Chapter 30. Pulmonary Hypertension

Pulmonary hypertension

• A loud pulmonic valve closure sound (P2), a right-sided S4, or a right ventricular heave.
• Electrocardiographic evidence of right ventricular hypertrophy.
• Presence of sustained elevation in mean pulmonary artery pressure ≥ 25 mm Hg.

Pulmonary arterial hypertension

• A subset of pulmonary hypertension.
• Elevated mean pulmonary artery pressure ≥ 25 mm Hg.
• Pulmonary arterial wedge pressure ≤ 15 mm Hg.

Pulmonary hypertension (PH) is a description of the finding of a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg and may occur in many settings. PH most commonly results from a variety of cardiac and pulmonary diseases that increase pulmonary artery pressure (PAP) either passively or through vasoconstriction. The term pulmonary arterial hypertension (PAH) describes a specific group of diseases characterized by a mPAP greater than 25 mm Hg and normal left heart filling pressures (pulmonary artery wedge pressure [PAWP] < 15 mm Hg) resulting from vasoconstriction and arteriopathy of the precapillary pulmonary arterioles. PAH may be idiopathic or associated with one or more underlying diseases such as connective tissue disease, human immunodeficiency virus (HIV) infection, or portal hypertension. In patients clinically suspected of having PH, echocardiography is often the first test performed to estimate PAP and evaluate right ventricular function. Further comprehensive testing is required to make a diagnosis and establish the etiology of PH.

PH commonly occurs in patients with left heart disease and hypoxemic lung disease. The development of PH in patients with heart or lung disease is an ominous sign and is generally associated with decreased survival. Treatment in this case is directed at the underlying condition (ie, bronchodilators, supplemental oxygen, valve repair, or heart failure treatment). Use of PAH-specific therapy in this setting is generally not beneficial and may worsen symptoms and mortality. In patients with PAH, increased pulmonary vascular resistance from vasoconstriction and arteriopathy results in increased PAP, leading rapidly to right heart failure and death. In this setting, PAH-specific therapy improves symptoms, exercise tolerance, and survival. Selection of therapies for patients with PAH is complex and requires understanding of any associated diseases, the severity of the patient's symptoms, as well as toxicities and drug interactions of PAH therapy. Early referral to a specialty center for patients with PAH is often crucial for confirmation of diagnosis, early initiation of appropriate therapy, and monitoring of response to treatment. Significant advances have been made over the past decade in improving clinicians' understanding of the clinical profile, pathobiology, and treatment of PAH.

PH is defined as a sustained elevation in the mPAP of 25 mm Hg or greater at rest. This is in contrast to a normal mPAP of 12–16 mm Hg. In healthy humans, the small arteriovenous pressure gradient generated by blood flow across the pulmonary circulation results from the large total vascular surface area and high pulmonary vascular compliance. The pulmonary vascular resistance (PVR) is quantified using Ohm's law [PVR = (mPAP – PAWP)/cardiac output (CO)] and describes the relationship between the pressure gradient and blood flow.

The World Health Organization has proposed a system to categorize PH into five groups on the basis of underlying etiology (Table 30–1). PH can also be categorized on a hemodynamic basis at right heart catheterization (Figure 30–1). PH is characterized based on the mPAP: mild (25–40 mm Hg), moderate (41–55 mm Hg), or severe (> 55 mm Hg).

Pulmonary Arterial Hypertension

Pathologic abnormalities in PAH are localized to the precapillary pulmonary arterioles, resulting in a characteristic hemodynamic profile that can be identified during right heart catheterization (RHC) (see Figure 30–1). PAH is defined by a sustained elevation of the mPAP ≥ 25 mm Hg and a PAWP or left ventricular end-diastolic pressure ≤ 15 mm Hg (normal PAWP, 8–12 mm Hg).

PAH is caused by a disparate group of diseases that have in common vasoconstriction and arteriopathy with remodeling of the precapillary pulmonary arterioles (see Table 30–1). PAH results in progressive cardiopulmonary deterioration, right heart failure, and death. While the prognosis for patients with PAH varies with the underlying cause, overall survival is poor. Figure 30–2 shows survival characteristics in patients with different subtypes of PAH.

The prevalence of PAH in the United States is estimated to be between 50,000 and 100,000 cases. Of these, only 15,000 to 25,000 are appropriately diagnosed and treated. Multicenter registry data suggest that most patients with PAH are women (with a 2:1 female-to-male ratio), with a mean age of 50 years. Seventy-five percent of patients with PAH have symptoms at rest or with minimal exertion. The mean duration of symptoms prior to diagnosis is 27 months.

Three processes contribute to pulmonary artery (PA) luminal narrowing in PAH: vasoconstriction, arterial remodeling, and thrombosis in situ (Figure 30–3). In susceptible individuals, pulmonary vascular injury leads to disruption of the homeostatic balance present in the healthy pulmonary arteries. Upregulation of vasoconstrictive and proproliferative mediators (ie, endothelin-1, serotonin, and thromboxane) and downregulation of vasodilatory and antiproliferative mediators (ie, nitric oxide, prostacyclin, and smooth muscle cell potassium channels) lead to increased vasoconstriction and disordered cell proliferation. In situ thrombus formation occurs as a result of increased platelet activation, increased blood stasis, upregulation of plasminogen activator inhibitor-1, and reduced fibrinolytic activity. The cellular processes that have been implicated in the pathogenesis of PAH are summarized in Figure 30–4.

PAH is termed idiopathic if no disease associated with PAH is present and heritable if there is an underlying genetic predisposition or familial occurrence of PAH. Idiopathic and heritable PAH are rare disorders with a prevalence of 15 cases per million per year and an incidence of 1–2 cases per million per year. Idiopathic and heritable PAH afflict predominantly young women, with a mean age at diagnosis of 35 years. These are progressive disorders with a high mortality (median life expectancy 2.8 years from diagnosis).

Mutations in the bone morphogenetic protein receptor (BMPR)-2 gene have been identified in approximately 50% of patients with heritable PAH. Those who inherit the mutation have a 10% risk of developing PAH. The genetic pattern of inheritance is autosomal dominant with incomplete penetrance and anticipation (subsequent generations manifest the disease at an earlier age). A mutation in the activin receptor-like kinase type-1 (ALK-1 or endoglin) often with coexistent hereditary hemorrhagic telangiectasia may have also been identified in patients with PAH. Both BMPR-2 and ALK-1 are members of the transforming growth factor β signaling pathway.

Diseases associated with PAH include collagen vascular diseases (especially systemic sclerosis), congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, drug (notably anorexigens) and toxin exposures, and other disorders as delineated in Table 30–1.

For those patients in whom PAH develops secondary to collagen-vascular disease, the prognosis is extremely poor. In patients with PAH associated with systemic sclerosis, for instance, the 1-year survival is approximately 50%.

Congenital systemic-to-pulmonary shunts result from ventricular or atrial septal defects, anomalous pulmonary venous drainage, patent ductus arteriosus, or an aorto- pulmonary window. Systemic-to-pulmonary shunts expose the pulmonary vasculature to a persistent high-flow state. This can lead to PA endothelial dysfunction, mediator activation, and reactive vasoconstriction. Vascular remodeling ensues and can progress to the point that shunt reversal occurs (Eisenmenger syndrome). Shunt reversal worsens hypoxemia and further exacerbates PAH. PAH may also develop many years after repair of a congenital shunt as a long-term consequence of vascular injury sustained prior to shunt repair.

PAH develops in approximately 5–10% of patients with portal hypertension. Porto-pulmonary hypertension can interfere with eligibility for liver transplantation because it is associated with high perioperative mortality.

It is estimated that PAH develops in 1 of every 200 patients with HIV infection. Those patients with HIV in whom PAH develops have a particularly poor prognosis (see Figure 30–2). Methamphetamine use is also associated with the development of PAH. The diet drug fenfluramine, which has been removed from the U.S. market, has also been associated with increased likelihood of PAH.

The disorders discussed thus far, while distinct, result in pulmonary endothelial and vascular smooth muscle cell dysfunction, maladaptive arterial remodeling, and increased vascular resistance. While prognosis of PAH varies based on the underlying disease, presence of PAH significantly increases the morbidity and mortality of all associated conditions.

Pulmonary Hypertension with Left-Sided Heart Disease

Elevation of left-sided cardiac filling pressures can lead to PH through passive congestion and retrograde transmission of elevated pressure to the PA tree. This is termed “postcapillary pulmonary hypertension” (see Figure 30–1A, C). Postcapillary PH is characterized hemodynamically by an mPAP ≥ 25 mm Hg, PAWP > 15 mm Hg, and a normal PVR. Elevation of left-sided cardiac filling pressures may result from aortic or mitral valve dysfunction, myocardial disease, pericardial disease, atrial myxoma with obstruction, or pulmonary vein compression. With chronic elevation of pulmonary venous pressures, upregulation of inflammatory cytokines, as well as vasoconstrictive and proproliferative mediators, results in reactive vasoconstriction. Elevation of PA pressure can therefore exist out of proportion to left-sided filling pressures. This entity is referred to as mixed PH or “reactive PH” and is characterized hemodynamically by an mPAP ≥ 25 mm Hg, PAWP > 15 mm Hg, and a PVR > 3 Wood units (240 dynes × s × cm−5).

Since the PVR is normal in pure postcapillary PH, optimal management of left-sided heart disease with appropriate therapies that reduce the left-sided cardiac filling pressure (ie, surgery for valvular dysfunction, diuretics, angiotensin-converting enzyme inhibitors, hydralazine) will result in normalization of the PAP. This may not be the case if mixed PH has developed, as is seen in patients with severe end-stage heart failure undergoing transplant evaluation. Targeted vasodilator therapy can often improve reactive PA vasoconstriction in this setting. However, “fixed” mixed PH that is refractory to vasodilator therapy from vascular arterial remodeling can pose a significant problem in patients undergoing heart transplantation. Acute right heart failure may occur when an unconditioned donor right ventricle is exposed to irreversibly high PVR after transplantation.

Pulmonary Hypertension Associated with Lung Diseases and Hypoxemia

PH is also associated with diseases that affect the lung parenchyma such as chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). PH secondary to lung disease is hemodynamically precapillary in origin (see Figure 30–1A, B). Several factors contribute to the development of PH in this setting. Disruption of capillary networks results in a decrease in the overall surface area of the pulmonary vascular bed and thereby increases PVR. Hypoxemia directly triggers pulmonary vasoconstriction and indirectly contributes to pulmonary vascular remodeling by resulting in upregulation of proproliferative mediators. Hyperviscosity secondary to hypoxia-induced erythrocytosis can worsen PH. Sleep-disordered breathing, alveolar hypoventilation disorders, and prolonged exposure to high altitude are other causes of PH associated with hypoxemia.

Treatment of these disorders is based on correction of the underlying disorder, provision of supplemental oxygen, and management of cor pulmonale. Although some benefits from PAH-specific therapy have been observed in ILD patients, these treatments also worsen hypoxemia because they inhibit physiologic pulmonary vasoconstriction and worsen ventilation-perfusion mismatch. Use of PAH-specific therapy in this setting is generally discouraged.

Pulmonary Hypertension Due to Chronic Thrombotic or Embolic Diseases

A massive, sudden pulmonary embolus (PE) may significantly increase PAP and cause hemodynamic collapse secondary to acute right ventricular failure. This scenario leads to death in approximately 20–40% of patients with acute PE. The presence of severe PH in this setting portends a poor prognosis and predicts an increased likelihood of chronic thromboembolic PH (CTEPH). In fact, most patients with pulmonary embolism experience complete resolution of thromboemboli within 30 days.

CTEPH occurs in up to 4% of patients following acute PE or 10% following recurrent PE. However 50% of patients diagnosed with CTEPH have no history of a thromboembolic event. Why some patients develop CTEPH is not well understood, but surgical specimens show evidence of persistence and organization of thromboembolic material as well as vascular remodeling characterized by intimal thickening with deposition of collagen and hemosiderin, atherosclerosis, and calcification. Vasculopathy and pathologic remodeling of unobstructed downstream pulmonary arterioles similar to that which occurs in idiopathic PAH also develops possibly secondary to abnormal blood flow.

Mortality in patients with CTEPH is high but, in selected patients, can be improved markedly with surgical pulmonary thromboendarterectomy (PTE). Excluding CTEPH as a cause of PH requires evaluation with a ventilation-perfusion scan followed by confirmatory conventional pulmonary angiography. Computed tomography (CT) pulmonary angiography is not adequately sensitive to definitively exclude the diagnosis. Early referral to a center that can perform PTE is needed.

Miscellaneous

This category of PH encompasses a diverse group of disorders that are hemodynamically precapillary in origin and includes sarcoidosis, histiocytosis X, lymphangiomatosis, and pulmonary vein compression.

Pathophysiologic Consequences of Pulmonary Hypertension

Elevations in PAP eventually result in right ventricular systolic failure from chronic pressure overload (Figure 30–5). In response, the right ventricle undergoes hypertrophic remodeling to maintain CO and compensate for increased afterload. Early on, the right ventricle can have supernormal function and normal-to-reduced chamber dimensions. Chronic right ventricular pressure overload results in persistent upregulation of proproliferative neurohormones, endothelin-1, and cytokines. These mediators contribute to the development of maladaptive hypertrophy with fibrosis and diastolic dysfunction.

If exposure to elevated PA pressure continues, the right ventricle dilates. This is an ominous sign because it signifies the presence of increased right ventricular wall stress. Increased wall stress, when coupled with increased heart rate, results in increased myocardial oxygen demand. This develops in concert with a reduction in the epicardial-to-endocardial coronary perfusion gradient secondary to increased right ventricular end-diastolic pressure. In sum, these changes result in a myocardial oxygen supply-demand mismatch and right ventricular ischemia. Right ventricular ischemia worsens systolic function, increases end-diastolic pressure, and promotes further ventricular enlargement. Tricuspid regurgitation secondary to annular dilatation often occurs and serves to further reduce effective right ventricular forward output.

Right ventricular dilation, in the setting of an intact pericardium, results in a shift of the interventricular septum toward the left ventricle. This, especially when coupled with increased intrapericardial pressure, impedes left ventricular filling (preload). In turn, when left ventricular filling is impaired, systemic CO is reduced.

Multiple mechanisms contribute to the development of hypoxemia in PH, even when intrinsic pulmonary disease (COPD, CTEPH) is absent. Pulmonary vascular remodeling and in situ thromboses disrupt normal capillary-alveolar gas exchange and raise the alveolar-to-arterial oxygen gradient. Increased pulmonary pressures can increase right atrial pressure and cause shunting through a patent foramen ovale. Because a patent foramen ovale is present in up to 30% of adults, right-to-left shunting should be considered in patients with PH and hypoxemia.

Symptoms & Signs

One of the major difficulties in PH management is the failure to make an early diagnosis. It takes an average of 2.5 years from symptom onset to PH diagnosis. This results, in part, from the fact that PH often presents with a subtle, nonspecific symptom complex. PH most commonly manifests as dyspnea on exertion or fatigue, but it can also manifest as chest pain or syncope (often with exercise). Once right ventricular failure occurs, lower extremity edema and ascites become manifest. The New York Heart Association (NYHA) and World Health Organization have proposed systems for categorizing the severity of symptoms secondary to PH (Table 30–2).

Physical Examination

Careful examination of the patient with PH can reveal clues not only about the presence or severity of PH but also about the underlying cause. A loud pulmonic valve closure (P2) or an early systolic ejection click may be heard as a consequence of marked elevation in PA pressures. With right ventricular hypertrophy and enlargement, a left parasternal lift can be palpated. Another manifestation of right ventricular hypertrophy with diastolic dysfunction is the right ventricular S4 gallop. A right-sided S3 is also appreciable in patients with significant elevation in the right ventricular end-diastolic pressure.

Often the holosystolic murmur of tricuspid regurgitation (although frequently without the classically described respiratory variation) and the less common diastolic murmur of pulmonic insufficiency are noted in patients with PH. Jugular venous distention, peripheral edema, and ascites become manifest in advanced PH with right heart failure. Cool extremities and diminished peripheral pulses are indicative of low CO and peripheral vasoconstriction in severe right ventricular failure.

A murmur of mitral or aortic stenosis, a left-sided S3, or severe bronchial wheezing and diminished breath sounds may be clues to the presence of left-sided heart disease or pulmonary parenchymal disease, respectively. Jaundice and spider angiomata may point to the presence of cirrhosis and portal hypertension. Connective tissue diseases may present not only with signs of PH but also with Raynaud phenomenon, arthritis, rashes, or other skin changes (ie, sclerodactyly).

Diagnostic Studies

Electrocardiography

The electrocardiogram (ECG) in patients with significant PH typically suggests right ventricular hypertrophy. There is often a distinct correlation between the amplitude of the R wave in V1, the R/S ratio in V1, and the severity of the PH. Classic ECG findings include right axis deviation and right atrial enlargement. Incomplete or complete right bundle branch block is also common. The ECG criteria for right ventricular hypertrophy and a typical ECG in a patient with PH are shown in Table 30–3 and Figure 30–6, respectively. The ECG is not sensitive enough to serve as a screening tool for PH.

Chest Radiography

Radiographic examination of the chest in a patient with PAH may show enlargement of the main pulmonary artery and its major branches, with distal pruning of peripheral arteries. The retrosternal space is often filled by the hypertrophic right ventricle on lateral projection. Pulmonary venous congestion and left atrial or left ventricular enlargement suggest the presence of a left-sided cause of PH. Hyperinflated lung fields or bullous changes point to a chronic pulmonary disorder with secondary PH. A classic chest radiograph of a patient with PAH is shown in Figure 30–7.

Echocardiography

Two-dimensional and Doppler echocardiography are essential to the noninvasive assessment of patients with suspected PH. Echocardiography can demonstrate cardiac structural changes such as right atrial or right ventricular enlargement, right ventricular hypertrophy, and PA enlargement. Flattening or leftward shift of the interventricular septum can also be identified. If the shift occurs during systole, it suggests ventricular pressure overload. If it occurs during diastole, it suggests volume overload. Leftward shift of the septum throughout the cardiac cycle suggests both right ventricular pressure and volume overload (Figure 30–8A, B). The left ventricle is often small and underfilled in PH, with normal systolic function (Figure 30–8B).

Echocardiography is also useful to assess the severity of tricuspid regurgitation (TR) and estimate pulmonary artery systolic pressure (PASP). PASP is estimated by entering the peak velocity of the TR jet right into the modified Bernoulli equation and adding the right atrial pressure estimated by evaluating respiratory change in the inferior vena cava diameter (PASP = 4v2 + right atrial [RA] pressure) (Figure 30–8C). Noninvasive PA pressure assessment is not only important in establishing a diagnosis of PH but also in monitoring response to therapy. Echocardiography-estimated PASP may by inaccurate when the peak velocity cannot be accurately assessed due to minimal TR, an eccentric TR jet, or severe TR. In patients with risk factors for PH and who have signs and symptoms concerning for PH, low estimated PASP may not exclude PH.

Echocardiography can also be helpful in detecting left-sided heart disease. A dilated, hypocontractile left ventricle, valvular disease, or left atrial myxoma can be identified or excluded on a routine echocardiogram. Color-flow and agitated saline injection can also be used to assess for the existence of congenital intracardiac or intrapulmonary shunts.

Lung Scintigraphy

Ventilation-perfusion (V/Q) lung scintigraphy is necessary during the evaluation of patients with PH to exclude CTEPH as the etiology of PH. In PAH, the V/Q scan may reveal a normal perfusion pattern, or it may show diffuse, patchy (“mottled”) perfusion defects. Parenchymal lung disease can also result in perfusion scan abnormalities, but typically, these are matched by ventilatory defects. In CTEPH, however, the lung perfusion scan demonstrates one or more segmental defects mismatched by the ventilation scan (Figure 30–9). An abnormal V/Q scan should prompt conventional pulmonary angiography to confirm the diagnosis of CTEPH.

Pulmonary Function Testing

Pulmonary function testing is helpful in PH because it can establish the diagnosis of underlying obstructive or restrictive pulmonary disease. Interpretation of pulmonary function test results should be tempered by an awareness that PAH can reduce diffusing capacity of carbon monoxide. If the total lung capacity is less than 70% of predicted, a high-resolution CT scan should be considered to evaluate for ILD.

Computed Tomography and Magnetic Resonance Imaging

CT scans and magnetic resonance imaging (MRI) of the chest can provide useful information in parenchymal lung disorders and several other conditions that can cause PH. Chest CT or MRI scans can demonstrate characteristic findings in patients with fibrosing mediastinitis and cystic fibrosis, as well as infiltrative or granulomatous lung diseases. Findings on CT pulmonary angiography may suggest a diagnosis of CTEPH; however, the test is not sensitive enough to exclude the diagnosis of CTEPH.

Cardiac Catheterization and Pulmonary Angiography

RHC represents the gold-standard test to establish the diagnosis of PH, ascertain its etiology, establish severity and prognosis, evaluate vasoreactivity, and assist in guiding therapy. RHC should be performed by a clinician with experience in the evaluation and management of patients with PH.

During RHC, a full cardiopulmonary hemodynamic profile is established by recording the right atrial, right ventricular, PA, and PAWP, as well as measuring the CO. The PVR ([mPAP – PAWP]/CO) is also determined during RHC. Arterial and venous oxygen saturations obtained during RHC are used to detect and determine the severity of shunts. Abnormalities of the left heart, such as aortic or mitral valve disease or left heart failure, will be suggested during RHC by the presence of an elevated PAWP. In patients with characteristics associated with diastolic heart failure (elderly with diabetes, hypertension, left ventricular hypertrophy, or left atrial enlargement), administration of a fluid bolus or exercise during RHC should be considered to exclude the presence of occult diastolic dysfunction.

Vasoreactivity testing is an important component of RHC in PAH. Acute vasoreactivity is tested using inhaled nitric oxide or intravenous prostacyclin or adenosine. A reduction in mean PA pressure > 10 mm Hg with a final mPAP ≤ 40 mm Hg suggests that reversible vasoconstriction, rather than fixed vascular remodeling, is the major mechanism for PAH. Less than 15% of patients with idiopathic PAH will respond to acute vasodilator testing, but a positive vasoreactivity trial identifies a subset of patients with superior overall prognosis and high likelihood of benefit from high-dose calcium channel blocker therapy.

Pulmonary angiography is not routinely performed in patients with PH. When ventilation-perfusion scintigraphy or CT pulmonary angiography suggests chronic thromboembolic disease, pulmonary angiography and angioscopy are needed to confirm the diagnosis and determine the extent and location of thromboembolic disease. Findings on pulmonary angiography determine if patients with CTEPH are operative candidates.

Lung Biopsy

A lung biopsy is infrequently required to determine the cause of PH. Lung biopsy can identify injected particulate matter in injection drug users, can establish the diagnosis of pulmonary veno-occlusive disease, and may identify causative pathogens in ILD. Due to its substantial morbidity, however, lung biopsy is seldom used. If lung biopsy is obtained in an individual with reversible PH, medial smooth muscle hypertrophy may be noted. In more advanced cases, necrotizing arteritis and plexiform lesions can be seen (Figure 30–10).

Functional Capacity and Exercise Testing

The use of the World Health Organization's functional classification and symptom-limited exercise testing can be very helpful in the evaluation of patients with PH. Exercise testing, particularly the 6-minute walk test, has been shown to predict mortality and allows for objective assessment of symptom burden. Baseline functional capacity and exercise testing utilizing the 6-minute walk test should be measured prior to initiation of therapy and serially to monitor response to treatment.

Other Studies

If sleep apnea is suspected, a full sleep study can be diagnostic. Liver biochemical testing and hepatic ultrasound are used to exclude liver cirrhosis and portal hypertension. Screening for connective tissue diseases (eg, scleroderma, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, polymyositis) should be performed with appropriate serologic and immunogenetic studies. Thyroid function and HIV testing should also be performed. Parasitic disease (schistosomiasis or filariasis) should be suspected and tested for in patients from endemic areas with PH. Tissue biopsy, complement fixation, blood smear, and skin testing are diagnostic tests of choice in such patients.

The differential diagnosis for PAH includes a number of well-defined causes of PH (see Table 30–1). Diagnostic efforts should be pursued vigorously, since PAH can progress rapidly and is associated with substantial morbidity and mortality. An algorithmic approach to diagnosis has been proposed by the American College of Chest Physicians and is shown in Figure 30–11.

Suspicion for PAH should be raised on the basis of clinical history and physical examination, as previously outlined. Initial diagnostic testing should include a baseline ECG and chest radiograph. Two-dimensional and Doppler echocardiography are recommended to noninvasively assess PASP and evaluate biventricular structure and function. Color-flow and agitated saline injection should be utilized to assess for the existence of congenital intracardiac or intrapulmonary shunts.

If echocardiography suggests that PH is present and no clear left-sided or congenital lesions have been identified, an evaluation for thromboembolic disease should be conducted. If evidence of CTEPH is present on V/Q scintigraphy, pulmonary angiography is performed to confirm the diagnosis and to evaluate for PTE candidacy.

Pulmonary disease can be assessed with chest radiograph, arterial oxygen saturation measurement, pulmonary function testing, and chest CT scan. If sleep apnea or sleep-disordered breathing is suspected, a thorough sleep study should be conducted. A serologic workup for common connective tissue diseases, thyroid disease, liver disease, and HIV is also required.

Assessment of functional capacity and symptom burden should be conducted using the World Health Organization's functional classification and 6-minute walk test. Exercise capacity correlates well with overall prognosis, and baseline 6-minute walk test values can help later evaluation of treatment response. RHC is also recommended at this stage in order to document right atrial pressure, pulmonary arterial pressure, and PAWP. CO, PVR, and vasoreactivity testing should also be assessed during RHC. If a patient has an elevated mPAP on RHC and no cause of PH has been identified, the diagnosis of idiopathic PAH has been made. Genetic testing should be discussed with the patient and family members.

Pulmonary Arterial Hypertension

Improvement in cardiopulmonary hemodynamics, exercise capacity, functional class, survival, and prevention of clinical worsening are the goals of PAH treatment. General measures in the management of PAH include symptom-limited, regular exercise to maintain skeletal muscle conditioning and overall cardiovascular fitness. Intense exercise should be avoided, especially if the patient with PAH has a history of exercise-induced syncope or presyncope. Patients should avoid high altitudes, and supplemental oxygen should be provided for air travel. Since patients with PAH have reduced cardiopulmonary reserve, immunization against influenza and pneumococcus is recommended.

Pregnancy in PAH deserves special attention. Patients with PAH should be counseled to avoid pregnancy because it is associated with significant (30%) mortality. Birth control should be discussed and contraceptive methods prescribed in women of childbearing age. Hemoglobin levels should be monitored regularly. In patients with Eisenmenger syndrome, erythrocytosis should be treated with phlebotomy only if symptoms of hyperviscosity develop. Patients with PAH should refrain from smoking and adhere to a sodium-restricted diet in the setting of right heart failure.

Patients with PAH require supplemental oxygen if they exhibit arterial oxygen desaturation at rest or with minimal exertion. Patients with PAH, particularly idiopathic PAH, should receive oral anticoagulant therapy with a goal international normalized ratio (INR) of 1.5 to 2.5. This recommendation is based on several nonrandomized clinical trials showing improved survival in patients with idiopathic PAH treated with warfarin.

Diuretic therapy is the mainstay of treatment for symptomatic PAH with volume overload. Digoxin may also help improve right-sided hemodynamics and is the preferred rate-controlling agent in the setting of atrial tachyarrhythmia. Digoxin has also been shown to reduce circulating catecholamine levels in patients with chronic PAH. However, no other data exist regarding the efficacy of cardiac glycosides (ie, digoxin) in PAH with right ventricular failure. Digoxin toxicity, especially in patients with severe hypoxia, renal insufficiency, or hypokalemia, is well recognized and warrants vigilance.

In patients with PAH and decompensated right heart failure, strategies to improve clinical status and restore end-organ perfusion include (1) afterload reduction with pulmonary vasodilators, such as oxygen, inhaled nitric oxide, prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors; (2) preload reduction with diuretics or ultrafiltration; and (3) augmentation of right ventricular function with inotropic therapy. Intravenous inotropes such as low-dose dobutamine or dopamine (1–2 mcg/kg/min) are of particular benefit in patients with right ventricular failure and hypotension in whom diuretic therapy is ineffective or in whom renal failure has developed (Figure 30–12).

Until 1996, high-dose calcium channel blockers were the only vasodilators available to treat PAH. Calcium channel blocker therapy may reduce PA pressure and right ventricular afterload, thereby improving right ventricular hemodynamics and increasing CO. Vasoreactivity testing identifies a subset of idiopathic PAH patients (less clear for the general PAH cohort) who may benefit from calcium channel blocker therapy. If a patient with PAH has a favorable response to acute vasodilator testing, a hemodynamically monitored trial of an oral calcium channel blocker, such as nifedipine, amlodipine, or diltiazem, may be undertaken. If a reduction in PA pressures occurs with preservation of CO, then the patient can be considered for long-term therapy. Verapamil is contraindicated due to its significant negative inotropic properties. Response to calcium channel blocker therapy should be assessed during a repeat RHC.

There are several limitations to calcium channel blocker therapy. Use of a calcium channel blocker is not advisable in patients with severe right ventricular failure or hypotension. Calcium channel blocker therapy is contraindicated in the absence of a positive vasoreactivity trial or a favorable hemodynamic response. Lastly, only a small percentage (< 7%) of patients with PAH who have acute vasoreactivity will have a sustained response to long-term calcium channel blocker therapy; therefore, close monitoring during calcium channel blocker therapy is needed.

Fortunately, the following drugs have been approved as alternatives for the treatment of PAH: oral bosentan and ambrisentan, oral sildenafil and tadalafil, inhalational iloprost and treprostinil, subcutaneous/intravenous treprostinil, and intravenous epoprostenol. These agents target the endothelin, nitric oxide, and prostacyclin pathways (Figure 30–13). These pathways are thought to mediate vascular tone and arterial remodeling. When used appropriately, these pulmonary vasodilators can improve symptoms and exercise capacity. Most of these agents delay time to clinical worsening. Only epoprostenol has been shown to improve survival in a randomized trial (Table 30–4).

Endothelin-1 is secreted by vascular endothelial cells and is a potent vasoconstrictor and mediator of smooth muscle cell proliferation. In addition, endothelin-1 enhances vascular fibrosis, increases platelet aggregation, promotes cardiac myocyte hypertrophy, and increases aldosterone production. Endothelin-1 is secreted in response to a variety of stimuli, including hypoxemia, endothelial sheer and pulsatile stress, and neurohormonal activation, as well as PH-related growth factors and cytokines.

Bosentan is an endothelin-A and -B receptor antagonist approved for the treatment of functional class III and IV PAH. Bosentan has been shown to increase 6-minute walk distance, decrease symptom burden, and delay clinical worsening in patients with idiopathic PAH and patients with associated PAH secondary to scleroderma (see Table 30–4). Bosentan also appears to have benefit in symptomatic patients with PAH secondary to congenital heart disease and Eisenmenger syndrome.

Transaminitis develops in approximately 11% of patients treated with bosentan, and monthly liver function testing in patients treated with bosentan is required. Transaminitis is usually reversible with cessation of treatment. A drop in hemoglobin is common and is usually not clinically significant; however, periodic monitoring of hemoglobin is recommended. Bosentan is highly teratogenic, and treated patients of childbearing potential must reliably utilize approved contraception and undergo monthly pregnancy testing. Side effects associated with bosentan include nasal congestion, flushing, anemia, and lower extremity edema.

Ambrisentan is a selective endothelin-A receptor antagonist that has recently been approved in the United States for PAH for functional class II and III patients. Ambrisentan significantly improves exercise capacity, delays time to clinical worsening, and improves cardiopulmonary hemodynamics. The incidence of transaminitis is approximately 3% at 1 year. Monthly liver function testing is no longer mandatory, but most experts still monitor liver function every 3–6 months. Importantly, ambrisentan has no significant interactions with warfarin or sildenafil. The drug is teratogenic, and so, as with bosentan, pregnancy must be avoided. Ambrisentan can cause peripheral edema, nasal congestion, and flushing.

In patients with PAH, nitric oxide bioavailability is significantly reduced. Nitric oxide is secreted by the endothelial cell and diffuses to the smooth muscle cell where it mediates vasodilation and exerts an antiproliferative effect via activation of the cyclic guanyl monophosphate (cGMP) pathway.

The nitric oxide pathway can be enhanced by administering exogenous inhaled nitric oxide. It can also be enhanced by inhibiting phosphodiesterase isoform-5, the enzyme responsible for the degradation of cGMP. Sildenafil and tadalafil are oral phosphodiesterase-5 (PDE-5) inhibitors known to dilate the PA bed without increasing left-sided filling pressures. They are approved for treatment of PAH patients with functional class II–IV symptoms. When administered long term, both agents improve exercise capacity, reduce symptom burden, and improve cardiopulmonary hemodynamics (see Table 30–4). Tadalafil but not sildenafil has been shown to delay clinical worsening. Tadalafil is dosed once daily compared to three times daily dosing for sildenafil. PDE-5 inhibitors can cause headache, flushing, dyspepsia, epistaxis, and visual changes.

Prostacyclin (PGI2) is a direct pulmonary and systemic vasodilator as well as an inhibitor of vascular remodeling and platelet aggregation. Prostacyclin is secreted by the endothelial cell and exerts its vascular effect by stimulating smooth muscle cell cyclic adenyl monophosphate (cAMP). The PGI2 pathway is downregulated in PAH. To enhance this pathway, exogenously synthesized epoprostenol (prostacyclin) and other prostanoids can be administered. Currently, Food and Drug Administration–approved prostanoids for PAH are administered through intravenous, subcutaneous, or inhalational routes. A summary of the pivotal trials that have led to approval of these agents for PAH is provided in Table 30–4.

Epoprostenol has a short half-life and is unstable if exposed to room temperature or light. It is degraded by gastric pH and must therefore be administered via continuous intravenous infusion. When added to conventional therapy, epoprostenol has been shown to improve exercise capacity, reduce symptom burden, improve cardiopulmonary hemodynamics, and reduce mortality in patients with PAH who have NYHA class III–IV symptoms. Major adverse effects of this agent relate to its complex delivery system and include infection, thrombosis, and pump malfunction. Due to its short half-life, brief interruption of epoprostenol infusion can result in rebound PH and cardiopulmonary collapse. Prostanoids, as a class, are known to cause headache, flushing, nausea, vomiting, diarrhea, arthralgias, myalgias, and jaw pain. Newer temperature-stable formulations of epoprostenol may simplify administration.

Treprostinil is a prostanoid that is premixed, stable at room temperature, and has a longer half-life than epoprostenol. Treprostinil can be administered subcutaneously as well as intravenously. In patients with NYHA class II–IV PAH, treprostinil improves exercise capacity, reduces symptoms, and improves cardiopulmonary hemodynamics (see Table 30–4). Inhalational iloprost has also been shown to improve clinical outcomes in patients with symptomatic PAH. Iloprost must be administered six to nine times daily to maintain efficacy. Treprostinil can also be administered by inhalation and is dosed four times daily. While iloprost and treprostinil have advantages over epoprostenol, epoprostenol is the only prostanoid shown to reduce mortality in advanced PAH.

Choosing the correct treatment regimen for the patient with PAH relies on an understanding of the underlying disease and of patient-specific factors. Disease severity, as assessed by integration of hemodynamic, clinical, and laboratory parameters, is crucial in selecting the appropriate treatment (Table 30–5; see Figure 30–11). Individual patient factors, such as comorbidities (ie, liver disease), concomitant drug therapy, or a history of medication nonadherence, may all influence treatment choice (Figure 30–14).

Invasive treatment options for PAH include atrial septostomy, lung transplantation, and combined heart-lung transplantation. Atrial septostomy has been performed as a palliative measure for patients with PAH and right heart failure or recurrent syncope. It is postulated that a right-left shunt in this setting improves left ventricular filling and CO. Atrial septostomy can, however, worsen hypoxia and increases the likelihood of paradoxical embolization. As such, it is recommended that atrial septostomy be performed only at experienced centers. Outcomes with lung and combined heart-lung transplantation are improving. One-year survival posttransplantation is 70%, and 5-year survival is 50%. Transplantation is reserved for PAH patients with heart failure and poor quality of life who continue to deteriorate despite maximal medical therapy.

Pulmonary Hypertension with Left-Sided Heart Disease

PH occurs in 25–30% of patients with left-sided heart disease and is associated with worse outcomes in this population. Treatment is dictated by the underlying disease process. Surgical or percutaneous treatment of aortic or mitral valve disease and treatment of coronary artery disease should be aggressively pursued as these interventions can improve left-sided filling pressures, reduce PA pressure, and improve symptoms. Standard therapy for systolic and diastolic heart failure is recommended. Supplemental oxygen is required for those who exhibit systemic oxygen desaturation.

Although limited data are available, oral or intravenous vasodilators (eg, nitrates or sildenafil, nitroprusside, nesiritide, milrinone) are sometimes used for the management of refractory cases of PH with left-sided heart disease. Calcium channel blocker therapy, with the possible exception of amlodipine, is contraindicated in systolic heart failure with PH. Endothelin-receptor antagonists are also contraindicated in left-sided heart failure because they have been shown to worsen heart failure and increase mortality. Intravenous epoprostenol is also contraindicated in the treatment of advanced systolic heart failure because it has been shown to increase mortality. Mechanical circulatory-assist devices and heart-lung transplantation are other therapies available for PH due to left-sided heart disease.

Pulmonary Hypertension Associated with Lung Disease or Hypoxemia

PH in persons with lung disease or hypoxemia, or both, is best relieved by treating the underlying disease. In this cohort, correction of hypoxemia is especially important. Bronchodilator therapy should be optimized for patients with obstructive pulmonary disease. Continuous positive airway pressure and weight loss often aid in the treatment of PAH patients with sleep-disordered breathing. Inflammatory conditions that lead to ILD should be sought and aggressively treated with anti-inflammatory agents. Specific pulmonary vasodilator therapy is controversial for PH associated with lung disease on the basis of insufficient evidence.

Cor pulmonale, or right heart failure secondary to lung disease, often develops in patients with PH. As previously outlined for PAH, sodium restriction and diuretics are the mainstays of right heart failure therapy. Digoxin and vasodilator therapy may be considered, although outcome data are lacking. For select, severely symptomatic patients with PH and lung disease, lung transplantation can improve quality of life and survival.

Pulmonary Hypertension Due to Chronic Thrombotic or Embolic Disease

Mortality in patients with CTEPH is high, and CTEPH should be excluded in all patients undergoing evaluation for PH. Patients with CTEPH in whom conventional pulmonary angiography demonstrates proximal surgically accessible disease may be candidates for PTE. At experienced centers, perioperative mortality following PTE is as low as 4.4%. Following PTE, most patients experience marked improvement in PAP, right heart function, NYHA class, and exercise capacity.

Residual PH occurs in approximately 10% of patients after PTE and appears to be linked to the degree of small vessel arteriopathy. Pathophysiologic similarities between PAH and CTEPH have prompted investigation into the usefulness of pulmonary vasodilator therapy for PH that persists after PTE and as bridging therapy. Encouraging data are emerging from small nonrandomized trials showing hemodynamic improvement in chronic thromboembolic PH patients with vasodilator therapy. The role for medical treatment in chronic thromboembolic PH is as yet incompletely defined and is an area of ongoing research.

PH is a progressive disorder associated with a high mortality rate. The underlying cause of the PH is a key factor in determining the prognosis and natural history of the disease (see Figure 30–2). Patients with PAH associated with connective tissue disease and those with PAH and HIV have the worst prognoses. Patients with congenital heart disease, by contrast, have the best prognosis (6-month survival is 89%). Even for patients with PH due to lung disease or hypoxemia, survival rates vary widely. Patients with PH and emphysema have a 6-month survival of 81%, whereas patients with PH and interstitial lung disease have a 6-month survival of 38%.

Clinical features and hemodynamic parameters also strongly influence survival. Markers of poor prognosis in PH include advanced functional class (NYHA III–IV) (see Table 30–2), poor exercise capacity (reduced 6-minute walk distance), resting hemodynamics consistent with right ventricular failure (high right atrial pressure, low cardiac output), elevated B-type natriuretic peptide, and presence of a pericardial effusion or significant right ventricular dysfunction on echocardiogram (see Table 30–5).