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Diagnosis is often delayed by a nonspecific presentation Update on strategies for managing pulmonary arterial hypertension

The Journal of Respiratory DiseasesThe Journal of Respiratory Diseases Vol 27 No 6
Volume 27
Issue 6

abstract: Pulmonary arterial hypertension (PAH) is 1 of 5 types of pulmonary hypertension (PH). Symptoms may include dyspnea on exertion, fatigue, near-syncope, and palpitations. Physical findings include lower extremity edema, jugular venous distention, and a loud P2. Findings on chest radiography, transthoracic echocardiography, and electrocardiography can suggest the presence of PAH; however, right heart catheterization is the gold standard for confirming the diagnosis and for differentiating PAH from other forms of PH. It is essential to exclude chronic thromboembolic PH, since this can be surgically corrected. The treatment of PAH depends on the severity. In addition to the standard treatments, such as diuretics and anticoagulation, more advanced treatment options include prostaglandin therapy (epoprostenol, treprostinil, and iloprost), endothelin receptor antagonists (bosentan), and phosphodiesterase inhibitors (sildenafil).

Pulmonary hypertension (PH) is a poorly understood syndrome resulting from a myriad of underlying causes. Pulmonary arterial hypertension (PAH) is 1 of 5 types of PH; this rare disorder primarily affects the small, precapillary pulmonary arteries.

The exact incidence of PAH is unknown; the most reliable epidemiologic data are for idiopathic PAH, which has an estimated incidence of 1 to 2 per million persons.1 Other forms of PH are much more common than PAH and, therefore, are more likely to be encountered by cardiologists, pulmonologists, and primary care physicians in clinical practice.2 It is important to elucidate the cause of PH, if possible, since this affects both treatment and prognosis.

PAH is classified into 3 categories: idiopathic PAH (formerly called primary pulmonary hypertension), familial PAH, and associated PAH. Although risk factors and predisposing conditions for PAH have been identified, the inciting pathogenic events remain poorly understood. However, PAH is being increasingly recognized and diagnosed, and the development of effective new therapies over the past 15 years has led to increased interest in and improved understanding of this disorder.

In this article, we will review the salient features of PAH. We will then focus on the current strategies for diagnosis and management of this disorder.


Pathology and genetics

Pulmonary vascular disease was first reported more than 100 years ago by the German physician Ernst von Romberg, who described pulmonary vascular sclerosis on an autopsy specimen.3,4 Idiopathic PAH was initially described by Dresdale and colleagues5 in 1951 in 3 patients who were found to have elevated pulmonary artery pressure (PAP) without evidence of a secondary cause. Their seminal report coined the term "primary pulmonary hypertension" and described the clinical hemodynamic characteristics and pathologic changes associated with primary PH (now idiopathic PAH). The pathologic changes in PAH are most pronounced in the small, precapillary arteries (less than 100 µm in diameter) and include smooth muscle medial hypertrophy, intimal proliferation, in situ thrombosis, and plexiform lesions; the latter are not associated with other types of PH (Figure 1).

A genetic basis for some forms of PAH has been identified. Two groups of investigators simultaneously reported mutations in bone morphogenetic protein receptor II (BMPRII) in patients with familial PAH.6,7

BMPRII is a member of the transforming growth factor-ß superfamily of receptors. Although the mechanism through which BMPRII mutations lead to disease is not known, it is likely to be related to disordered regulation of growth in the pulmonary arteries.

Mutations in BMPRII have been found in patients with idiopathic PAH and in a small number of patients with PAH associated with congenital heart disease.8,9 Mutations have also been found in patients with pulmonary venoocclusive disease, a rare subset of PAH in which there is significant pulmonary venous involvement in addition to arterial changes.10


The Third World Symposium on Pulmonary Arterial Hypertension in 2003 resulted in a modification of the previous classification of PH developed in 1998.2 PH is now classified into 5 categories: PAH, PH with left heart disease, PH associated with pulmonary disease or hypoxemia, PH resulting from chronic thrombotic or embolic disease, and miscellaneous (Table 1). Categories other than PAH are described as follows:

PH associated with left heart disease: Examples of diseases in this category are systolic and diastolic heart failure and mitral stenosis. With left-sided atrial or ventricular disease and left-sided valvular disease, passive and reactive PH are caused by "back pressure" from the left side of the heart.

PH associated with pulmonary disease or hypoxemia: Disorders in this category lead to alveolar hypoxia and cause PH primarily by the mechanism of hypoxic pulmonary vasoconstriction. These diseases include chronic obstructive pulmonary disease (COPD), interstitial lung disease, and lung disease caused by chronic exposure to high altitude.

PH that results from chronic thrombotic or embolic disease: Thrombi and emboli cause PH primarily through the obliteration of the large pulmonary arteries. However, associated pulmonary vascular remodeling in the small, muscular arteries has also been described in these patients and may contribute to the increased pulmonary vascular resistance.11

Miscellaneous: This category includes diseases such as sarcoidosis, pulmonary Langerhans cell histiocytosis, and compression of pulmonary vasculature caused by fibrosing mediastinitis.


Clinical presentation

The clinical presentation of PAH is nonspecific; therefore, the diagnosis is often delayed while other, more common diseases are being considered. The most common symptoms of PAH are dyspnea on exertion, fatigue, near-syncope, and palpitations.

Chest pain with exertion may also occur and is thought to be related to ischemia of the right ventricle resulting from the increased demand imposed by exercise. As PAH advances, symptoms that become more prominent include right ventricular failure-induced ascites, right upper quadrant abdominal pain resulting from liver congestion, and syncope.

The physical examination can be helpful in making the diagnosis. In particular, findings of jugular venous distention, hepatojugular reflux, a palpable right ventricular heave, a loud P2, a right-sided S3 or S4, and murmurs of tricuspid regurgitation or pulmonic insufficiency (Graham Steell murmur) are often appreciated on cardiac examination. Additional physical findings include lower extremity edema, right upper quadrant tenderness, a pulsatile liver, decreased peripheral pulses, prolonged capillary refill, and peripheral or peri- oral cyanosis.1

Findings that may suggest alternative diagnoses include systemic hypertension and elevated body mass index (both of which are risk factors for pulmonary venous hypertension), crackles, and clubbing. Other diagnoses to consider are cardiac disorders--such as ischemic cardiovascular disease, left-sided heart failure, cardiac arrhythmia, and valvular heart disease--and pulmonary diseases-- such as asthma, COPD, interstitial lung disease, and recurrent pulmonary embolism (which can predispose to PH).

Diagnostic tests

PAH is defined as a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg with a pulmonary wedge pressure (PWP) less than 15 mm Hg. However, the mPAP is considerably higher than this in most patients with PAH. The Patient Registry for the Characterization of Primary Pulmonary Hypertension from the NIH reports an mPAP of 60 ± 18 mm Hg.12

Although PAP can be quite elevated, right ventricular function reflects the severity of disease more accurately. Compared with other hemodynamic measurements, right atrial pressure that is greater than 20 mm Hg was associated with the poorest outcome in the NIH registry study. Poor cardiac output and reduced mixed venous saturation are other markers of severe, advanced disease.13,14

The diagnosis of PAH is most often indicated by the results of transthoracic echocardiography. Other tests that can aid in the diagnosis are chest radiography, CT of the chest, and electrocardiography. Right heart catheterization is the gold standard for differentiating PAH from other forms of PH and for making the diagnosis.15

Additional studies that should be conducted are pulmonary function tests, a ventilation-perfusion scan, and a 6-minute walk with ambulatory oxygen saturations. Patients are also generally classified according to the New York Heart Association's Functional Classification, with a class I patient having no activity limitation and a class IV patient having symptoms at rest.16 At large centers, most patients with PAH are functional class III at the time of diagnosis.

Common echocardiographic findings that indicate PH include enlargement of the right atrium and right ventricle, depressed right ventricular function, tricuspid regurgitation, pulmonic insufficiency, and a "D-shaped" interven- tricular septum reflecting right ventricular pressure and volume overload. Injection of agitated saline at the time of echocardiography may also reveal right-to-left shunting, indicating the presence of an atrial septal defect or patent foramen ovale.

Echocardiography can be used to obtain important information concerning left ventricular systolic or diastolic dysfunction or left-sided valvular heart disease. It can also be used to estimate systolic PAP. We believe, however, that the other findings are more important, especially since, in our experience, the estimated pressure can diverge from measured pressure by as much as 40 mm Hg. Therefore, while echocardiography can often raise the possibility of PAH, direct measurement of hemodynamics is necessary for both the diagnosis and the determination of severity of PAH.

Findings on chest radiography include cardiomegaly with prominence of the right-sided structures, enlarged proximal pulmonary arteries, and pruning of the pulmonary vasculature (Figure 2). Chest radiography may also reveal abnormalities that contribute to or cause other types of PH. These abnormalities include parenchymal lung disease; valvular heart disease, including left atrial enlargement in mitral stenosis; vascular engorgement and a widened vascular pedicle; Kerley B lines; and calcification of the pericardium.

Chest CT is more sensitive for delineating abnormalities of the heart, pulmonary vasculature, and lung parenchyma. Enlargement of the main pulmonary artery to a diameter greater than that of the ascending aorta is sometimes the first sign of PH (Figure 3).

Acute or chronic pulmonary emboli can also be evaluated with CT angiography of the pulmonary circulation. In our opinion, however, a ventilation-perfusion scan remains the study of choice to evaluate for chronic thromboembolic PH (CTEPH). Unless multiple segmental or greater defects are present on ventilation-perfusion scan, the diagnosis of CTEPH can be excluded (Figure 4).

An ECG commonly demonstrates evidence of right atrial enlargement or right ventricular hypertrophy in patients with PH. A right bundle-branch block may also be present. However, the ECG findings may be fairly unremarkable--even in cases of significant PH.

Although all of the studies described here can strongly suggest PAH, direct measurement of hemodynamics by right heart catheterization is required for confirmation.17 This should be performed in all patients who have evidence of elevated pulmonary pressure on echocardiography before initiation of medical therapy or surgical intervention. Right heart catheterization provides direct measurement of pressures in the right atrium, right ventricle, and pulmonary arteries. It also measures PWP and cardiac output, which allows for calculation of pulmonary and systemic vascular resistance. In addition, saturations can be obtained to evaluate for left-to-right intracardiac shunting.

When PAH is diagnosed, acute vasodilator testing should be performed using inhaled nitric oxide, intravenous adenosine, or intravenous epoprostenol.17 A positive response during acute vasodilator testing is defined as a decrease in mPAP to 40 mm Hg or less, with a decrease of at least 10 mm Hg and a normal or increased cardiac output. Acute vasoreactivity, as defined above, predicts a favorable response to calcium channel blocker (CCB) therapy, and these patients generally have an excellent long-term prognosis.17

Once the diagnosis of PAH is established, evaluation for associated causes and conditions must be performed. A history of anorexigen use (particularly fenfluramine and dexfenfluramine) as well as a history of use of illegal substances, such as cocaine, amphetamines, and methamphetamines, should be ascertained. Use of these substances has been associated with the development of idiopathic PAH.2,18 Although familial PAH is rare, a family history of PH or unexplained death at a young age should be sought.

Sleep apnea generally does not cause more than mild PH; however, a history consistent with sleep-disordered breathing should prompt further evaluation. Polysomnography should be performed in patients with a history suggestive of sleep apnea.

In older patients and in patients with risk factors for coronary artery disease seen at our center, we have a low threshold for performing coronary angiography or a stress test, since coronary artery disease can contribute to symptoms and affect the response to therapy. This is much less of a concern in the evaluation of PH in younger patients, in whom we rarely perform coronary angiography or a stress test unless there is a strong family history of coronary artery disease.

Laboratory studies that should be routinely obtained include a complete blood cell count, complete metabolic profile, antinuclear antibody test, HIV antibody test, thyroid function tests, and testing for antiphospholipid antibodies. In patients with abnormal liver function, serologic tests for hepatitis should be performed. Measurement of brain natriuretic peptide has been shown to be a good marker of right heart function and to have prognostic value.19


The treatment of PH is highly dependent on the underlying cause. Efforts aimed at treating the underlying disease should be the focus of therapy in patients with PH caused by left heart disease, pulmonary disease or hypoxemia, and chronic thromboembolic disease. Treatment of the underlying disease will result in improvement in pulmonary hemodynamics if, in fact, the underlying disease is responsible for PH. Even patients with multifactorial causes of PH may benefit from treatment of underlying diseases.

The diagnosis of CTEPH deserves special mention, because this form of PH can be cured surgically with pulmonary thrombo-endarterectomy. When findings on a ventilation-perfusion scan, CT angiogram, or conventional pulmonary angiogram indicate CTEPH, the patient should be treated with anticoagulation (in the absence of contraindications). The patient should then be referred to a center specializing in PH for consideration of pulmonary thromboendarterectomy.

Patients with PAH should avoid taking ß-blockers and CCBs with significant negative inotropic activity (such as verapamil) unless required to control arrhythmia. In addition, the use of sympathomimetic medications such as pseudoephedrine, which can cause vasoconstriction, should also be avoided in patients with PAH.

As with other cardiopulmonary disorders, general health maintenance measures should also be undertaken. Patients with PAH who smoke should be counseled to discontinue smoking. Attention to pneumococcal and influenza vaccination should be part of routine care.

Many patients have questions about the recommended level of daily exertion. Our approach is to counsel patients to continue to exert themselves as tolerated. If dyspnea, palpitations, light-headedness, or near-syncope are experienced, the patient's activity level should be reduced. In addition, the occurrence of these symptoms with levels of activity that were previously well tolerated may indicate a worsening of their condition, and patients should contact their treating physician immediately.

The specific treatment of PAH can be divided into basic and advanced therapy. Basic therapy includes diuretics, salt restriction, anticoagulation, oxygen, digoxin, and CCBs. Advanced medical therapy includes prostaglandin therapy (epoprostenol, treprostinil, and iloprost), endothelin (ET) receptor antagonists (bosentan), and phosphodiesterase inhibitors (sildenafil) (Table 2). ET receptor antagonists block the ability of ET to bind to either the ETA receptor alone or to both ETA and ETB receptors; prostacyclin derivatives attempt to repair prostacyclin deficiency by providing its synthetic salt or analogs in pharmacologic doses; and phosphodiesterase type 5 (PDE-5) inhibitors prevent the degrada- tion of cyclic guanosine monophosphate (cGMP), the mediator through which nitric oxide exerts its effects. Published guidelines for treatment of PAH provide a good reference for clinicians.20

It must be stressed that the agents listed above that constitute advanced medical treatment have been studied only in patients with PAH and are not indicated for use in patients with other forms of PH. In fact, the use of precapillary vasodilators in patients with pulmonary venous hypertension can precipitate acute pulmonary edema and may be associated with severe clinical deterioration.

Basic therapy

Diuretics are essential in the treatment of patients who have clinically significant PH and evidence of increased central venous pressure. Diuretics may improve right heart function by reducing right ventricular preload, thus shifting the filling pressure of the right ventricle back to a point on the Starling curve that is closer to ideal.

The dose of diuretics can be titrated based on the presence of ascites, lower extremity edema, and jugular venous distention and on blood urea nitrogen and creatinine levels. Prerenal azotemia may need to be maintained in some patients for optimal benefit. Salt restriction is a necessary adjunct to diuretics, and patients should be counseled on the importance of compliance with a low-sodium diet.

In some patients with severe right heart failure and hyponatremia, free water intake must be limited. Unless there is evidence of an intracardiac shunt, oxygen therapy should be prescribed for patients with resting, exertional, or nocturnal hypoxemia. Some specialists who routinely treat patients with PAH prescribe digoxin. Long-term treatment with digoxin for PAH has not been studied, so there are no data supporting long-term benefit; however, there is some evidence that digoxin may decrease sympathetic activity.21

The use of warfarin is considered to be the standard of care in the treatment of idiopathic PAH, although no randomized studies have been performed to demonstrate benefit. The data supporting routine anticoagulation in idiopathic PAH consist of 2 retrospective trials that include 293 patients and 1 prospective study of 64 patients.22-24 These studies demonstrated survival benefit in patients with idiopathic PAH or aminorex-induced PH who were treated with warfarin. No studies have been performed in patients with PAH that is associated with other disorders; an expert consensus statement suggested that the benefit of anticoagulation in these patients is likely to be small.25

CCBs are beneficial in the management of patients with PAH who demonstrate acute pulmonary vasoreactivity during acute vaso- dilator challenge performed dur-ing right heart catheterization. Although these agents have been the focus of much attention as a treatment for PAH, only a small minority of patients will benefit from them.26

CCBs were initially reported to be effective in 26.6% of patients (17 of 64) with idiopathic PAH who were studied at a single institution.23 However, a more recent retrospective study involving 557 patients reported that only 6.8% of patients treated with CCBs demonstrated long-term improvement in hemodynamics, functional status, and survival.26 CCBs have been studied almost exclusively in patients with idiopathic PAH and familial PAH; efficacy has not been reported for the treatment of other conditions associated with PAH.

Advanced therapy

Prostaglandin I2 (prostacyclin), produced by the vascular endothelium, is a short-acting pulmonary and systemic vasodilator that also inhibits platelet aggregation and smooth muscle growth.27 Decreased synthesis of prostacyclin has been demonstrated in patients with PAH.28 Epoprostenol, the synthetic salt of prostacyclin, must be given by continuous intravenous infusion because of its short half-life of 2 to 3 minutes in vivo.

Efficacy of continuous intravenous epoprostenol for the treatment of idiopathic PAH was first reported in 1984.29 In the 1990s, epoprostenol was evaluated in a series of randomized multicenter studies, the largest of which enrolled 81 patients with idiopathic PAH.30-32 These studies demonstrated improvement in hemodynamics, exercise capacity, and survival.33 Improvement in exercise capacity and hemodynamics has also been demonstrated in patients with PAH associated with other diseases.34,35 More recently, the long-term survival benefit associated with treatment with epoprostenol has also been described for patients with idiopathic PAH compared with historical controls.36-38

Epoprostenol, which is dosed according to body weight, is generally initiated at a dose of 2 ng/kg/min and titrated upward based on symptomatic improvement and side effects. Adverse side effects are dose-related and often include flushing, headache, jaw pain, nausea, diarrhea, and lower extremity pain.

The complications of continuous intravenous infusion of epoprostenol include local catheter exit site infections; bacteremia and septicemia; catheter-related thrombosis; and catheter/pump malfunctions leading to interruption of infusion, which can produce hemodynamic deterioration.30-32 This therapy is usually managed at large referral centers. Administration of this medication requires close patient follow-up and an experienced coordinator to trouble-shoot the variety of problems that can arise.

Treprostinil is a prostacyclin analog with a pharmacologic profile similar to that of epoprostenol. Like epoprostenol, treprostinil has also been shown to be effective in improving hemodynamics and exercise capacity in patients with PAH.39 Treprostinil possesses chemical stability at room temperature, resulting in a half-life of 3 to 4 hours. This prolonged half-life (relative to epoprostenol) allows for subcutaneous administration. Compared with intravenous epoprostenol, treprostinil has several advantages, such as a smaller and less complex drug delivery system and the avoidance of a long-term indwelling catheter with its associated complications.

The major disadvantage of subcutaneously administered treprostinil is infusion site pain: most patients treated with subcutaneous treprostinil experience either site pain or discomfort. This pain is often difficult to treat, and it lim- its rapid up-titration of the medication. Over time, the side effects of treprostinil may lessen, and at higher doses, patients may derive benefits similar to those of epoprostenol.

Recently, treprostinil was approved for intravenous administration (in addition to subcutaneous delivery). There are limited data on the efficacy of intravenous treprostinil; thus, it is difficult to make any recommendations regarding its use at this time.

Iloprost is another prostacyclin analog that can be given by inhalation or intravenously. It has a half-life of 45 minutes and therefore must be administered 6 to 9 times per day when given by inhalation.40-43 In a randomized multicenter study of patients with PAH, improvement in exercise capacity was demonstrated with iloprost.42 The findings of this study contributed to the FDA approval of iloprost in 2004 for the treatment of PAH in the United States; iloprost had previously been approved for such use in Europe.

Beraprost is a stable oral prostacyclin analog approved in Japan for the treatment of PAH. Two randomized studies have shown discordant results. A 3-month study in Europe revealed improvement in exercise capacity; however, a 12-month study in the United States, which was terminated early, provided no evidence of improvement in exercise capacity.44,45 Beraprost is not available in the United States for treatment of PAH.

Although the results of treatment of PAH with beraprost have been disappointing, in recent years, effective oral therapies have been developed. The first of these drugs is bosentan, an ET-1 receptor antagonist. ET-1 is an endogenous vasoconstrictor that induces vascular smooth muscle proliferation. Elevated ET-1 levels in plasma and pulmonary arteries have been demonstrated in patients who have PAH.46 In 2 randomized multicenter studies involving patients with PAH, bosentan was shown to improve symptoms, exercise capacity, and hemodynamics.47,48 In addition, bosentan increased time to clinical worsening.

Bosentan was approved for the treatment of PAH in late 2001. A study of 169 PAH patients initially treated with bosentan reported a survival benefit compared with predicted survival using the NIH idiopathic PAH registry survival equation.49 Bosentan is taken twice daily and is well tolerated by most patients. The most common adverse effects are headache, nasopharyngitis, flushing, lower extremity edema, hypotension, and liver function test abnormalities.50

About 10% of patients taking bosentan have elevations in liver function test results, most often during the first few months of therapy (although they may occur after a year or more of treatment). Therefore, liver function tests must be done before initiation of bosentan, followed by monthly testing during treatment. In addition, women of childbearing age must use 2 forms of birth control and obtain the results of monthly pregnancy tests because of the potential teratogenicity of bosentan.50

Sildenafil inhibits PDE-5, which is responsible for the breakdown of cGMP. cGMP is the mediator through which nitric oxide, an endogenous vasodilator, exerts its vasodilatory effects. Studies in patients with idiopathic PAH have shown a decrease in the level of circulating nitric oxide metabolites, a marker of impaired production.51

Inhibition of PDE-5, which is found in large amounts in the lung, results in increased intracellular cGMP concentrations and subsequent smooth muscle relaxation.51,52 In a recently completed randomized placebo-controlled trial, sildenafil was shown to improve exercise capacity and hemodynamics compared with placebo in patients with PAH.53 Based on these data, sildenafil was approved in 2005 for the treatment of PAH.

Atrial septostomy and lung transplantation are other therapeutic options for patients with advanced PAH refractory to medical therapy. Atrial septostomy (the creation of an intraatrial shunt) is reserved for patients with severe right heart failure, generally as a bridge to transplantation. The septostomy relieves the pressure on the right ventricle. However, it tends to initially cause hypoxemia from intracardiac shunting; this hypoxia eventually improves as right ventricular function and cardiac output improve.

Lung transplantation remains the only curative treatment for patients with PAH who are appropriate candidates. However, with a 5-year survival rate of less than 50%, transplantation is far from a panacea. Chronic rejection, for which there is no effective treatment, remains the "Achilles' heel" of lung transplantation.

The treatment of PH, particularly PAH, has advanced in the past 2 decades. PH has evolved from a disease with a uniformly poor prognosis to a disease for which there is treatment and hope for many patients. When a patient with PH is encountered, referral to a center with expertise in the management of PH for further evaluation and consideration for treatment is recommended.



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