C h a p t e r 2 3
Disorders of Ventilation and Gas Exchange
591
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
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
A
B
D
C
Normal
Hypertrophic
muscularis
Intimal
fibrosis
Endothelium
Internal
elastic lamina
Muscularis
Pulmonary
hypertension (early)
Pulmonary
hypertension (late)
External
elastic lamina
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
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.)
