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At a glance

Primary Pulmonary Hypertension is a progressive disease characterized by raised pulmonary vascular resistance, which results in impaired right-heart function as a consequence of the increased right ventricular afterload and occurring in the absence of an identifiable cause.

Synonyms

Idiopathic Pulmonary Hypertension (IPAH); Pulmonary Hypertension (PHT); Precapillary Pulmonary Hypertension.

History

First described clinically and hemodynamically in 1951 by American physician D. T. Dresdale.

Incidence

Approximately 1 to 3:1,000,000 population per year in the United States and internationally.

Genetic inheritance

Autosomal dominant inheritance with incomplete penetrance and a 2.5:1 female predilection. A worsening of the disease occurs in successive generations.

Pathophysiology

Primary pulmonary hypertension (PPH) is caused by heterozygous mutation in the BMPR2 gene located at chromosome 2q33 in 75% of patients. In addition, 10 to 20% of patients with idiopathic pulmonary arterial hypertension have these mutations. Further autosomal-dominant mutations in ACVRL1, ENG, CAV1, and KCNK3 genes have been identified to cause primary pulmonary hypertension. Current theories on pathogenesis focus on abnormalities in interaction between endothelial and smooth muscle cells. Endothelial-cell injury may result in an imbalance in endothelium-derived mediators, favoring vasoconstriction. Defects in ion-channel activity in smooth muscle cells in the pulmonary artery may contribute to vasoconstriction and vascular proliferation. Inflammatory oxidant mechanisms and deficiency in nitric oxide (NO) have also been implicated in the pathogenesis of pulmonary hypertension. In addition, the findings of frequent monoclonal endothelial cell proliferation in PPH also suggest that a somatic genetic alteration similar to that present in neoplastic processes might be responsible for the pathogenesis of PPH.

Diagnosis

On chest radiography, the width of the pulmonary arteries is increased and the peripheral lung fields are clear. The electrocardiogram demonstrates right ventricular hypertrophy, as does echocardiography. Cardiac catheterization with measurement of pulmonary artery pressures demonstrates elevation of systolic pulmonary artery pressure greater than 35 mmHg or mean pulmonary artery pressure greater than 25 mmHg. Histology shows extension of muscle layers into small pulmonary arteries that are normally nonmuscular. The cross-sectional area of the pulmonary vascular bed is also decreased. Histopathology shows plexiform lesions composed of proliferating endothelial cells present in 20 to 80% of cases of primary pulmonary hypertension. Other diagnostic testing primarily excludes secondary causes. Clinical genetic testing for BMPR2, ACVRL1, ENG, SMAD9, CAV1, and KCNK3 is available.

Clinical aspects

Neonatal pulmonary hypertension results in right-to-left shunting via the foramen ovale, or ductus arteriosus, or both. Right-heart failure is inevitably present. It is usually lethal. In older children or adults, the predominant symptoms include exertional dyspnea and fatigue, which result from fixed cardiac output in response to exertion. PPH occurs most commonly in young and middle-age women; mean survival from onset of symptoms ...

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