Diagnosis

Symptoms, Signs, and Clinical History

Because of the insidious onset of symptoms, PAH is often advanced at the time of diagnosis. Dyspnea on exertion is a common presenting symptom, but it is sometimes attributed to deconditioning or other cardiorespiratory ailment. Chest pain, mimicking angina pectoris, may occur. Patients with advanced disease may present with syncope or signs and symptoms of right-sided heart failure, including lower extremity edema, jugular venous distention, and ascites.

The clinical history should focus initially on exclusion of underlying causes of PH. Important clues to an underlying condition might include previous history of a heart murmur, deep venous thrombosis or pulmonary embolism, Raynaud’s phenomenon, arthritis, arthralgias, rash, heavy alcohol consumption, hepatitis, heavy snoring, daytime hypersomnolence, morning headache, and morbid obesity. A careful family history should be obtained. Medication exposures, particularly to appetite suppressants and amphetamines, should be noted. Cocaine is a powerful vasoconstrictor and may contribute to the development of PH. Intravenous drug abuse has been associated with the development of PAH.

Physical Examination

Signs of PAH may not become apparent until late in the disease. Findings such as an accentuated second heart sound, a systolic murmur over the left sternal border, jugular venous distention, peripheral edema, and/or ascites might suggest the presence of PH and right ventricular dysfunction. Associated systemic diseases such as collagen vascular disease or liver disease may also become apparent during routine examination.

Laboratory evaluation can provide important information in detecting associated disorders and contributing factors. A collagen vascular screen including antinuclear antibodies, rheumatoid factor, and erythrocyte sedimentation rate is often helpful in detecting autoimmune disease, although some patients with IPAH will have a low-titer positive antinuclear antibody test.⁹ The scleroderma spectrum of disease, particularly limited scleroderma, or the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias), has been associated with an increased risk for the development of PAH.^10,¹¹ Liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase) may be elevated in patients with right ventricular failure and passive hepatic congestion but may also be associated with underlying liver disease. Liver disease with portal hypertension has been associated with the development of PH. Thyroid disease may occur with increased frequency in patients with IPAH and should be excluded with thyroid function testing.¹² Human immunodeficiency virus (HIV) testing and hepatitis serologic studies should be considered in patients at risk. Routine laboratory studies such as complete blood cell count, complete metabolic panel, prothrombin time, and partial thromboplastin time are recommended during the initial evaluation and as indicated to monitor the patient’s long-term clinical status.

Echocardiography

Doppler echocardiography is useful in estimating the severity of PH and detecting left-sided heart disease. Findings may include enlargement of the right ventricle, flattening of the interventricular septum, and compression of the left ventricle. Bubble contrast echocardiography may detect a right-to-left shunt, but exclusion of a left-to-right intracardiac shunt may require cardiac catheterization with an oximetry series. Echocardiography may be a useful noninvasive means of long-term follow-up,^13,¹⁴ although not all patients have suitable echocardiographic windows.

Radiographic Evaluation and Exclusion of Thromboembolic Disease

Chest radiography may reveal enlargement of the central pulmonary vessels and evidence of right ventricular enlargement. Evidence of parenchymal lung disease may be apparent. When parenchymal lung disease is suspected, pulmonary function testing and high-resolution computed tomography (CT) of the chest may be indicated. Ventilation/perfusion (V/Q) lung scanning should be performed in an attempt to exclude chronic recurrent pulmonary thromboembolic disease, which is among the most preventable and treatable causes of PH. Diffuse mottled perfusion can be seen in IPAH, whereas larger segmental and subsegmental mismatched defects are suggestive of chronic recurrent pulmonary thromboembolic disease. Intermediate results on V/Q lung scanning may require pulmonary arteriography to obtain a definitive diagnosis. Although contrast medium–enhanced CT has been popularized recently for the diagnosis of acute pulmonary thromboembolic disease, there is limited experience with this technique in chronic thromboembolic disease. Accordingly, we recommend caution at present in using contrast-enhanced CT to exclude chronic recurrent thromboembolic disease.

Pulmonary Function Testing

Pulmonary function testing is indicated to detect underlying parenchymal lung disease. The diffusing capacity is often reduced in pulmonary vascular disease, consistent with impaired gas exchange.

Right-Sided Heart Catheterization and Vasoreactivity Testing

Right-sided heart catheterization remains an important part of the evaluation. Left-sided heart dysfunction and intracardiac shunts can be excluded, the degree of PH can be accurately quantified, and cardiac output can be measured. Pulmonary vascular resistance can then be calculated. Acute pulmonary vasoreactivity can be assessed using a short-acting agent such as prostacyclin (epoprostenol), inhaled nitric oxide, or intravenous adenosine.¹ The consensus definition of a positive acute vasodilator response in a PAH patient is a fall of PAPm of at least 10 mm Hg to ≤40 mm Hg, with an increased or unchanged cardiac output. The primary objective of acute vasodilator testing in patients with PAH is to identify patients who might be effectively treated with oral calcium channel blockers. The acute response to a short-acting agent such as prostacyclin has been shown to be predictive of the response to a calcium channel blocker.¹⁴ Unstable patients or those in severe right-sided heart failure who would not be candidates for treatment with calcium channel blockers need not undergo vasodilator testing.

Treatment

General Care

Warfarin, Oxygen, Diuretics, Digoxin, and Vaccination

Improved survival has been reported with oral anticoagulation in IPAH.^15,¹⁶ The target International Normalized Ratio (INR) in these patients is 1.5 to 2.5. Anticoagulation of patients with PAH due to other underlying processes such as scleroderma or congenital heart disease is controversial. Generally, patients with PAH treated with chronic intravenous epoprostenol are anticoagulated in the absence of contraindications, owing in part to the additional risk of catheter-associated thrombosis.

Hypoxemia is a pulmonary vasoconstrictor and can contribute to the development or progression of PAH. It is generally considered important to maintain oxygen saturations at greater than 90% at all times. Supplemental oxygen use is more controversial in patients with Eisenmenger physiology but may decrease the need for phlebotomy and potentially reduce the occurrence of neurologic dysfunction and complications.

Diuretics are indicated in patients with evidence of right ventricular failure and volume overload (i.e., peripheral edema and/or ascites). Careful dietary restriction of sodium and fluid intake is important in the management of patients with PAH with right-sided heart failure. Rapid and excessive diuresis may produce systemic hypotension, renal insufficiency, and syncope. Serum electrolytes and measures of renal function should be followed closely in patients receiving diuretic therapy.

Although not extensively studied in PAH, digitalis is sometimes utilized in refractory right ventricular failure or atrial dysrhythmias. Drug levels should be followed closely, particularly in patients with impaired renal function.

Because of the potentially devastating effects of respiratory infections in PAH, immunization against influenza and pneumococcal pneumonia is recommended.

Calcium Channel Blockers

Patients with IPAH who respond to vasodilators and calcium channel blockers ¹⁵ generally have improved survival. Unfortunately, this tends to represent a relatively small proportion of patients, comprising fewer than 20% of IPAH patients and even fewer patients with other causes of PAH.

Prostanoids

Prostacyclin, a metabolite of arachidonic acid produced primarily in vascular endothelium, is a potent systemic and pulmonary vasodilator that also has antiplatelet aggregatory effects. A relative deficiency of endogenous prostacyclin may contribute to the pathogenesis of PAH.¹⁷

Epoprostenol

Epoprostenol therapy is complicated by the need for continuous intravenous infusion. The drug is unstable at room temperature and is generally best kept cold before and during infusion. It has a very short half-life in the bloodstream (<6 minutes), is unstable at acidic pH, and cannot be taken orally. Because of the short half-life, the risk of rebound worsening with abrupt/inadvertent interruption of the infusion, and its effects on peripheral veins, it should be administered through an indwelling central venous catheter. Common side effects of epoprostenol therapy include headache, flushing, jaw pain with initial mastication, diarrhea, nausea, a blotchy erythematous rash, and musculoskeletal aches and pain (predominantly involving the legs and feet). These tend to be dose dependent and often respond to a cautious reduction in dose. Severe side effects can occur with overdosage of the drug. Acutely, overdosage can lead to systemic hypotension. Chronic overdosage can lead to the development of a hyperdynamic state and high-output cardiac failure.¹⁸ Abrupt or inadvertent interruption of the epoprostenol infusion should be avoided because this may lead to a rebound worsening of PH, with symptomatic deterioration and even death. Other complications of chronic intravenous therapy with epoprostenol include line-related infections (which can range from small exit-site reactions to tunnel infections and cellulitis to bacteremic infections with sepsis), catheter-associated venous thrombosis, systemic hypotension, thrombocytopenia, and ascites.

Treprostinil

Treprostinil, a prostacyclin analog with a half-life of 3 hours, is stable at room temperature. An international placebo-controlled, randomized trial demonstrated that treprostinil improved exercise tolerance, although the 16-meter median difference between treatment groups in 6-minute walk distance was relatively modest.¹⁹ Treprostinil also improved hemodynamic parameters. Common side effects included headache, diarrhea, nausea, rash, and jaw pain. Side effects related to the infusion site were common (85% of patients complained of infusion-site pain, and 83% had erythema or induration at the infusion site). Treprostinil is also approved for intravenous delivery based on bioequivalence with the subcutaneous route and is also approved as an inhaled preparation administered in doses of 6 to 54 µg, 4 times daily.²⁰

Inhaled Iloprost

Iloprost is a chemically stable prostacyclin analog with a serum half-life of 20 to 25 minutes.²¹ In IPAH, acute inhalation of iloprost resulted in a more potent pulmonary vasodilator effect than acute nitric oxide inhalation.^21,²² In uncontrolled and controlled studies of iloprost for various forms of PAH,^23,²⁴ inhaled iloprost at a total daily dose of 30 to 200 µg divided in 6 to 12 inhalations improved functional class, exercise capacity, and pulmonary hemodynamics for periods up to 1 year of follow-up. The treatment was generally well tolerated except for mild coughing, minor headache, and jaw pain in some patients. The most important drawback of inhaled iloprost is the relatively short duration of action, requiring the use of 6 to 9 inhalations a day.

Beraprost

Beraprost sodium is an orally active prostacyclin analog ²⁵ that is absorbed rapidly in fasting conditions. It has been evaluated in peripheral vascular disorders such as intermittent claudication,²⁶ Raynaud’s phenomenon, and digital necrosis in systemic sclerosis,²⁷ with variable results. Although several small, open, uncontrolled studies reported beneficial hemodynamic effects with beraprost in patients with IPAH, two randomized double-blind, placebo-controlled trials have shown only modest improvement and suggest that beneficial effects of beraprost may diminish with time.^28,²⁹

Endothelin Receptor Antagonists

Endothelin-1 is a vasoconstrictor and a smooth muscle mitogen that may contribute to the pathogenesis of PAH. Endothelin-1 expression, production, and concentration in plasma ^30,³¹ and lung tissue³² are elevated in patients with PAH, and these levels are correlated with disease severity.

Bosentan

Bosentan is a dual endothelin receptor blocker that has been shown to improve pulmonary hemodynamics and exercise tolerance and delay the time to clinical worsening in PAH patients falling into NYHA Classes III and IV.^33,³⁴ The most frequent and potentially serious side effect with bosentan is dose-dependent abnormal hepatic function (as indicated by elevated levels of alanine aminotransferase and/or aspartate aminotransferase). Because of the risk of potential hepatoxicity, the FDA requires that liver function tests be performed at least monthly in patients receiving this drug. Bosentan may also be associated with the development of anemia, which is typically mild; hemoglobin/hematocrit should be checked regularly.

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