Pulmonary arterial hypertension (PAH) is a complex disease state that can be difficult to diagnose accurately and to treat effectively. It is defined as a sustained increase in pulmonary arterial pressure to more than 25 mm Hg at rest or to more than 30 mm Hg with exercise, with a mean pulmonary capillary wedge pressure and left ventricular end-diastolic pressure of less than 15 mm Hg.1 PAH has an estimated prevalence of 30 to 50 cases per million, and idiopathic pulmonary hypertension has an incidence rate of one to two cases per million per year.2
In 2003, the World Health Organization reclassified pulmonary hypertension into five broad categories: (1) pulmonary hypertension, including idiopathic (primary) pulmonary hypertension; (2) pulmonary hypertension involving the left side of the heart; (3) pulmonary hypertension associated with hypoxemia or chronic obstructive pulmonary disease; (4) pulmonary hypertension as a result of chronic thrombotic disease, embolic disease, or both; and (5) miscellaneous (pulmonary hypertension associated with sarcoidosis, Langerhans cell histiocytosis, or compression of pulmonary vessels). Vasoconstriction, remodeling of the pulmonary vessel wall, and thrombosis in situ are thought to cause the increased pulmonary vascular resistance that characterizes this disease.3 Endothelial dysfunction is also a culprit. These findings suggest that perturbations in the normal relationships between vasodilators and vasoconstrictors (endothelin-1), between growth inhibitors and mitogenic factors, and between antithrombotic and prothrombotic determinants are present.4
In addition to these intrinsic determinants, there are three associated environmental factors that have strong associations with the development of PAH. Hypoxia induces vasodilation in systemic vessels but induces vasoconstriction in the pulmonary vasculature.4 Anorexogens have been associated with the development of PAH since the 1960s. The most recent culprits are fenfluramine (Pondimin) and dexfenfluramine (Redux), which were developed in the 1980s. It has been noted that an increase in pulmonary pressure can occur after as little as 3 to 4 weeks of exposure to these agents.4 Central nervous system stimulants, such as cocaine and methamphetamine, have also been associated with an increased risk of PAH. An autopsy study of 20 heavy cocaine users showed that the lungs of four of them had medial hypertrophy of the pulmonary arteries without evidence of foreign body embolization.4
Several coexisting conditions have been associated with an increased propensity toward PAH. Connective tissue disorders have a high correlation with PAH. Diffuse scleroderma is associated with PAH in as many as one third of patients, and limited scleroderma (CREST syndrome [calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telan-giectasia]) occurs in as many as 50% of patients with PAH. Patients with systemic lupus erythematosus also have PAH, although less commonly than those with scleroderma.5
Human immunodeficiency virus (HIV) infection and its association with PAH is well documented, although the mechanisms remain unclear.5 The cumulative incidence of PAH was 0.6% in a cohort of HIV-infected patients, a rate 6 to 12 times as high as in the general population. PAH was diagnosed in all stages of HIV infection without a relationship to CD4 cell count, but it appears to be related to the duration of infection.4
There is an uncommon association between portal hypertension and PAH. Hemodynamic studies have found PAH in 2% to 5% of patients with cirrhosis; the prevalence may be higher (3.5% to 8.5%) in patients referred for liver transplantation.4 Certain hemoglobinopathies have a high concurrence with PAH. In patients with sickle cell anemia, the estimated incidence of PAH as shown by echocardiography varies between 8% and 30%. Recent studies have confirmed that PAH increases the risk of death in patients with sickle cell disease.4
A diagnosis of PAH should be considered in patients who present with breathlessness in the absence of overt signs of specific heart or lung disease. Other symptoms of PAH can include fatigue, weakness, angina, syncope, and abdominal distention. The presence of these symptoms at rest is reported only in very advanced cases.6 One of the initial physical findings is the increased intensity of the P2 heart sound. Auscultation may reveal a systolic ejection murmur.
A large a wave in the jugular venous pulse may occur due to reduced compliance of the hypertrophied right ventricle. A left parasternal (right ventricular) heave may be noted. Late findings in PAH include hepatomegaly, peripheral edema, and ascites, which are signs of right ventricular failure.5
Severe PAH may be associated with prominent v waves in the jugular venous pulse as a result of tricuspid regurgitation, and an S3 may possibly be pres-
ent. Uncommonly, the left laryngeal nerve may become paralyzed as a consequence of compression by a dilated pulmonary artery (Ortner’s syndrome).5
Confirmation of PAH requires certain diagnostic tests. The electrocardiogram (ECG) may provide evidence suggestive of PAH. It may show right ventricular hypertrophy or strain. Findings of chronic right ventricular overload, such as right axis deviation and incomplete or complete right bundle branch block, may also be present. However, the ECG does not have sufficient sensitivity (55%) and specificity (70%) to be a screening tool for detecting significant PAH.6 The classic chest radiograph may show central pulmonary arterial dilation and loss (pruning) of peripheral blood vessels in patients with PAH. In later disease, there may be right ventricular and right atrial dilatation.
Transthoracic echocardiography (TTE) is an excellent noninvasive screening test for the patient suspected of having PAH. TTE usually shows enlargement of the right atrium and ventricle with normal or small left ventricular dimensions.5 Abnormal ventricular septal motion as a result of right ventricular volume and pressure overload is characteristic.5
Doppler echocardiographic quantitation of pulmonary artery pressure can be obtained by measuring the maximum velocity (Vmax) of the tricuspid regurgitant jet and by using the Bernoulli formula (P = 4V2), where P = pressure and V = velocity. Doppler echocardiography sometimes overestimates the pulmonary artery pressure and may even suggest PAH in normal individuals.5
The use of the 6-minute walk test can be effective in evaluating patients with known PAH. In randomized clinical trials, results of the 6-minute walk have been shown to be an independent predictor of mortality.5 Cardiac cathe-terization (of the right and left sides
of the heart) is the gold standard for diagnosis and quantification of PAH. It also allows for an assessment of prognosis. PAH cannot be confirmed without cardiac catheterization.
The diagnosis of PAH does not necessarily preclude an active lifestyle. Patients with advanced PAH and symptoms of dizziness, lightheadedness, or severe dyspnea are at increased risk for life-threatening syncope, however.3
Women of childbearing age should be counseled against pregnancy. Pregnancy in patients with PAH is associated with an unacceptably high maternal and fetal mortality rate.5 When chronic hypoxemia develops in the setting of PAH, supplemental oxygen therapy is indicated to maintain oxygen saturation above 90%.3
Diuretic therapy appears to have a marked benefit in patients with PAH. Clinical improvement has been achieved with diuretics in patients with right-sided heart failure.3 The fear that diuretics will induce systemic hypotension is unfounded because the main factor limiting cardiac output is pulmonary vascular resistance, not pulmonary blood volume.5
Digoxin (Lanoxin) may be most beneficial in the treatment of PAH patients with concomitant intermittent or chronic atrial fibrillation. There are no data from long-term, randomized, double-blind studies to provide clear treatment guidelines regarding the use of digitalis.3
The rationale for treating PAH patients with anticoagulant therapy is based on the presence of traditional risk factors for venous thromboembolism. These include congestive heart failure, sedentary lifestyle, and thrombophilic disposition. There are no data to specifically support the use of anticoagulation therapy in PAH. The consensus from limited studies is that a target international normalized ratio of 1.5 to 2.5 is recommended.3
Prostacyclin is the main product of arachadonic acid in the vascular endothelium. It induces the relaxation of the vascular endothelium and vascular smooth muscle by stimulating production of cyclic adenosine monophosphate (c-AMP).3 Epoprostenol sodium (Flolan) has been approved for the treatment of PAH since the 1990s. Continuous pump infusion epoprostenol has been shown in randomized clinical trials to improve quality of life and symptoms related to primary pulmonary hypertension. Benefits included improved results for the 6-minute walk test, decline in mean atrial pressure, decline in mean pulmonary pressure, and increase in cardiac output.5
Iloprost (Ventavis) is a chemically stable prostacyclin analogue that is available in an aerosol formulation.6 One study showed a reduction of 10% to 20% in mean pulmonary artery pressure after a single inhalation of iloprost, which lasted for 45 to 60 minutes.6 Because of the short half-life of iloprost, however, frequent inhalations are required (up to 12 times per day).5 Overall, inhaled iloprost was well tolerated, with cough, flushing, and headache being the most common side effects.6 At present, iloprost is not available in the United States.5
In addition to exerting a direct vasoconstrictor effect, endothelin-1 stimulates the proliferation of vascular smooth muscle cells, induces fibrosis, and is a proinflammatory mediator.3 Bosentan (Tracleer) is a nonselective endothelin-receptor blocker that is approved by the Food and Drug Administration (FDA) for the treatment of PAH. In a 12-week, placebo-controlled trial of 32 patients with PAH, bosentan was superior to placebo in increasing the distance walked in the 6-minute walk test (mean gain, 76 m) and in improving hemodynamic measurements.3 Patients receiving bosentan also had improvement in the time to clinical worsening, which included lung transplantation, hospitalization for PAH, and death.3
The treatment of pulmonary hypertension has been handicapped in the past by limited therapeutic choices. Recently, the FDA has approved sil-denafil, under the trade name Revatio, for the treatment of pulmonary hypertension. In a double-blind study versus placebo involving 277 patients, sildenafil was shown to increase (placebo corrected) the 6-minute walk distances of 45 to 50 m; effects were seen at the 4-week mark. The effects were sustained until the close of the study at 12 weeks. There was also a notable decrease in mean pulmonary artery pressure and systemic vascular resistance.7
It is becoming increasingly apparent that the combination of pathophysiology of disease and targeted pharmacotherapy are changing the treatment of this disease. The approval of sildenafil represents a continuation of the progress that has been made in treating this debilitating disease state.