Primary (or idiopathic) pulmonary hypertension is an uncommon disease, the diagnosis of which can be established only after a thorough search for the usual causes of pulmonary hypertension. The patient with primary pulmonary hypertension typically is a young female between the ages of 20 and 40, although older and younger patients of either sex have been described. The clinical and laboratory features of severe pulmonary hypertension are present, but there is no evidence of parenchymal pulmonary disease or of primary heart disease, nor is there evidence for the occurrence of pulmonary emboli. Anatomic verification often has been necessary to distinguish clearly the primary form of pulmonary hypertension from that due to multiple pulmonary emboli, although angiography and radioisotope scanning methods have facilitated this differentiation considerably.
The findings on pathologic examination of patients with primary pulmonary hypertension usually are confined to the right side of the heart and lungs. The right atrium often is enlarged and the right ventricle is hypertrophied. Frequently, the large pulmonary arteries exhibit atherosclerotic plaques. The disease process involves the small pulmonary arteries (between 40 and 300 u.m in diameter), which exhibit muscular hypertrophy and intimal hyperplasia, sometimes with fibrosis. On occasion, a necrotizing arteritis may be encountered. Other histologic studies have shown a reduced number of small arteries, as well as fewer capillaries in the alveolar wall. Electron-microscopic studies have documented an increase in thickness of the endothelial cells and basement membranes of alveolar capillaries, and some capillaries are blocked by the abnormal epithelial cells. Medial hypertrophy of muscular pulmonary arteries may be the first response to prolonged pulmonary vasoconstriction, but in later stages of the disease concentric laminar intimal fibrosis and plexiform lesions appearing as cellular, intraluminal tufts (so-called plexogenic pulmonary arteriopathy) may develop. Patients with recurrent pulmonary thromboembolism may clinically resemble patients with primary pulmonary hypertension, but histologic sections of the lung exhibit various degrees of organization of pulmonary thromboemboli; some may be recanalized, there may be fibrous septa and eccentric fibrosis in the vessels; secondary medial hypertrophy of muscular arteries may be marked, but plexiform lesions arc not present. In infants and young children with pulmonary venoocclusive disease the clinical picture may suggest primary pulmonary hypertension, and the pulmonary wedge pressure may be normal. Organized thrombotic disease is found in the venules and small veins, together with proximal hypertrophy of the muscular venous wall and secondary medial hypertrophy in the pulmonary arterioles.
Rarely, disease of the systemic arterial vascular bed resembling that found in the pulmonary blood vessels has been described. The syncope and sudden death which may occur in this disease have been attributed in some patients to involvement of the coronary arterial branch supplying the sinoatrial node.
The cause of primary pulmonary hypertension is unknown, but a number of possible etiologic factors have been suggested. A few patients with primary pulmonary hypertension have been reported in whom minimal changes were found in the pulmonary vessels on pathologic examination, and this observation has raised the possibility that a neurohumoral vasoconstrictor mechanism is involved. Support for this view has been provided by the observation that the pulmonary vascular resistance can be acutely reduced in some patients with this disease by the infusion of vasodilators, or by administering oxygen. A febrile illness may precede the onset of the disease by a variable period and has been implicated in the etiology. In 15 to 20 percent of female patients with this disorder, symptoms begin soon after pregnancy, which has prompted the suggestion that unrecognized thromboemboli or amniotic fluid emboli during pregnancy may play a role. In other patients, it seems quite possible that the disease may represent an end stage of earlier, unrecognized emboli originating from the legs or pelvic veins. An apparent association between an increased occurrence of primary pulmonary hypertension and use of the anorectic agent aminorex fumarate, a drug having structural similarity to ephedrine, was observed in Europe between 1967 and 1970. The alkaloids in many species of crotalaria plants used in herbal brews may cause pulmonary hypertension in human beings, as demonstrated experimentally in rats. The use of oral contraceptives may bear a relation to the occurrence of pulmonary hypertension, particularly in patients with predisposing factors such as systemic lupus erythematosus or a family history of primary pulmonary hypertension.
Raynaud’s phenomenon precedes the onset of primary pulmonary hypertensive disease by a number of years in an appreciable number of patients. This association and the occurrence of Raynaud’s disease in scleroderma, disseminated lupus erythematosus, rheumatoid arthritis, and dermatomyositis have led to the speculation that primary pulmonary hypertension may represent a form of collagen vascular disease. Moreover, primary pulmonary hypertension and collagen vascular disease, including lupus erythematosus, have been reported to occur simultaneously in a number of patients. It also has been suggested that the disease may be congenital and present from birth: however, the closely packed, parallel elastic fibers in the main pulmonary arteries in patients having Eisenmenger’s syndrome from birth, described by some investigators, usually have not been observed in patients with primary pulmonary hypertension. Finally, primary pulmonary hypertension has been reported in a number of families: sometimes more than two members and up to three generations have been affected. A fibrinolytic defect was reported in one family study.
Some studies have suggested that the response of the pulmonary vascular bed is labile early in the course of this disease, as evidenced by a response to vasodilating agents and oxygen. It also has been proposed that the disease tends to progress. Thus, serial cardiac catheterizations have shown a tendency for the pulmonary vascular resistance to increase and to become fixed. With the development of severe pulmonary vascular disease, abnormal elevation of the pulmonary arterial pressure occurs, often to a striking degree, and the pulmonary arterial pressure may be equal to that in the systemic arterial bed. The pulmonary arterial wedge pressure is normal in patients with primary pulmonary hypertension, the cardiac output is normal or reduced, and no intracardiac shunts are detected. In many patients the mean right atrial pressure is elevated, and the a wave in the right atrium may be markedly elevated, an indication of the forceful atrial contraction necessary to fill the hypertrophied right ventricle. With the long-standing overload on the right side of the heart, right ventricular failure finally develops. In some patients, peripheral cyanosis occurs secondary to reduced cardiac output, and occasionally central cyanosis becomes evident at the end stage of the disease because of right-to-left shunting through a patent foramen ovale. Mild systemic arterial desaturation is quite common, even in the absence of heart failure, and may be due to shunting within the lungs. Pulmonary function in patients with primary pulmonary hypertension generally is normal, although hyperventilation often is present, resulting in hypocapnia and a decreased serum bicarbonate concentration. A low carbon monoxide-diffusing capacity has been described in some patients.