outcome in these patients. At catheterization, an attempt at pulmonary valvoplasty is made, even if the valve is atretic, except when the tricuspid valve and right ventricle are so diminutive that they cannot contribute significantly to the circulation. If a valvoplasty is successful, PGE₁ is continued for several days because the severe right ventricular hypertrophy prevents adequate filling and the patient remains ductus dependent for adequate pulmonary blood flow. However, the ventricle remodels rapidly if the obstruction is relieved, and the PGE₁ often can be discontinued within a week.

If the valvoplasty is unsuccessful or considered inadequate after 7 to 10 days, surgery is indicated. Patients in whom a right ventricular outflow tract is identified angiographically should have a pulmonary valvotomy performed. A small right ventricular cavity alone does not preclude executing a valvotomy. However, if the coronary arterial supply is mainly from sinusoids, decompression of the right ventricle must be avoided. In infants with an adequate right ventricular size, pulmonary valvotomy alone is advised, but PGE₁ infusion is continued for a few days postoperatively as in pulmonary valvoplasty. If the right ventricle is considered inadequate initially or after several days, a systemic-pulmonary shunt is also performed. In some centers, the ductus is kept open with a stent, but the role of this in comparison to a surgical shunt has not been defined. The valvotomy permits the right ventricle to eject some blood and promotes progressive chamber enlargement, whereas the shunt initially provides the bulk of increased pulmonary blood flow that is essential for survival. The pulmonary valvotomy and shunt performed in the neonatal period for this malformation usually do not provide optimal long-term results. Reoperation 3 to 5 years later usually becomes necessary because of persistent or recurrent right ventricular outflow tract obstruction. The second-stage operation involves right ventricular outflow tract reconstruction and placement of an outflow patch graft with ligation of the shunt. If the right ventricle remains inadequate, either a bidirectional Glenn procedure is performed so that the right ventricle handles only inferior vena caval blood or, in the worst patients, a modified Fontan-Kreuzer procedure is done. If there is a right ventricular dependent coronary circulation and ongoing myocardial ischemia from birth, cardiac transplantation should be considered.

TETRALOGY OF FALLOT

Tetralogy of Fallot is the most common cyanotic heart lesion encountered in untreated patients with cyanotic congenital heart disease who survive beyond infancy. Four structural abnormalities constitute the tetralogy: right ventricular outflow tract stenosis, ventricular septal defect, dextroposition and ventricular septum overriding of the aorta, and right ventricular hypertrophy. There is wide anatomic variation, with resultant physiologic and clinical variations.

The basic lesion is anterocephalad malalignment of the outlet septum relative to the muscular septum. This is associated with unequal division of the truncus arteriosus into small pulmonary and large aortic components. The malalignment together with secondary hypertrophy of the muscle form the primary site of obstruction to blood flow in the infundibulum or outflow tract of the right ventricle. In addition, the pulmonary valve is often stenotic, and the pulmonary valve annulus and pulmonary arteries are often hypoplastic. In the most severe form (tetralogy of Fallot with pulmonary atresia), the distal infundibular outflow tract and pulmonary valve are atretic, and the pulmonary artery and main pulmonary arterial branches may be severely hypoplastic or atretic. Often, large aortopulmonary collaterals supply most of the lung. The ventricular septal defect is usually large, perimembranous with outlet extension, and near the tricuspid and aortic valves. The aorta arises directly over the ventricular septal defect; the degree of overriding varies greatly.

Because of the pulmonary outflow tract obstruction, varying amounts of systemic venous blood are shunted across the ventricular septal defect into the aorta, resulting in cyanosis. Pulmonary artery pressure and pulmonary blood flow are reduced.

CLINICAL FEATURES

The clinical findings at birth vary with the severity of the pulmonary stenosis, but few infants with the tetralogy of Fallot remain asymptomatic or acyanotic. Cyanosis may not be present at birth; as long as the ductus arteriosus remains patent, there may be adequate pulmonary blood flow, or the outflow tract obstruction may not be severe at birth. Hypercyanotic episodes with paroxysmal hyperpnea may occur spontaneously or after early morning feedings or prolonged crying. The attacks may last only a few moments and have no sequelae; they may cause obtundation, limpness, deep exhaustion, or sleep; rarely, they may end in unconsciousness, convulsions, or even death. Because approximately one-third of patients with the tetralogy of Fallot begin to have hypoxic spells by 4 or 5 months of age, palliative or corrective surgery is usually done electively within a few months of birth. Thus, the pediatrician rarely sees these episodes any more. A few of these infants have minor spells. Their cyanosis may not increase much, but they cry inconsolably. They are often misdiagnosed as “colic.” Putting them on the abdomen with a knee chest position aborts the crying (see below) and may make the diagnosis. In the very rare instance in which an infant does not undergo correction, exercise tolerance in the child varies in proportion to the severity of the cyanosis. Young children with the tetralogy of Fallot and severe cyanosis often adopt a characteristic squatting position after exertion. This maneuver increases arterial oxygen saturation, probably by increasing systemic arterial resistance. A final group of patients shows little or no evidence of cyanosis in infancy or early childhood (acyanotic tetralogy of Fallot); cyanosis on exertion gradually becomes more manifest as they grow older. Occasionally, even in this group, very rapid clinical change toward the classic severely cyanotic tetralogy of Fallot can occur.

In the rare, untreated patient, major late complications include brain abscess, cerebral thrombosis with hemiplegia, and infective endocarditis. Growth and development are generally delayed in proportion to the degree of cyanosis. Infective endocarditis is particularly common in children who have palliative systemic-pulmonary shunts rather than correction. Prophylactic antibiotic therapy is no longer routinely recommended for most of these repaired patients, although unrepaired or palliated patients still require prophylaxis (see Chapter 484).

Physical examination shows a right ventricular systolic heave along the lower left sternal border. A single loud second heart sound corresponding to aortic valve closure is generally heard best at the lower left sternal border, rather than being heard best at the upper right or both the upper right and left sternal border. This physical sign is important, especially in a neonate when trying to differentiate an acyanotic tetralogy of Fallot from a ventricular septal defect. When closure of the pulmonary valve is audible at the upper left sternal border, it is delayed and diminished in intensity. In patients with moderate right ventricular outflow tract obstruction, the mid-to-high pitch systolic murmur is loud and harsh, stenotic or pansystolic in quality, and best heard at the middle or lower left sternal border. Rarely, a continuous murmur of persistent ductus arteriosus is heard at the upper left sternal border. As there is less ejection through an increasingly stenotic pulmonary outflow tract, the murmur will shorten in duration and will increase in pitch.

The heart is of normal size, and lung fields are poorly vascularized, signifying diminished pulmonary blood flow. The right ventricular outflow tract and main pulmonary artery segments are usually hypoplastic, resulting in a concavity of the upper left margin of the cardiac silhouette instead of the normal convexity. A characteristic “sheep’s nose,” “coeur en sabot,” or boot-shaped heart may be present, particularly with pulmonary atresia. The ascending aorta is generally large. In about 25% of the patients, a right-sided aortic arch is present and is recognized by observing a right-sided rather than left-sided indentation on the trachea. The superior vena caval shadow may be displaced to the right. When bronchial collateral circulation is well developed, diffuse fine vascular markings are noted throughout the lung. Rarely, markedly decreased left lung vascular markings indicate absence or stenosis of the left pulmonary artery.

There are right-axis deviation and right ventricular hypertrophy, although in the newborn infant, the diagnosis of pathologic right ventricular hypertrophy by electrocardiogram is more difficult because of the normal right ventricular dominance at this age.

In tetralogy of Fallot, the dilated aortic root overrides a large adjacent ventricular septal defect, and varying degrees of right ventricular infundibular obstruction, pulmonary valve stenosis, and hypoplasia or narrowing of the main pulmonary artery and left pulmonary artery are revealed by echocardiogram. Doppler examination confirms the severity of the obstruction and demonstrates systolic turbulence in the main pulmonary artery.

The acute severe episodes of dyspnea and hypoxemia, termed blue spells or hypercyanotic episodes, in some infants with the tetralogy of Fallot reflect a further acute reduction in the pulmonary blood flow. These spells may occur even if the infant is not cyanotic at rest. The precipitating mechanisms are probably multiple: prolonged crying may decrease pulmonary blood flow because of prolonged expirations; decreases in right ventricular preload and systemic vascular resistance because of sleeping, fever, or spontaneous vasomotor changes decrease pulmonary blood flow and increase the right-to-left shunt; and constriction of the right ventricular infundibulum may occur, further decreasing pulmonary blood flow, although it is uncertain whether this truly occurs.

TREATMENT

As with many significant congenital heart abnormalities, the treatment is ultimately surgical. For the neonate with prominent cyanosis, prompt infusion of PGE₁ is important. Corrective or palliative surgery is usually performed within 2 to 4 months of birth, but in the rare patient who has not had surgery, medical therapy is primarily directed toward acute relief of hypercyanotic episodes and preventing the complications of right-to-left shunts.

Hypercyanotic episodes may be treated by placing the infant on the abdomen in a knee-chest position or holding the infant with the legs flexed on the abdomen. Oxygen should be given to lessen dyspnea and cyanosis but is not very helpful because of the very low pulmonary blood flow. Morphine sulfate (0.2 mg/kg body weight subcutaneously) is especially effective in terminating a prolonged or severe attack. If the spell is protracted and severe and does not respond to the foregoing therapy, metabolic acidemia ensues, and intravenous fluid bolus administration and correction with intravenous sodium bicarbonate are essential. Vasopressors can be given either early in the attack or if other therapy fails; phenylephrine, 0.02 mg/kg intravenously or 0.1 mg/kg intramuscularly, will raise systemic resistance and thus increase pulmonary blood flow. If possible, phenylephrine should be given by continuous intravenous infusion, generally at a dose of 2 to 5 μg/kg/min. Recently, a nasal fentanyl spray of 2 μg/kg was reported as being effective. In infancy, these attacks may be precipitated by a relative iron-deficiency anemia (hypochromic microcytic), and such patients should have iron therapy until the hematocrit reaches levels of 50% to 55%. Further increase in the hematocrit results in a marked rise in blood viscosity, with progressive impediment to blood flow and risk of cerebral thrombosis. Any hypercyanotic episode is an absolute indication for surgery, so it is now rare to need to treat anemia except in the immediate preoperative period. If surgery is contraindicated for some reason, oral propranolol has been given at a dosage of 0.5 to 1.0 mg/kg orally every 6 hours to prevent or reduce the frequency of paroxysmal dyspneic attacks. Some cardiologists have reported that balloon dilation and stent placement of the infundibulum and pulmonary valve may improve pulmonary blood flow enough for 6 to 12 months in the case that surgery needs to be delayed or is unavailable.

Early elective surgery is indicated for infants with tetralogy of Fallot with or without pulmonary atresia, even in the absence of symptoms. Patients with the tetralogy of Fallot and patent right ventricular outflow tracts can have intracardiac surgical repair of the malformation by skilled congenital heart surgeons in the first months of life with low operative mortality. The ventricular septal defect is closed, the infundibular muscle is resected, and sometimes right ventricular outflow and main pulmonary artery patches are placed to augment the outflow tract. Pulmonary valvotomy is also performed in most patients, but enlargement of the pulmonary valve annulus with a transannular patch is avoided unless the annulus is critically small. Rarely, an infant cannot be repaired because of marked pulmonary artery hypoplasia, (usually with Di George or Alagille syndrome) and a systemic-pulmonary anastomosis or a right ventricular outflow patch is performed without closure of the ventricular septal defect. Balloon dilation of the pulmonary arteries can then be performed in the catheterization laboratory in anticipation of later correction.

Although repair of tetralogy of Fallot with pulmonary atresia has in recent years become increasingly successful, the operative risk and late complications and death are higher than for uncomplicated tetralogy of Fallot. Unifocalization of the often discontinuous sources of pulmonary blood flow to a central system is required before the standard repair. This may be done in one or multiple stages. The 10- and 20-year survival rates excluding operative and early hospital deaths are approximately 80% and 65%, respectively, as compared with 95% for simple tetralogy of Fallot over the same intervals.

Surgical correction for most patients with uncomplicated tetralogy of Fallot results in excellent survival. Residual or recurrent small left-to-right shunts are uncommon, but residual mild or moderate right ventricular–pulmonary outflow tract obstruction and regurgitation are common. Those who have marked pulmonary regurgitation and very dilated right ventricles may eventually develop congestive heart failure and may be at higher risk for sudden death, especially if they have very wide QRS intervals. These patients are candidates for pulmonary valve replacement, currently primarily performed surgically but increasingly being performed by catheter insertion. A few patients have surgically induced complete AV block and require an implanted pacemaker. About 1% to 3% have serious late dysrhythmias, particularly ventricular tachycardia, probably related to reentry mechanisms at the site of right ventricular tissue excisions, and about 1% to 2% die suddenly, presumably from dysrhythmias. Dysrhythmias should be suspected if these patients after surgery complain of dizzy spells, syncope, or palpitations, and appropriate diagnostic studies and therapy applied.

TETRALOGY-LIKE LESIONS

The clinical findings in patients with DORV, single ventricle, or d- or l-transposition of the great arteries with a ventricular septal defect, when associated with severe pulmonic or subpulmonic stenosis, may closely resemble the findings in tetralogy of Fallot. These other malformations can be diagnosed with ease by 2-dimensional and Doppler echocardiography.

PULMONARY ARTERIOVENOUS MALFORMATION

Occasionally fistulas connect the pulmonary artery and vein so that some pulmonary blood flow bypasses the alveoli. The fistulas may be large and discrete, single or multiple, or there may be numerous small fistulas scattered throughout the lungs. Many of these fistulas occur in patients with Osler-Weber-Rendu syndrome (hereditary hemorrhagic telangiectasia). They are frequently complicated by brain abscess, hemoptysis, or intrapleural hemorrhage. Coil embolization of the fistulas can be performed in the catheterization laboratory to improve arterial oxygen saturation, although fistulas may occasionally recur in the same or other lung segments.

AORTIC MALPOSITION

The second major group of congenital heart defects that present with severe cyanosis in the newborn period has the common finding that the aorta is malposed across the ventricular septum to arise from the right ventricle. This malposition occurs in such a manner (anterior and to the right with situs solitus) that the aorta is committed to receiving systemic venous return. Thus, even with a very large pulmonary flow, the patient can be very cyanotic. The most common heart lesion with aortic malposition is complete transposition of the great arteries. In this defect, the pulmonary artery is also malposed, arising from the left ventricle. In most patients, the ventricular septum is intact. Because the great arteries arise from the inappropriate ventricles, these are discordant ventriculoarterial connections. The AV connections, however, are normal (concordant).

TRANSPOSITION OF GREAT ARTERIES

Complete transposition of the great arteries is the most common cardiac cause of cyanosis in the neonate, and until recently, it accounted for the majority of deaths in infants with cyanotic congenital heart disease under 1 year of age. Once almost universally fatal, the prognosis has changed dramatically in recent years with the introduction of palliative and corrective procedures.

MORPHOLOGY AND PHYSIOLOGY

In transposition of the great arteries, the systemic venous return traverses the right atrium and right ventricle and is ejected into the transposed aorta arising from the right ventricle; the pulmonary venous return traverses the left atrium and left ventricle and is ejected back into the lungs via the transposed pulmonary artery. There are thus 2 separate circulations in parallel instead of in series. This arrangement is incompatible with life without some communications to permit oxygenated pulmonary venous blood to enter the systemic circulation and systemic venous blood to enter the pulmonary circulation. In about 70% of patients with complete transposition, the ventricular septum is intact, and intracardiac shunting occurs only through a stretched foramen ovale or, rarely, a secundum atrial defect; consequently, cyanosis is extreme. Infants with an associated large ventricular septal defect have better mixing between the 2 circulations and so have higher systemic oxygen saturations. Although a patent ductus arteriosus may be demonstrated in about half of the newborn infants with transposition, it closes functionally and anatomically soon after birth in most patients. A persistent large patent ductus arteriosus is uncommon, particularly malignant in terms of the risk of severe pulmonary vascular disease, and requires prompt recognition and therapy. Left ventricular outflow tract stenosis of varying degrees also may be present; it most often results from a fibrous ridge or collar in the outflow tract of the left ventricle. Common AV canal, AV valve atresia, severe pulmonary valve stenosis or atresia, coarctation of the aorta, or right aortic arch is rare in complete transposition of the great arteries.

The major consequences of d-transposition of the great arteries are severe hypoxemia, metabolic acidemia, and congestive heart failure. The level of systemic arterial oxygen saturation depends on the transfer of oxygenated pulmonary venous blood to the systemic circuit as well as the reciprocal transfer of systemic venous return to the pulmonary circuit. These transfers are a function of the size of the shunting sites: foramen ovale, ostium secundum defect, ventricular septal defect, patent ductus arteriosus, and bronchial collateral circulation. Other important factors, particularly in patients with large ventricular septal defect, are the hemodynamic consequences of pulmonary outflow tract stenosis and increased pulmonary vascular resistance; if outflow resistance is high, it will restrict the pulmonary blood flow and the volume of the oxygenated pulmonary venous return and reduce the systemic arterial oxygen saturation. The existence of the systemic and pulmonary circulatory pathways in parallel instead of in series usually results in high cardiac outputs for both the right and left ventricles, with consequent cardiac dilation and myocardial failure. Myocardial function can be further compromised by the markedly desaturated aortic blood flow entering the coronary circulation.

Pulmonary vascular obstructive disease has been observed both by microscopy and by cardiac catheterization to be more common and to progress at an unusually rapid rate in infants with d-transposition of the great arteries and large ventricular septal defect, as contrasted to infants with large ventricular septal defect and normally related great arteries. About 75% of all infants with d-transposition of the great arteries and large ventricular septal defect older than 1 year of age have advanced pulmonary vascular obstructive disease, and histologic studies demonstrate moderate pulmonary vascular disease lesions in many infants with large ventricular septal defect by 3 to 4 months of age. Associated pulmonic stenosis, early intracardiac correction with closure of the ventricular septal defect, or early surgical pulmonary artery banding protects against the development of pulmonary vascular obstructive disease in this lesion. Accordingly, palliative pulmonary artery banding or intracardiac repair should be considered before the patient is 3 to 4 months of age. Significant pulmonary vascular obstructive disease has even been seen in about 5% of the transposition patients with intact ventricular septum who survive early infancy.

CLINICAL MANIFESTATIONS

In the absence of a ventricular septal defect, the aorta receives all of the desaturated systemic venous return and can receive pulmonary venous blood only via an interatrial communication. However, these infants often do not have atrial septal defects. Thus, as occurs normally, pulmonary blood flow increases dramatically at birth, and the increase in pulmonary venous return tends to close the foramen ovale. If this occurs, the neonate with transposition may become critically cyanotic soon after birth, a problem intensified by closure of the ductus arteriosus. If this occurs, an emergency balloon atrial septostomy to establish an atrial left-to-right shunt should be performed. In the interim, particularly if the infant is not at a major medical center with a neonatal cardiology program, PGE₁ can be very beneficial by increasing pulmonary blood flow, which in turn increases pulmonary venous return and left atrial pressure and thus forces pulmonary venous blood to cross to the right atrium. This may be lifesaving but may occur at the expense of very high left atrial pressures. Thus, the neonate should be intubated if there are signs of any respiratory compromise. In addition, immediate supportive therapy for metabolic acidemia and maintenance of body temperature should be instituted.

Balloon atrial septostomy is performed via the femoral or umbilical vein during neonatal cardiac catheterization or even under echocardiographic visualization in the intensive care nursery. A transvenously introduced catheter bearing a balloon is advanced through the foramen ovale into the left atrium, where the balloon is inflated to a diameter of 8 to 10 mm. The catheter and inflated balloon are then abruptly withdrawn into the right atrium, thus rupturing the septum primum valve of the fossa ovalis, enlarging the interatrial communication, and providing for more adequate mixing of blood. The systemic arterial oxygen tension often rises initially, but if it remains low despite PGE₁ and an adequate balloon septostomy, a transfusion of blood is often helpful. By increasing circulating volume and atrial pressures, a transfusion can dramatically increase the left-to-right atrial shunt. In a few infants shunting is minimal because of pulmonary arterial hypertension, and treatment with nitric oxide, sildenafil, or even extracorporeal membrane oxygenation might be required. After a few days of stabilization, almost all infants with simple transposition today undergo surgical repair.

In order to consider this group of lesions along lines of blood flow, one has to make the initial assumption that the aorta is committed to the systemic venous (right) ventricle and then consider blood flow from the right atrium onward. Defects in the atrial, AV, and ventricular septa may occur, the latter of which is frequently associated with either pulmonic stenosis or DORV (Taussig-Bing anomaly), which is associated with aortic outflow obstruction.

Most infants with an intact ventricular septum become critically ill the first few hours after birth, but if there is a large ventricular septal defect, cyanosis may be slight, and congestive heart failure may not become evident until a few weeks after birth. Characteristically, attention is first directed to the infant with inadequate intracardiac mixing by nursery personnel who observe cyanosis or abnormal oximetry in an otherwise apparently healthy infant. A high index of suspicion is needed for early diagnosis; except for persistent cyanosis and progressive hyperpnea in the first hours after birth, the infant may appear well developed and minimally distressed, there are no distinctive murmurs, and the chest radiograph and electrocardiogram may be deceptively normal.

On auscultation, the second heart sound is usually interpreted as loud and single and is heard best usually at the upper left rather than the upper right sternal border, but careful auscultation often reveals narrow splitting with a soft pulmonary valve closure. The murmurs are usually unimpressive in the newborn with an intact ventricular septum, but there may be a short grade 2 to 3/6 ejection systolic murmur at the middle of the left sternal border. A loud harsh systolic murmur in a slightly older infant usually indicates a ventricular septal defect or left ventricular outflow tract stenosis.

Infants with transposition of the great arteries and large ventricular septal defect develop prominent heart failure and modest cyanosis by 3 to 4 weeks of age. Increasing tachypnea, dyspnea, and excessive perspiration are noted. Cyanosis may increase, but often it remains relatively mild because of good circulatory mixing. Pulmonary rales and hepatomegaly may be striking.

The electrocardiogram may not be helpful in the newborn infant because it shows right-axis deviation and right ventricular hypertrophy of a degree that may be normal for a neonate. After 5 days of age, however, persistence of a positive T wave over the right precordium suggests abnormal right ventricular hypertrophy. In the older infant with an intact ventricular septum, right atrial hypertrophy and overt right ventricular hypertrophy are present.

The radiographic findings can vary from near normal to grossly abnormal. In the neonate the heart is small, but it enlarges over the first 1 to 2 weeks after birth. The classic transposition cardiac silhouette, an egg-shaped or oval heart with a narrow superior mediastinum and small thymic shadow, is diagnostic, but it is present early in only about one-third of the newborn infants.

Two-dimensional and Doppler echocardiography constitute the major tools for morphologic diagnosis and functional assessment, showing the transposed great arteries, with the aorta arising anterior and to the right from the morphologic right ventricle, and the pulmonary artery arising posterior and to the left from the morphologic left ventricle. The sites, direction, and magnitude of shunts can be seen, and assessments of ventricular pressures can be made. In addition, echocardiography may also show coronary artery patterns and the presence of intramural segments that may become relevant at the time of the arterial switch operation.

TREATMENT

After initial stabilization with balloon atrial septostomy, PGE₁ infusion, intubation and ventilation, and correction of any metabolic derangements, the patient is often allowed to stabilize for a few days. During that time, full evaluation of associated lesions and coronary arterial anatomy is made. In the absence of lesions such as subpulmonary or pulmonary valve stenosis, arterial switch surgery is performed. It is now the treatment of choice, primarily because it returns systemic ventricular function to the left ventricle and because midterm follow-up studies indicate preservation of normal ventricular function and no significant incidence of postoperative arrhythmias. The operation involves transecting the great arteries, switching their attachments above the semilunar valves, and transplanting the coronary arteries from the preoperative anterior aortic root (new pulmonary root) to the preoperative posterior pulmonary arterial root (new aortic root). For infants with intact ventricular septum or an insignificant ventricular septal defect, it is critical to perform this operation under 8 weeks of age while the left ventricular pressure and muscle mass have not yet regressed to those of a low pressure, thin-walled pulmonary ventricle dictated by the transposition physiology. Current experience for the 1-stage arterial switch repair in neonates in centers with neonatal cardiac surgical proficiency indicates early operative survival of 95% or more. Freedom from reoperation (most often done to relieve surgically induced supravalvar pulmonic stenosis) is also 90% to 95%. For the infant with d-transposition and a large ventricular septal defect, the primary management problems are left ventricular failure and pulmonary hypertension with the early onset of pulmonary vascular disease. Occasionally there may be myocardial ischemia caused by coronary arterial problems associated with the switch. Currently, neonatal arterial switch repair with closure of the ventricular septal defect has significantly improved the prognosis for this subset of transposition patients to about 90% survival over 5 years.

TRANSPOSITION OF THE GREAT ARTERIES WITH PULMONARY STENOSIS

In the infant with transposition of the great arteries and intact ventricular septum, slight or moderate left ventricular outflow tract stenosis may be present or develop in the subpulmonary region. This obstruction may be predominantly muscular and dynamic or predominantly fibromuscular and fixed. The degree of obstruction is usually modest and only severe degrees of anatomic obstruction should be relieved by resection or conduit bypass at the time of the open-heart procedure.

When a ventricular septal defect is present with severe subvalvar left ventricular outflow tract stenosis, the clinical picture may mimic the tetralogy of Fallot. Symptoms may begin at birth, with severe cyanosis and paroxysmal hypoxemic spells; the pulmonary vascular markings on the radiograph are decreased. If the pulmonary stenosis is not severe, cyanosis and clinical symptoms are not extreme initially, but they may become so as the infant matures. Two-dimensional echocardiography and selective left ventriculography can define the extent and site of the pulmonary stenosis.

In the extremely cyanotic newborn infant with transposition and severe subpulmonary or pulmonary stenosis or atresia, the safest treatment is to perform a systemic-pulmonary shunt. Intracardiac repair is difficult and should be postponed until a later date. Surgical repair (Rastelli procedure) consists of repair of the ventricular septal defect with an intracardiac ventricular baffle so as to connect the left ventricle to the aorta. Then an extracardiac valve-bearing conduit is placed between the right ventricle and the distal stump of the pulmonary artery, to bypass completely the severely stenosed left ventricular outflow tract. Other surgical procedures are the Lecompte and Nikaidoh operations. In the Lecompte operation, the conal septum is removed so that the baffle connecting the left ventricle to the aorta is not obstructed, and the pulmonary trunk is disconnected from the left ventricle and pulled across to connect to the right ventricle, usually without a pulmonary valve. The Nikaidoh operation dissects the whole aortic root off the right ventricle and connects it to the left ventricle; the ventricular septal defect is closed with a patch, and the pulmonary artery is connected to the right ventricle either directly or with a conduit. Both these latter operations have better midterm results than the original Rastelli operation.

TAUSSIG-BING ANOMALY

DORV is a rare group of lesions that is one of the types of malposition of the great arteries. Both the aortic and pulmonary valves are positioned over the right ventricle, there is often conal (outlet septum) tissue below both orifices, and the only outflow from the left ventricle is through the ventricular septal defect, which may be either subpulmonary or subaortic, or rarely uncommitted. When the pulmonary artery is committed to the right ventricle and the aorta overrides the ventricular septal defect, there is usually subpulmonic stenosis, and the physiology and treatment are similar to tetralogy of Fallot. When the aorta is committed to the right ventricle and the pulmonary orifice is related to and overriding the ventricular septal defect (Taussig-Bing anomaly), the hemodynamics and clinical findings are similar to those of transposition of the great arteries with large ventricular septal defect and pulmonary hypertension. An associated coarctation of the aorta is present in about 25% of these patients.

Corrective surgical procedures are increasingly successful for Taussig-Bing anomaly. Arterial switch repair as for d-transposition is the operation of choice, providing the great arteries are not too different in diameter, with early and midterm outcomes similar to those of transposition with a large ventricular septal defect. Any aortic arch abnormalities are corrected surgically either before or at the same time as the intracardiac repair. When the arterial size discrepancy is severe or intracardiac anatomy makes correction problematic, a pulmonary artery band is often performed at the same time as the aortic arch repair, and definitive surgery is delayed until a later date.

TOTAL ANOMALOUS PULMONARY VENOUS CONNECTION

Total anomalous pulmonary venous connection accounts for about 2% of all congenital heart malformations seen in the first year of life and is characterized by absence of any direct connection between the pulmonary veins and the left atrium. The pulmonary veins are connected either directly to the right atrium or to various systemic veins draining toward the right atrium, such as right superior vena cava, azygous vein, left innominate vein, coronary sinus, ductus venosus, or various combinations of these connections. The pulmonary veins almost always come together to form a common channel that lies behind but is separate from the left atrium. This proximity provides the key to successful corrective surgery. The embryologic basis for the malformation is a failure of development of the connection of the common pulmonary vein with the left atrium, and consequently, an anomalous union occurs between the pulmonary vein plexus of the developing lung buds and one of several systemic venous structures. Three main anatomic types of connection have been described: supracardiac, cardiac, and infracardiac (also called infradiaphragmatic). In about 45% of the patients, pulmonary venous return to the heart proceeds from the confluence immediately posterior to the left atrium via a left vertical venous trunk that joins the left innominate vein, which joins the right superior vena cava in normal fashion (supracardiac). In about 25% the anomalous drainage pathway descends below the diaphragm, usually to connect with the ductus venosus, and the pulmonary venous drainage eventually returns to the heart via the inferior vena cava (infracardiac). In the cardiac type, the pulmonary veins may be connected directly to the right atrium or the coronary sinus. Occasionally, veins from different lung lobes drain into different parts of the venous system (mixed connections).

The physiologic and clinical features of one important subgroup of infants with total anomalous pulmonary venous connection are dictated by pulmonary venous obstruction at some level in the pulmonary venous drainage pathway. In the infradiaphragmatic type, severe obstruction to pulmonary venous return is invariable. Obstruction may result from the length and narrowness of the common trunk, compression in the esophageal hiatus of the diaphragm, or more often from the constriction that normally occurs in the ductus venosus and the resistance that the total pulmonary venous return faces when it must pass through the portal-hepatic circulation. Supracardiac drainage pathways also may manifest pulmonary venous obstruction, but this occurs less frequently. The site of obstruction may be a localized intrinsic constriction, but more frequently, it occurs where the left vertical vein is compressed as it passes between the left pulmonary artery anteriorly and the left bronchus posteriorly, rather than passing anterior to the pulmonary artery. Obstruction may also occur with other types of anomalous connection.

Associated intracardiac anomalies have been described in up to 30% of patients with total anomalous pulmonary venous connection. These anomalies are usually complex lesions such as common AV canal or transposition of the great arteries or single-ventricle complexes and are most often associated with heterotaxy syndrome (right or left atrial isomerism).

HEMODYNAMICS

All pulmonary venous blood returns to the right atrium, where it mixes with the systemic venous return. A variable proportion then passes to the systemic circulation through a stretched patent foramen ovale into the left atrium, ventricle, and aorta; the remainder passes to the pulmonary circulation through the tricuspid valve into the right ventricle and pulmonary artery. Systemic arterial desaturation is present as a result of the obligatory right-to-left shunting of blood at the atrial level, although, rarely, streaming of pulmonary venous blood into the left atrium gives near-normal aortic saturations. The arterial oxygen saturation varies widely but is rarely decreased significantly enough to impair oxygen delivery and depends on the ratio of pulmonary to systemic blood flow. Because the pulmonary venous blood joins with systemic venous blood at or before the right atrium, the oxygen saturations tend to be similar in all 4 chambers of the heart and in the 2 great arteries.

Most infants with supracardiac and cardiac types have little or no pulmonary venous obstruction and consequently have high pulmonary blood flow, various degrees of pulmonary hypertension, and relatively low pulmonary vascular resistance. These infants generally survive the first few weeks and months of life but may succumb to severe congestive heart failure during the first year of life unless surgically corrected. All infants with the infradiaphragmatic type and about one-third of the infants with the other types manifest severe pulmonary venous obstruction and so have severe pulmonary hypertension, restricted pulmonary blood flow, pulmonary venous engorgement, interstitial pulmonary edema, and severe hypoxemia. Pulmonary artery pressures often exceed systemic pressures, and death is common in the first weeks of life if the disorder is not corrected. In all types of total anomalous pulmonary venous connection, the pressures in the right atrium are invariably higher than those in the left atrium, and occasionally pulmonary venous obstruction may result from restriction of flow across the foramen ovale.

CLINICAL FEATURES

About 80% to 90% of all patients manifest tachypnea, congestive heart failure, and failure to thrive early in infancy. In the group without pulmonary obstruction, cyanosis may be minimal, but cyanosis becomes more significant as congestive heart failure progresses. In the newborn period, the heart is hyperdynamic, and the second heart sound may be widely split with increased intensity of P₂; murmurs are only rarely heard. If diagnosis is delayed, the auscultatory findings change. A quadruple gallop rhythm frequently develops. A soft ejection systolic murmur is present along the left sternal border, and a mid-diastolic inflow rumble is usually heard at the lower left sternal border and apex.

In infants with the obstructed form of total anomalous pulmonary venous drainage, there is very early onset of severe dyspnea. The clinical picture is that of rapidly progressive dyspnea, pulmonary edema, intense cyanosis, and right heart failure. The second heart sound is loud and narrowly split, and a gallop rhythm may be heard. Murmurs are not prominent, but a soft blowing systolic murmur of tricuspid regurgitation may be heard at the lower left sternal border.

In the unobstructed group, the radiographic examination shows marked cardiac enlargement with pulmonary vascular engorgement that might give the initial appearance of neonatal respiratory distress syndrome. In the supracardiac type, a pathognomonic configuration termed “figure of 8” or “snowman” may be recognized beyond infancy; this silhouette is formed by the dilated left vertical vein, innominate vein, and right superior vena cava sitting astride the dilated heart.

A characteristic chest radiograph is present in those infants with pulmonary venous obstruction. The heart is normal or slightly enlarged, and the lung fields show a diffuse, hazy reticulated pattern superficially resembling the ground-glass appearance seen in the respiratory distress syndrome. Because of this and the lack of diagnostic murmurs, one is likely to misdiagnose these patients as having some form of diffuse interstitial pneumonitis if one relies on the radiograph alone. Early 2-dimensional echocardiographic diagnosis of a normal versus an abnormal heart is critical, especially if the apparent lung disease is not improving.

The electrocardiogram shows right ventricular hypertrophy and commonly also right atrial hypertrophy. The hypertrophy is often in excess of the normal right ventricular dominance at birth, as demonstrated by a qR complex in the right precordial leads, poor left forces, and the lack of inversion of the T waves over the first few days of life.

Two-dimensional echocardiography can establish the diagnosis and anatomy subtype of pulmonary venous connection with a high degree of sensitivity and specificity particularly in infants who have atrial situs solitus, unifocal rather than mixed pulmonary venous connections, and no evidence of other major congenital defects. It is thus critical that all infants with severe respiratory distress and cyanosis at birth undergo echocardiography early in their course, particularly if extracorporeal membrane oxygenation is being considered. Cardiac catheterization with angiography in these critically ill infants, no matter how carefully executed, may make them even more ill and may be of little diagnostic value.

TREATMENT

For the severely obstructed group, rapid clinical deterioration and early death are invariable without surgical treatment. Aggressive treatment of hypoxemia and metabolic acidemia should be instituted, diuretics given, and continuous positive airway pressure with oxygen supplementation should be provided while preparations are made for surgical correction with cardiopulmonary bypass.

With all types of single connections, the aim of surgical correction is to reincorporate the common pulmonary vein into the left atrium. Because this chamber may be small, correction is carried out with a wide parallel incision between the posterior aspect of the atria and the anterior wall of the common pulmonary vein as the heart is lifted out of the pericardium. The interatrial septum may be replaced to the right of the anastomosis to enlarge the functional left atrium. The anomalous connection is simply ligated and divided.

In the unobstructed type, corrective surgery dramatically restores the normal circulatory pathways with a modest surgical risk under the best circumstances. When severe pulmonary venous obstruction is present, particularly for the infradiaphragmatic type, the surgical mortality has been higher, but prompt referral, aggressive management of metabolic acidemia, and early emergency surgery have had increasing success, with excellent long-term results. However, it is important to note that early (2–4 months) postoperative pulmonary venous obstructions have been observed in about 10% of these patients. These obstructions result either from an anastomotic stricture or from a particularly malignant form of diffuse pulmonary venous fibrosis at the venous ostia or within the lobar veins. The prognosis in the latter group of patients is very poor.

HYPOPLASTIC LEFT HEART SYNDROME

The term hypoplastic left heart syndrome describes a group of malformations characterized by marked underdevelopment of the entire left side of the heart. The right side of the heart is dilated and hypertrophied and supports both pulmonary and systemic circulations through a patent ductus arteriosus. The specific anatomic abnormalities include underdevelopment of the left atrium and ventricle, stenosis or atresia of the aortic or mitral orifices, and marked hypoplasia of the ascending aorta. Most commonly, aortic and mitral atresia coexist, and the left ventricular cavity is minute or completely obliterated. Rarely, mitral atresia is present associated with a ventricular septal defect. In one study, hypoplastic left heart syndrome accounted for nearly 25% of cardiac deaths in the first year of life (New England Regional Infant Cardiac Registry).

HEMODYNAMICS

The essential hemodynamic abnormality is the absence or gross inadequacy of left ventricular function. Pulmonary venous blood passes from left to right atrium via the patent foramen ovale, and this interatrial communication is often small and restrictive to blood flow, causing severe left atrial and pulmonary venous hypertension. The ventricular septum is almost always intact. The right ventricle functions as the systemic ventricle as well as the pulmonary ventricle by delivering blood into the aorta through the widely patent ductus arteriosus. The pulmonary vascular resistance must be high to provide for this systemic function of the right ventricle. Furthermore, as the ductus arteriosus constricts intermittently, there is intermittent restriction to systemic blood flow.

In the rare condition of mitral atresia with ventricular septal defect, all the pulmonary venous blood passes through a foramen ovale to mix with systemic venous return. Blood then enters the enlarged right ventricle from which it passes into the pulmonary artery and, through a ventricular septal defect, into the hypoplastic left ventricle and the aorta. If the foramen ovale permits a large left-to-right shunt, these infants initially do quite well but then go into congestive heart failure because of a torrential pulmonary blood flow.

CLINICAL FEATURES

Most infants with hypoplastic left heart complex are acutely ill, with signs of congestive heart failure within the first days or weeks after birth; those with aortic atresia succumb usually within the first few days after birth.

There are signs and symptoms of severe right-sided and left-sided heart failure: cyanosis of varying degree, and often a characteristic grayish pallor and poor peripheral pulses, which contrast with hyperdynamic cardiac pulsations. The major hemodynamic abnormalities are pulmonary venous hypertension and inadequate maintenance of the systemic circulation. Murmurs are not prominent, but a short soft midsystolic murmur and mid-diastolic rumble may be present. The second heart sound is single, heard loudest at the upper left sternal border and is accentuated until clinical deterioration with gross right heart failure is advanced.

The chest radiograph shortly after birth may show only slight cardiac enlargement, but with clinical deterioration, striking generalized cardiac enlargement and moderately prominent pulmonary vascular markings appear. Pulmonary venous obstruction may be indicated by hazy lung markings.

The electrocardiogram at birth may show normal right ventricular dominance, but if the infant survives a few days, right atrial and right ventricular hypertrophy are usual. Left-sided forces are often decreased, as evidenced by the absence of a septal q wave even out to V₇ and V₈ and only a small r wave in V₅ and V₆.

The 2-dimensional echocardiogram is diagnostic by imaging a hypoplastic ascending aorta, atresia or marked stenosis of the mitral and aortic orifices, and an obliterated or minute posterior left ventricle in conjunction with a dilated, large anterior right ventricle and large patent ductus arteriosus. These findings together with the clinical picture obviate the need for any additional invasive diagnostic studies.

TREATMENT

Supportive therapy directed at congestive heart failure, hypoxemia, and metabolic acidemia is of only limited benefit, and survival beyond the first week or 10 days of life is rare in the absence of maintenance of ductus patency with PGE₁. Although the anatomic and functional abnormalities in hypoplastic left heart syndrome are formidable, 3 different management programs are being pursued in some centers. Most often, staged reconstruction (Norwood procedure) is applied to the available structures to salvage a physiologically effective circulation by a 3-stage operative approach. Ductus closure, the immediate cause of rapid circulatory collapse and death in these neonates, is modified by a PGE₁ infusion to maintain a widely patent ductus arteriosus. Surgical approaches and subsequent management are reviewed in Chapter 492.

The second approach, particularly in children with significant ventricular dysfunction and/or severe tricuspid valve regurgitation, consists of neonatal orthotopic cardiac transplantation. Although there are major difficulties related to shortage of donor hearts, excellent results have been obtained with a low operative mortality. While the child is awaiting transplantation, the ductus arteriosus may be kept open by a stent or the prolonged use of PGE₁.

More recently, a third hybrid approach has been practiced. The ductus arteriosus is kept open with a stent, and the surgeon bands the right and left branch pulmonary arteries. This procedure is much less stressful for a sick neonate and has relatively low mortality. Then several months later the stent is removed, the main pulmonary artery is anastomosed to the ascending aorta as in a first stage Norwood, the right ventricle and the pulmonary artery are connected, and a Glenn procedure is done. In this procedure, a high-mortality first stage of the usual Norwood procedure done in very sick, small infants is replaced with a more complicated second stage.

SINGLE VENTRICLE

A single-ventricle (or univentricular) malformation is diagnosed when there is 1 ventricular chamber that receives both the mitral and tricuspid orifices or a common AV orifice. About 70% to 80% of single-ventricle malformations are derived from an l-bulboventricular loop (as opposed to the normal d-looping) and manifest bulboventricular inversion. These hearts have a single right-sided, morphologically left, ventricle with absence of the inflow portion of the right ventricle. There is persistence of a rudimentary anterior and left-sided right ventricular outflow chamber that communicates proximally with the single ventricle through a ventricular septal defect (persistent bulboventricular foramen) and distally with an l-transposed aorta. The pulmonary artery is posterior and arises from the single ventricle. Stenosis or atresia of the pulmonary outflow tract is also common, as is coarctation of the aorta, although they do not coexist—as in all congenital heart lesions, one or the other outflow tract may be obstructed, but almost never both. Subaortic stenosis as a result of a decrease in size of the bulboventricular orifice is relatively common and may occur after the pulmonary artery has been banded. Complex associated anomalies are usual, and they include dextrocardia, right atrial isomerism, common AV canal, and total anomalous pulmonary venous connection.

The term common ventricle has been used to distinguish a rare type of single-ventricle heart that has a well-developed right as well as left ventricular inflow tract; in such a heart, the univentricular chamber represents essentially a huge ventricular septal defect.

HEMODYNAMICS

The hemodynamics and clinical picture vary, depending on the pulmonary blood flow and the associated intracardiac malformations. Some degree of systemic arterial desaturation is always present because of mixing of the pulmonary and systemic venous blood in the single ventricle or, in some, an associated common atrium. With significant pulmonary stenosis or atresia, cyanosis may be severe, the heart size small, and the pulmonary vascular markings diminished. In contrast, when there is no pulmonary stenosis, the clinical and hemodynamic findings are dictated by the relationship between pulmonary and systemic vascular resistances and blood flows. In the infant, and in the older child when pulmonary vascular resistance is low, there will be torrential pulmonary blood flow with marked cardiomegaly and severe congestive heart failure. In the surviving child, increasing pulmonary vascular disease may moderate the excessive flow to the lungs.

CLINICAL FEATURES

With severe pulmonary stenosis, the systolic ejection murmur is usually loud; with pulmonary atresia, no murmurs may be heard except in the presence of AV valve insufficiency. An aortic ejection click may be heard; the second heart sound is usually single and loud. With markedly increased pulmonary blood flow, cyanosis may be quite mild, the systolic ejection murmur pansystolic, the second heart sound loud and narrowly split, and a third heart sound and short mid-diastolic rumble are often present.

The chest radiograph establishes the extent of cardiomegaly and pulmonary blood flow and the shape of the heart silhouette—straightened left heart border is often characteristic and should suggest the diagnosis of a single left ventricle with small rudimentary right ventricular outflow tract associated with l-malposition of the great arteries.

The electrocardiogram is nonspecific, presenting either right- or left-axis deviation and a precordial QRS pattern suggesting either right, combined ventricular, or left ventricular dominance. Large unchanging equiphasic or negative complexes across the entire precordium should raise a suspicion of single-ventricle malformation.

Two-dimensional echocardiography can establish the diagnosis of single-ventricle complex and provide additional anatomic details such as the presence of 2 AV orifices or 1 large common orifice, the orientation of the rudimentary outflow chamber, pulmonary outflow tract stenosis, and possibly anomalous pulmonary venous connections.

CARDIAC CATHETERIZATION

Cardiac catheterization and angiography may be helpful in differentiating certain particularly complex malformations such as “criss-cross” or “upstairs-downstairs” hearts and for identifying pulmonary or subpulmonary stenosis, measuring the pulmonary vascular resistance, establishing the anatomic course of the rudimentary small outlet chamber and the spatial relationships and connections of the cardiac chambers and great vessels, and determining the details of abnormal pulmonary or systemic venous connections. Magnetic resonance imaging is also helpful for assessing complex anatomic details.

TREATMENT

The management of single ventricle is discussed in detail in Chapter 492. The clinical course and prognosis are often grave, but palliation and long-term salvage have been effected for infants with decreased pulmonary blood flow by surgically creating either systemic-pulmonary or cavopulmonary anastomoses and for infants with increased pulmonary blood flow by pulmonary artery banding, with subsequent progression to the modified Fontan circulation. If there is subaortic stenosis, the proximal pulmonary arterial trunk can be anastomosed to the aorta (Damus-Kaye-Stansel procedure). Occasionally, a prosthetic septum has been successfully placed in some forms of single-ventricle hearts. These formidable procedures have been significantly aided by the recent recognition in such hearts of abnormal disposition of the cardiac specialized conduction tissue arising from an anterior rather than a normal posterior AV node and coursing as the bundle of His astride the anterior (conal) septum.

TRUNCUS ARTERIOSUS

Truncus arteriosus, constituting 2% of all congenital heart lesions, is characterized by the emergence of only a single arterial trunk from the ventricular chambers, and this vessel supplies the coronary, pulmonary, and systemic circulations proximal to the aortic arch. A truncal valve, usually with 3 or 4 leaflets, overrides a ventricular septal defect, which is always present. The pulmonary arteries generally arise as a single vessel or as 2 separate vessels from the posterior or lateral wall of the truncus. Truncus arteriosus must not be confused with the relatively common lesion tetralogy of Fallot with pulmonary atresia, also characterized by a single large vessel—the aorta—that arises from the heart. In tetralogy of Fallot with pulmonary atresia, however, there is a hypoplastic or atretic pulmonary artery attached to the right ventricular outflow region, and the lungs are supplied with blood by pulmonary arteries arising from a ductus arteriosus or from major aortopulmonary collateral vessels usually arising from the thoracic descending aorta. Similar to these patients, though, a large percentage of infants with truncus arteriosus have partial deletion of chromosome 22q11. About 30% to 50% have a right aortic arch. Rarely, interrupted aortic arch is present with the descending aorta being supplied from the main pulmonary artery via the ductus arteriosus.

HEMODYNAMICS

The right and left ventricles eject blood at systemic pressure into the common arterial trunk; thus, the coronary arteries, pulmonary arteries, and aorta receive a mixture of venous and oxygenated blood at systemic pressure. Pulmonary flow is markedly increased in infancy because there are usually primary pulmonary artery branches of adequate size and the pulmonary vascular resistance is initially not greatly increased. Consequently, cyanosis is minimal, and the hemodynamics as well as the clinical picture are those of a large left-to-right shunt. The pulmonary circulation may be restricted in a few patients by the development of pulmonary vascular obstructive disease or rarely by hypoplastic or stenotic pulmonary arteries arising from the truncus; in 16% of patients, 1 pulmonary artery is absent.

CLINICAL FEATURES

Symptoms usually appear in the first weeks or months of life and are consistent with a large left-to-right shunt: left heart failure, dyspnea, wheezing, frequent respiratory infections, and poor physical development. Failure to thrive is universal. In the infant, cyanosis is often not apparent or is minimal at rest because the pulmonary blood flow is so high. The heart is hyperdynamic, and peripheral pulses are prominent or bounding. The second heart sound is loud and single because of the single set of semilunar valves. A prominent systolic ejection click is heard very commonly at the lower and middle left sternal border. A harsh systolic murmur may best be heard along the middle left sternal border, and a continuous murmur can be heard at the base or lateral chest wall in older infants and children. In newborn or young infants, particularly those with marked congestive heart failure, only a systolic murmur may be heard, similar to the findings in some newborn infants with a large patent ductus arteriosus. Severe truncal valve regurgitation may be suspected from a prominent to-and-fro quality in the murmur. Truncal valve stenosis occurs rarely.

If pulmonary flow is restricted, either by high pulmonary vascular resistance or by stenotic or hypoplastic pulmonary arteries, cyanosis is more severe, congestive heart failure is unusual, only a minimal systolic murmur of short duration and low intensity is heard, and there may be a faint continuous bruit representing bronchial pulmonary collateral flow.

Radiographic findings also depend on the size of the pulmonary arteries and the pulmonary blood flow pattern. In most infants there is considerable cardiac enlargement, with increased pulmonary vascular markings. When pulmonary blood flow is decreased, both heart size and pulmonary vascular markings are less prominent. A right aortic arch is common (30–50%), and the hilar origin of the pulmonary artery may appear superiorly displaced.

The electrocardiogram demonstrates right ventricular or combined ventricular hypertrophy but may demonstrate ST-segment and T-wave inversion in the precordial leads. This particular finding has been associated with low diastolic blood pressures and anatomically small coronary artery openings.

Two-dimensional echocardiography establishes the diagnosis by demonstrating a large, single arterial vessel overriding the ventricular septum and identifying a main or primary branch pulmonary artery arising directly from this common trunk. The ductus arteriosus is often absent except with an interrupted aortic arch. Cardiac catheterization is rarely indicated in the young infant, but, if performed, selective angiography reveals the common trunk arising from the heart and the origin of the pulmonary arteries from the truncus.

TREATMENT

The prognosis is variable, depending to a considerable degree on the pulmonary blood flow pattern; about 75% of infants if unoperated die within the first 3 to 12 months from heart failure. Corrective surgery is quite successful, provided the patient is free from significant pulmonary vascular disease, which often develops by 3 to 4 months of age. The ventricular septal defect is closed to leave the aorta arising from the left ventricle, the pulmonary arteries are removed from their truncal origin, and a valved conduit is placed from the free right ventricular wall to the pulmonary arteries to form a new right ventricular outflow tract (Rastelli procedure). At present, the lowest operative mortality and the highest long-term survival are achieved by corrective surgery done under 3 months of age. The child will have the periodic conduit changes as he or she grows. Truncal valve regurgitation, modest in about 25% but severe in about 5% to 10%, remains an important factor in late mortality; sometimes truncal valve replacement is needed.

MALPOSITIONS

A heart abnormally situated in the thorax is said to show malposition. Such hearts often have abnormalities of chamber localization and great artery attachments as well as septal defects, valve anomalies, and outflow obstructions. Describing the basic structure of such a complex heart requires description of 3 cardiac segments (atria, ventricles, and great arteries) and should include not only positional interrelationships but also connections of ventricles to atria and great arteries.

SITUS AND ATRIA

The right and left atria may be regarded as extensions of the systemic and pulmonary veins, respectively, so that the body situs indicates the positions of the atria. Body situs is determined by certain organs that are normally asymmetric. The normal body configuration, situs solitus, is characterized by a right lung with 3 lobes and an eparterial bronchus, a left lung with 2 lobes and a hyparterial bronchus, asymmetric tracheobronchial branching, a liver with a major lobe on the right, a left-sided stomach and spleen, right-sided venae cavae, morphologically distinct atria, and a specific orderly arrangement of the gastrointestinal tract. Situs inversus is characterized by a mirror-image configuration of the asymmetric organs, including the gastrointestinal tract. In addition to these 2 asymmetric forms of situs, 2 roughly symmetric body configurations have been found with right and left atrial isomerism. Right atrial isomerism is characterized by bilateral right-sidedness, with bilateral 3-lobed lungs, each with a typical right bronchial branching pattern, a horizontal liver with equal-sized lobes, and bilateral morphologic right atria, each with a sinoatrial node. The spleen is usually absent (asplenia), and this may also be regarded as a feature of bilateral right-sidedness. In contrast, left atrial isomerism is characterized by bilateral left-sidedness involving lungs, bronchi, and the atria. There are usually multiple (2–30), roughly equal-sized spleens with a total mass equal to that of a normal-sized spleen clustered together on both sides of the dorsal mesogastrium (polysplenia). This is in contrast to accessory spleens, which are small isolated splenic masses in addition to a normal spleen. Malrotations of the bowel are common in both asplenia and polysplenia. Right and left atrial isomerism replace the terms asplenia and polysplenia, respectively, because splenic morphology and isomerism do not always match. In general, organ symmetry is more variable with left than with right isomerism.

VENTRICLES

The primitive cardiac tube normally bends to the right and forms a d-loop, so that the anatomic right ventricle lies to the right of the anatomic left ventricle. Such a loop is appropriate or concordant for a situs solitus individual; that is, the right atrium connects to the right ventricle, and the left atrium connects to the left ventricle. Conversely, an l-loop is concordant for a situs inversus individual. Occasionally a discordant loop forms (l-loop in situs solitus or d-loop in situs inversus); the anatomic right atrium connects to the anatomic left ventricle, and anatomic left atrium connects to anatomic right ventricle.

GREAT ARTERIES

Great arteries may be described by their ventricular connections and positional interrelationships. Ventricular connections may be normal (pulmonary artery from right ventricle, aorta from left ventricle), double-outlet right or left ventricle (DORV or DOLV, respectively), or transposition (aorta from right ventricle, pulmonary artery from left ventricle). The positional interrelationships may be described as d (dextro), where the aortic valve is to the right of the pulmonary artery; l (levo), where the aortic valve is to the left; or o (ortho), where the aorta is directly in front of the pulmonary artery—these terms are not to be confused with d-loops and l-loops. Usually great-artery interrelationships reflect ventricular interrelationships; however, there are enough exceptions that description of both segments is preferable.

The right ventricular infundibulum (or conus) is usually the most anterior cardiac structure and connects with the anterior great artery. Accordingly, normally related great arteries usually have an anterior pulmonary artery, transpositions have an anterior aorta, and double-outlets tend to have side-by-side vessels. Vessels arising from the left ventricle almost always lack a conus, and so their valves are more caudad than are those arising from the right ventricle.

Discordant loops (solitus/l-loop or inversus/d-loop) are almost always associated with transposition of the great arteries. The sequential arrangement of chambers and great arteries in these patients is such that the flow is potentially normal, and so these lesions have been called (physiologically) corrected transposition of the great arteries. Any abnormal circulation in these hearts is the result of associated abnormalities such as septal defects or AV valve stenoses or regurgitation, 1 or more of which occur in nearly all. The conduction pathways are also abnormal and may produce various degrees of AV block.

CARDIAC POSITION

A heart predominantly in the left hemithorax is termed levocardia and is normal for situs solitus. If the heart is mainly in the right hemithorax, it is referred to as dextrocardia, the normal for situs inversus. Cardiac position within the thorax may be influenced by external forces (eg, a hypoplastic right lung or left diaphragmatic eventration may displace the heart to the right). In the absence of such external factors, cardiac position is most closely related to concordance or discordance of the bulboventricular loop. Concordant loops nearly always have normal ventricular position for that situs—that is, left-sided heart for situs solitus and right-sided heart for situs inversus. Exceptions are few and tend to be accompanied by less severe, if any, cardiac abnormalities. Discordant loops in situs solitus or situs inversus and (because atrial symmetry precludes concordance) all loops in atrial isomerisms have variable cardiac positions; for example, an l-loop in situs solitus (or atrial isomerism) can have a right-sided, left-sided, or midline heart. Similarly, a d-loop in situs inversus or atrial isomerism can have any position.

VASCULAR RINGS AND SLINGS

These anomalies arise from abnormal persistence and dissolution of all or some of the paired embryonic aortic arches that connect the embryonic truncus arteriosus to the paired dorsal aortas. Abnormal development of these arteries may produce no symptoms (aberrant right subclavian artery, right aortic arch) or may press on the esophagus or trachea and cause dysphagia and airway obstruction. Therefore, diagnosis can usually be made by examining the characteristic indentations that the abnormal arteries make on the barium-filled esophagus or the trachea. Confirmation by echocardiography, computerized tomography, or magnetic resonance imaging has replaced aortography. Physical examination of the heart and the electrocardiogram are usually normal.

Infants with severe obstructions are very ill with vomiting, choking, and often dysphagia, so that feeding and weight gain are poor. Wheezing and stridor, usually inspiratory, are often prominent and made worse by feeding. Frequently, these infants hyperextend their heads to reduce tracheal compression. Episodes of cyanosis, apnea, or unconsciousness occur. Most of these infants develop symptoms before 3 months of age. Less severe obstruction may present with recurrent respiratory infections.

The most common anomaly is an aberrant right subclavian artery. When the proximal rather than the distal part of the right fourth arch is absorbed, the right subclavian artery runs posteriorly from the descending thoracic aorta to reach the right arm, passing obliquely up and to the right behind the esophagus and indenting it posteriorly. This anomaly so rarely causes symptoms that even if it is found, some other cause of esophageal or respiratory symptoms should be sought. On the other hand, some children with dysphagia are cured when the artery is repositioned. In adults, many of these aberrant arteries develop aneurysms at their origins, and these can rupture.

If the distal fourth arch disappears on the left rather than on the right, there will be a right aortic arch and a mirror-image arrangement of arteries to the arms and head. This is not a cause of symptoms, but the prominent radiographic shadow that the arch casts on the right side of the mediastinum may be mistaken for enlarged nodes or a tumor. A right aortic arch is found in about 25% of patients with the tetralogy of Fallot and about 50% with truncus arteriosus.

Most anomalies that cause serious symptoms encircle the esophagus and trachea to form a vascular ring. The most common of these is the double aortic arch, which can result from failure of absorption of any part of the embryonic fourth arches. The right and left arches indent the right and left sides of the trachea and the esophagus, and the right arch indents the esophagus posteriorly as it passes to the left behind the esophagus to join the left arch, usually the smaller arch, and form the descending aorta. Sometimes the descending aorta is right sided, and the left arch is retroesophageal. Division of one of the arches, usually the smaller posterior one, opens the constricting ring and is curative; this can be done by open or thoracoscopic surgery. However, deformity of the tracheobronchial tree may cause residual postoperative airway problems.

Almost as common is the right aortic arch that becomes a constricting ring because of a retroesophageal left-sided patent ductus arteriosus or ligamentum arteriosum. The combination produces indentations on the esophagus and trachea similar to those that occur with a double arch. Division of the ductus or ligamentum is curative. Note that infants with any of these aortic arch anomalies may have a complete or partial DiGeorge syndrome, associated with a deletion in chromosome 22q11.