Porth's Essentials of Pathophysiology, 4e

591

Disorders of Ventilation and Gas Exchange

C h a p t e r 2 3

penetrance, with some individuals inheriting the trait without exhibiting the disease. A causal relationship has been established between several appetite-suppressant drugs, including fenfluramine, and the development of PAH. Although the drug has been removed from the world market, many were exposed before that time. Pulmonary arterial hypertension is also associated with human immunodeficiency virus (HIV) infection. The mechanism by which HIV infection produces PAH remains unknown, but treatment of HIV infection does not appear to affect the severity or natural history of the underlying pulmonary hypertension. Other condi- tions associated with PAH include portal hypertension and persistent pulmonary hypertension in the newborn. Although the specific mechanisms responsible for the vascular changes that occur in PAH remain unknown, a number of mechanisms have been proposed 64 including diminished levels of nitric oxide and prostacyclin, two potent vasodilators. Nitric oxide is produced locally in the lungs, and prostacyclin is produced by the vascu- lar endothelium. Moreover, increased levels of several growth factors, including endothelin-1, vascular endo- thelial growth factor, and platelet-derived growth fac- tor, may contribute. Endothelin-1 is a peptide produced by the vascular endothelium that has potent vasocon- strictor and paracrine effects on vascular smooth mus- cle. Results of studies relating these mechanisms to the structure and function of the pulmonary arterial circula- tion have already been translated into targeted therapies for PAH. Symptoms of PAH typically progress from shortness of breath and decreasing exercise tolerance to right heart failure, with marked peripheral edema and functional limitations. Other common symptoms include fatigue, angina, and syncope (fainting) or near-syncope. The diag- nosis of primary pulmonary hypertension is based on an elevated pulmonary artery pressure and an absence of disorders that cause secondary pulmonary hypertension. Treatment for primary pulmonary hypertension con- sists mainly of measures to improve right heart function as a means of reducing fatigue and peripheral edema. Supplemental oxygen may be used to increase exercise tolerance. The calcium channel blockers (nifedipine, dil- tiazem) may be effective early in the course of the dis- ease but offer little in advanced stages. More recent medications for treatment of primary pulmonary arterial hypertension include prostacy- clin analogues, endothelin receptor antagonist, and phosphodiesterase type 5 inhibitors. Continuous long- term infusion of prostacyclin (e.g., epoprostenol), a potent pulmonary vasodilator, has been shown to pro- vide symptomatic benefits and improved survival in selected patients. 63–66 Because of its short half-life (3 to 5 minutes), the drug must be administered by continu- ous intravenous infusion through an indwelling cath- eter with an automatic ambulatory pump. Properties of the drug other than its vasodilating effects include inhibition of platelet aggregation and beneficial vascu- lar remodeling effects. Endothelin, which is a potent vasoconstrictor and stimulator of vascular smooth muscle proliferation, is believed to be important in the

Endothelium

Muscularis

Internal elastic lamina

External elastic lamina

A

Normal

Hypertrophic muscularis

Intimal fibrosis

B

C

Pulmonary hypertension (early)

Pulmonary hypertension (late)

D

It is a rare and debilitating disorder characterized by abnormal proliferation and contraction of vascular smooth muscle, coagulation abnormalities, and marked intimal fibrosis leading to obliteration or obstruction of the pulmonary arteries and arterioles (Fig. 23-14). The resulting increase in pulmonary artery pressure results in progressive right heart failure, low cardiac output, and death if left untreated. A familial form of PAH appears to be inherited as an autosomal dominant trait with a variable but low occluded by concentrically thickened intimal fibrosis and thickening of the media due to pulmonary arterial hypertension. (From Bearsley MB,TravisWD, Rubin E.The respiratory system. In: Rubin R, Strayer DS, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer Health | Lippincott Williams & Wilkins; 2012:592.) FIGURE 23-14. (A) Normal pulmonary artery. (B) Mild pulmonary hypertension with thickening of the media of the pulmonary artery. (C) Pulmonary artery with extensive intimal fibrosis and thickening of vascular smooth muscle. (D) Micrograph of a small pulmonary artery that is virtually