Pulmonary hypertension and right ventricular failure

Pulmonary hypertension (PH) is defined by an elevated mean pulmonary artery pressure (mPAP) of >20 mm Hg and may be precapillary or postcapillary in etiology. Precapillary PH is further characterized by an elevated pulmonary vascular resistance (PVR) of ≥3 Wood units and a pulmonary arterial wedge pressure of ≤15 mm Hg. Management of postcapillary PH, which is caused by left-sided heart dysfunction, typically involves treating the underlying process. Medications used to treat precapillary PH are often not only ineffective for postcapillary PH but may in fact be harmful, potentially leading to the development of pulmonary edema or systemic hypotension.

The World Health Organization (WHO) categorizes PH into five groups based on their underlying pathophysiology: (1) pulmonary arterial hypertension (PAH), (2) PH caused by left heart disease, (3) PH caused by lung diseases and/or hypoxia, (4) PH caused by pulmonary artery obstructions, and (5) PH with unclear and/or multifactorial mechanisms. PAH can be idiopathic (IPAH, previously known as primary PH [PPH]) or may occur in association with a variety of underlying disease processes, such as collagen vascular disease, portal hypertension, congenital systemic-to-pulmonary shunts, drug or toxin exposure, or human immunodeficiency virus (HIV) infection. IPAH is principally a disease of young women, but it can affect all age groups and both sexes. A genetic predisposition may underlie a substantial proportion of these cases and is referred to as heritable pulmonary arterial hypertension (HPAH).

Initial therapy may be directed at an underlying cause or contributing factors, such as using continuous positive airway pressure (CPAP) and supplemental oxygen for PH associated with obstructive sleep apnea. After the identification and treatment of underlying associated disorders and contributing factors, specific therapy for PAH should be considered. IPAH carried a very poor prognosis (median survival rate of approximately 2.8 years from the time of diagnosis) through the mid-1980s. Subsequently, a number of therapeutic options have been developed, and 14 have been approved by the U.S. Food and Drug Administration (FDA), falling into three classes of drugs: (1) prostanoids, including epoprostenol (intravenous), treprostinil (subcutaneous, intravenous, inhaled, or oral), iloprost (inhaled), and selexipag (oral); (2) endothelin receptor antagonists (ERAs), including bosentan, ambrisentan, and macitentan (all oral); and (3) drugs acting on the nitric oxide pathway, including the phosphodiesterase (PDE) type-5 inhibitors, sildenafil and tadalafil (both oral), and the guanylate cyclase activator, riociguat (oral).

Diagnosis

Symptoms, signs, and clinical history

As a result of the insidious onset of symptoms, PAH is often advanced at the time of diagnosis. Dyspnea upon exertion is the most common presenting symptom, but it is sometimes attributed to deconditioning or another cardiorespiratory ailment. Chest pain mimicking angina pectoris may also 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 the exclusion of underlying causes of PH. Important clues to an underlying condition might include a previous history of a heart murmur, deep venous thrombosis (DVT) or pulmonary embolism, Raynaud 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 exposure, particularly to appetite suppressants and amphetamines, should be noted. Cocaine is a powerful vasoconstrictor that may contribute to the development of PH, and intravenous drug use has also 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 ascites might suggest the presence of PH and right ventricular (RV) dysfunction. Associated systemic diseases, such as collagen vascular disease or liver disease, may also become apparent during routine examination.

Laboratory evaluation

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. The scleroderma spectrum of disease, particularly limited scleroderma, or the CREST syndrome (i.e., calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasias), has been associated with an increased risk of the development of PAH. ^, Liver function tests (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) may be elevated in patients with RV 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. HIV testing and hepatitis serologic studies should be performed. 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

Transthoracic echocardiography (TTE) is the initial test of choice in assessing the severity of PH and detecting left-sided heart disease. Findings may include elevated peak tricuspid regurgitant jet velocity, elevated estimated pulmonary artery systolic pressure, RV enlargement, 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 useful as part of a long-term follow-up, ^, although not all patients have suitable echocardiographic windows.

Radiographic evaluation and exclusion of thromboembolic disease

Chest radiography may reveal an enlargement of the central pulmonary vessels and evidence of RV enlargement. Evidence of parenchymal lung disease may also be apparent. When parenchymal lung disease is suspected, pulmonary function testing and high-resolution computed tomography (CT) of the chest may be indicated. Because of its high sensitivity, ventilation/perfusion (V/Q) scanning is the imaging modality of choice to exclude chronic thromboembolic disease–related PH (CTEPH), which is among the most preventable and treatable causes of PH. Diffuse mottled perfusion can be seen in IPAH, whereas larger segmental and subsegmental mismatch defects are suggestive of CTEPH. Because any process that leads to decreased perfusion without an associated decrease in ventilation will result in a mismatch, V/Q scanning lacks specificity for CTEPH. CT pulmonary angiography (CTPA) is thus an important adjunct to V/Q scanning, not only to exclude other disease processes in which similar mismatch defects can be seen but also to define the extent and location of thromboembolic disease before surgical evaluation. Although CTPA remains the imaging modality of choice for acute pulmonary embolism, it lacks the sensitivity of V/Q scanning for CTEPH, particularly at the subsegmental level, and caution should be exercised when using it to exclude CTEPH.

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, cardiac output can be measured, and PVR can be calculated. Acute pulmonary vasoreactivity can be assessed using a short-acting agent, such as prostacyclin (epoprostenol), inhaled nitric oxide, or intravenous adenosine. The consensus definition of a positive acute vasodilator response in a patient with PAH is a decrease in mPAP by ≥10 mm Hg to ≤40 mm Hg with increased or unchanged cardiac output. The primary objective of acute vasodilator testing in patients with PAH is to identify the subset of patients who might be effectively treated with oral calcium channel blockers; response to a short-acting pulmonary vasodilator has been shown to be predictive of a response to calcium channel blockers. 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

Although earlier studies suggested improved survival with oral anticoagulation in PAH, the benefits were primarily seen in patients with IPAH and not present in those with other forms of PAH. More recent studies have not only failed to demonstrate a survival advantage in patients with IPAH treated with anticoagulation, but they have demonstrated an increased mortality in patients with PAH secondary to most other causes. Generally, patients with PAH who are treated with chronic intravenous epoprostenol are anticoagulated in the absence of contraindications, owing in part to the additional risk of catheter-associated thrombosis. All patients with CTEPH should receive lifelong anticoagulation.

Hypoxemia is a pulmonary vasoconstrictor and can contribute to the development or progression of PAH. It is generally considered important to maintain oxygen saturations greater than 90% at all times, although data supporting the role of supplemental oxygen in PH are largely based on expert opinion or extrapolated from clinical trials that evaluated its use in patients with chronic obstructive pulmonary disease (COPD). Although no randomized controlled trials have yet addressed the role of supplemental oxygen in PH, a post hoc analysis of data from a large, observational study demonstrated improved survival among patients with PAH and severely reduced diffusing capacity who were treated with supplemental oxygen.

Diuretics are indicated in patients with evidence of RV failure and volume overload. Careful dietary restriction of sodium and fluid intake is important in the management of patients with PAH and 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 used in refractory RV 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 patients with PH, immunization against influenza, coronavirus disease 2019 (COVID-19), and pneumococcal pneumonia is recommended.

Calcium channel blockers

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

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