Cor Pulmonale

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Introduction to Cor Pulmonale

Cor pulmonale is defined as an alteration in the structure and function of the right ventricle (RV) of the heart caused by a primary disorder of the respiratory system. Pulmonary hypertension is often the common link between lung dysfunction and the heart in cor pulmonale. Right-sided ventricular disease caused by a primary abnormality of the left side of the heart or congenital heart disease is not considered cor pulmonale, but cor pulmonale can develop secondary to a wide variety of cardiopulmonary disease processes. Although cor pulmonale commonly has a chronic and slowly progressive course, acute onset or worsening cor pulmonale with life-threatening complications can occur.[1]

Etiology and Pathophysiology of Cor Pulmonale

The pathophysiology of cor pulmonale is a result of increased right-sided filling pressures from pulmonary hypertension that is associated with diseases of the lung. The increased afterload leads to structural alterations in the right ventricle (RV) including RV hypertrophy (RVH) which can be seen in chronic cor pulmonale.

Acute cor pulmonale: pulmonary embolism (more common) and acute respiratory distress syndrome (ARDS). The underlying pathophysiology in a massive pulmonary embolism causing cor pulmonale is the sudden increase in pulmonary resistance. In ARDS, RV overload can occur due to mechanical ventilation and the pathologic features of the syndrome itself.[2] Mechanical ventilation, especially higher tidal volumes, requires a higher transpulmonary pressure.

In the case of ARDS, cor pulmonale is associated with an increased possibility of right-to-left shunting through a patent foramen ovale, which carries a poorer prognosis.[3]

Several different pathophysiologic mechanisms can lead to pulmonary hypertension and, subsequently, to cor pulmonale. The World Health Organization (WHO) has five classifications for pulmonary hypertension, and all except one of these groups can result in cor pulmonale (WHO Classification group 2 is pulmonary artery hypertension due to left ventricular [LV] dysfunction).[4] Note the following WHO classifications:

The end result of the above mechanisms is increased pulmonary arterial pressure and resistance.

RV and LV output

The RV is a thin-walled chamber that is a better volume pump than a pressure pump. It is better suited to adapt to changing preload than afterload. With an increase in afterload, the RV systolic pressure is increased to maintain the circulatory gradient. At a critical point, a further increase in pulmonary arterial pressure and resistance produces significant RV dilatation, an increase in RV end-diastolic pressure, and RV circulatory failure.

A decrease in RV output leads to a decrease in LV filling, which results in decreased cardiac output. Because the right coronary artery originates from the aorta, decreased LV output causes decreased right coronary blood flow and ischemia to the RV wall. What ensues is a vicious cycle between decreases in LV and RV output.

RV and LV morphogenesis

Genetic investigations have confirmed that morphogenesis of the right and left ventricle originated from different sets of progenitor cells. Their differing embryologic origins could explain the differing rates of hypertrophy of the right and left ventricles.[5]

RV overload

RV pressure and volume overload is associated with septal displacement toward the left ventricle. Septal displacement, which can be visualized on echocardiography, is an additional factor that decreases LV filling and output in the setting of cor pulmonale and RV enlargement.

Epidemiology of Cor Pulmonale

Although the prevalence of COPD in the United States is reported to be about 15 million, the exact prevalence of cor pulmonale is difficult to determine, as physical examination and routine tests are relatively insensitive for the detection of pulmonary hypertension and RV dysfunction.

Cor pulmonale is estimated to account for 6-7% of all types of adult heart disease in the United States, with chronic obstructive pulmonary disease (COPD) due to chronic bronchitis or emphysema the causative factor in more than 50% of cases. Mortality in patients with concurrent COPD and cor pulmonale is higher than that in patients with COPD alone. In addition, cor pulmonale accounts for 10-30% of decompensated heart failure–related admissions in the United States.[6]

In contrast, acute cor pulmonale is usually secondary to massive pulmonary embolism. Acute massive pulmonary thromboembolism is the most common cause of acute life-threatening cor pulmonale in adults; 50,000 deaths in the United States are estimated to occur per year from pulmonary emboli and about half occur within the first hour due to acute right heart failure.

Globally, the incidence of cor pulmonale varies widely among countries, depending on the prevalence of cigarette smoking, air pollution, and other risk factors for various lung diseases.[7]

Cor Pulmonale Presentation

The clinical manifestations of cor pulmonale may be nonspecific. The symptoms may be subtle, especially in early stages of the disease, and they may be mistakenly attributed to the underlying pulmonary pathology.

Symptoms

Patients may report a combination of fatigue, tachypnea, exertional dyspnea, and cough. Anginal chest pain can also occur and may be due to right ventricular ischemia or pulmonary artery stretching, which typically do not respond to nitrates. A variety of neurologic symptoms may be seen due to decreased cardiac output and hypoxemia.

Hemoptysis may occur due to rupture of a dilated or atherosclerotic pulmonary arteriole. Other conditions, such as tumors, bronchiectasis, and pulmonary infarction, should be excluded before attributing hemoptysis to pulmonary hypertension. Rarely, the patient may complain of hoarseness due to compression of the left recurrent laryngeal nerve by a dilated pulmonary artery.

In advanced stages, passive hepatic congestion secondary to severe right ventricular failure may lead to anorexia, right upper quadrant abdominal discomfort, and jaundice. In addition, syncope with exertion, which may also be seen in severe disease, reflects a relative inability to increase cardiac output during exercise with a subsequent drop in the systemic arterial pressure.

Elevated pulmonary artery pressure can lead to elevated right atrial, peripheral venous, and capillary pressure. By increasing the hydrostatic gradient, it leads to transudation of fluid and accumulation of peripheral edema. Although this is the simplest explanation for peripheral edema in cor pulmonale, other factors may contribute, especially in a subset of patients with chronic obstructive pulmonary disease (COPD) who do not have an increase in right atrial pressure. A decrease in glomerular filtration rate (GFR) and filtration of sodium as well as stimulation of arginine vasopressin (which decreases free water excretion) by hypoxemia may play important pathophysiologic roles in this setting and may even have a role for peripheral edema in patients with cor pulmonale.[8]

Signs

Physical findings may reflect the underlying lung disease or pulmonary hypertension, right ventricular hypertrophy (RVH), and RV failure. An increase in chest diameter, labored respiratory efforts with retractions of the chest wall, distended neck veins with prominent a or v waves, and cyanosis may be seen.

On auscultation of the lungs, wheezes and crackles may be heard as signs of underlying lung disease. Turbulent flow through recanalized vessels in chronic thromboembolic pulmonary hypertension[9] may be heard as systolic bruits in the lungs. On percussion, hyperresonance of the lungs may be a sign of underlying COPD.

Splitting of the second heart sound with accentuation of the pulmonic component can be heard in the early stages. A systolic ejection murmur with a sharp ejection click over the region of the pulmonary artery may be heard in advanced disease, along with a diastolic pulmonary regurgitation murmur. Other findings upon auscultation of the cardiovascular system may be RV third and fourth sounds or the systolic murmur of tricuspid regurgitation.

RVH is characterized by a left parasternal or subxiphoid heave. Hepatojugular reflux and pulsatile liver are signs of RV failure with systemic venous congestion. In severe disease, ascites can also be present.

Examination of the lower extremities reveals evidence of pitting edema. Edema in cor pulmonale is strongly associated with hypercapnia.[10]

Diagnostic Considerations

A general approach to diagnose cor pulmonale and to investigate its etiology starts with routine laboratory tests, chest radiography, and electrocardiography (see the separate sections below). Echocardiography gives valuable information about the disease and right ventricular (RV) function, as well as assisting in determining the etiology of pulmonary hypertension and cor pulmonale. Right heart catheterization is the most accurate but invasive test to confirm the diagnosis of cor pulmonale and gives important information regarding underlying causes.[11, 12]

Once a diagnosis of cor pulmonale is made, it should be followed by further investigation to determine the underlying lung pathology. Sometimes a common lung disease such as chronic obstructive pulmonary disease (COPD) is not the only lung pathology causing cor pulmonale; other lung diseases may coexist. Thus, pulmonary function tests may be required to confirm the presence of other lung pathologies. Ventilation/perfusion (V/Q) scanning or chest computed tomography (CT) scanning may be performed if the patient’s history and physical examination suggest pulmonary thromboembolism as the cause or if other diagnostic tests do not provide a specific etiology.

Imaging studies may show evidence of underlying cardiopulmonary diseases, pulmonary hypertension, or RV enlargement. Cardiac magnetic resonance (CMR) imaging is another form of noninvasive imaging that does not use ionizing radiation. CMR can be used to evaluate cor pulmonale, and it is useful in determining RV structure, remodeling, and function; this modality is especially useful in assessing pulmonary artery dimensions when compared to traditional echocardiography.

Differentials

When diagnosing cor pulmonale, it is important to consider the possibility of thromboembolic disease and primary pulmonary hypertension as possible etiologies. In addition, also assess for the following conditions:

Diagnostic Tests

Laboratory investigations are directed toward defining the potential underlying etiologies as well as evaluating the complications of cor pulmonale. In specific instances, appropriate laboratory studies may include the following:

Arterial Blood Gas Analysis

Arterial blood gas measurements may provide important information about the level of oxygenation and type of acid-base disorder.

Brain Natriuretic Peptide

Brain natriuretic peptide (BNP) is a peptide hormone that is released in response to volume expansion and the increased wall stress of cardiac myocytes. BNP helps to promote diuresis, natriuresis, vasodilation of the systemic and pulmonary vasculature, and reduction of circulating levels of endothelin and aldosterone. As a result, both congestive heart failure due to left ventricular (LV) failure and cor pulmonale due to noncardiac pulmonary hypertension can lead to elevations in plasma BNP. Although not specific, severe acute decompensated LV heart failure can result in higher levels of BNP.

Chest Radiography

In patients with chronic cor pulmonale, the chest radiograph may show enlargement of the central pulmonary arteries with oligemic peripheral lung fields. Pulmonary hypertension should be suspected when the right descending pulmonary artery is larger than 16 mm in diameter and the left pulmonary artery is larger than 18 mm in diameter. Right ventricular enlargement leads to an increase of the transverse diameter of the heart shadow to the right on the posteroanterior view and filling of the retrosternal air space on the lateral view. These findings have reduced sensitivity in the presence of kyphoscoliosis or hyperinflated lungs.

Electrocardiography

Electrocardiographic (ECG) abnormalities in cor pulmonale reflect the presence of right ventricular hypertrophy (RVH), RV strain, or underlying pulmonary disease (see the image below). Such ECG changes may include the following:

Severe RVH may reflect as Q waves in the precordial leads that may be mistakenly interpreted as an anterior myocardial infarction (however, as electrical activity of the RV is significantly less than the left ventricle [LV], small changes in RV forces may be lost in the ECG). See the image below.



View Image

This ECG shows some typical abnormalities that may be seen in cor pulmonale and other chronic pulmonary diseases: (1) R/S ratio >1 in V1 and <1 in V6....

Additionally, many rhythm disturbances may be present in chronic cor pulmonale; these range from isolated premature atrial depolarizations to various supraventricular tachycardias, including paroxysmal atrial tachycardia, multifocal atrial tachycardia, atrial fibrillation, atrial flutter, and junctional tachycardia. These dysrhythmias may be triggered by processes secondary to the underlying disease, (eg, anxiety, hypoxemia, acid-base imbalance, electrolyte disturbances, excessive use of bronchodilators, heightened sympathetic activity). Life-threatening ventricular tachyarrhythmias are less common.

In selected cases, pulmonary function testing may be indicated to determine underlying obstructive or interstitial lung disease.

2-D and Doppler Echocardiography

Two-dimensional (2-D) echocardiography usually demonstrates signs of chronic right ventricular (RV) pressure overload. As this overload progresses, increased thickness of the RV wall with paradoxical motion of the interventricular septum during systole occurs. At an advanced stage, RV dilatation occurs, and the septum shows abnormal diastolic flattening. In extreme cases, the septum may actually bulge into the left ventricular (LV) cavity during diastole, resulting in decreased LV diastolic volume and reduction of LV output.

Doppler echocardiography is used to estimate pulmonary arterial pressure, taking advantage of the functional tricuspid insufficiency that is usually present in pulmonary hypertension. This imaging modality is considered the most reliable noninvasive technique to estimate pulmonary artery pressure. However, the efficacy of Doppler echocardiography may be limited by the ability to identify an adequate tricuspid regurgitant jet, which may be further enhanced by using saline contrast.[13]

Several methods exist to assess RV function. One method includes tricuspid annular plane systolic excursion (TAPSE), which is measured by viewing the heart in the apical four-chamber view and using the M-mode function along the lateral tricuspid annulus. By measuring the distance traveled of this reference point during systole, the longitudinal shortening of the RV can be used as a surrogate for global RV function. Limitations include inadequate M-mode placement and the assumption that one segment of RV motion is representative of the entire RV.

Strain, which is distinct from measuring wall-motion abnormalities in traditional echocardiography, involves measuring myocardial deformation to quantitatively assess myocardial function. Two methods currently exist for measuring strain, including tissue Doppler imaging (TDI) and 2-D speckle tracking. TDI uses postprocessing to convert velocity to strain and strain rates, but it is significantly limited by the Doppler angle of incidence. 2-D speckle tracking uses greyscale to detect speckle patterns by tracking natural acoustic markers to calculate velocity vectors with 2-D ultrasonography. However, 2-D speckle tracking relies on high image quality.[14, 15]

Additionally, myocardial performance index (MPI) can also be used to measure RV function by calculating the isovolumetric relaxation time and contraction time divided by the ejection time. Higher MPI indicates greater RV dysfunction, and it is independent of RV chamber size and geometry. 

Pulmonary Thromboembolism Imaging Studies

Pulmonary thromboembolism has a wide range of clinical presentations—from massive embolism with acute and severe hemodynamic instability to multiple chronic peripheral embolisms—that may present with cor pulmonale.[16]

Pulmonary angiography was historically the gold standard for diagnosing acute pulmonary embolism. The injection of a radiocontrast dye under fluoroscopy allows for direct imaging of the pulmonary vasculature. This has been largely replaced by computed tomography pulmonary angiography (CTPA), which involves the injection of an iodinated contrast while obtaining CT scanning of the chest. CTPA is both sensitive and specific and only requires intravenous (IV) access; as a result, it is the first-line diagnostic imaging modality to diagnose a suspected pulmonary embolism.

Ventilation/perfusion (V/Q) scanning is often performed in cases in which the iodinated contrast agent used in CTPA is contraindicated (eg, pregnancy, renal insufficiency, contrast allergy). By comparing both ventilation and perfusion using a radionucleotide, perfusion deficits within areas of normal ventilation are highly suspicious of a pulmonary embolism. V/Q scanning is the test of choice in diagnosing chronic thromboembolic pulmonary hypertension (CTEPH), as it is more sensitive than CTPA.[17]

Ultrafast, ECG-gated CT scanning

Ultrafast, electrocardiographically (ECG)-gated computed tomography (CT) scanning has been evaluated to study right ventricular (RV) function. In addition to estimating RV ejection fraction (RVEF), this imaging modality can estimate RV wall mass. Although the use of ultrafast, ECG-gated CT scanning is still experimental, with further improvement, it may be used to evaluate the progression of cor pulmonale in the near future.

Magnetic Resonance Imaging

Cardiac magnetic resonance (CMR) imaging has been used as a method of providing high-quality images and diagnostic capabilities that are currently being explored. Electrocardiographic (ECG)-gated techniques and respiratory motion suppression have enabled protocols that can provide valuable information about right ventricular (RV) mass, septal flattening, and ventricular function. By incorporating gadolinium, myocardial scar and fibrosis can also be evaluated via CMR. Such a technique can be useful in determining the size and location of an infarction. Spin echo, which causes blood to appear black, can be used for anatomic imaging and identifying abnormal myocardium, and cine imaging, in which blood appears bright and the myocardium appears dark, can help in the assessment of wall motion abnormalities, valve function, and patterns of blood flow. As a result, CMR is being explored to better characterize and quantify pulmonary hypertension.[18, 19]

Nuclear Imaging

Radionuclide ventriculography can noninvasively determine right ventricular ejection fraction. Myocardial perfusion may also show a permanent increase in brightness of the right ventricle.[20]

Ventilation/perfusion (V/Q) scanning can be particularly useful in evaluating patients with cor pulmonale, especially if pulmonary hypertension is due to chronic thromboembolic pulmonary hypertension (CTEPH). V/Q scans are performed by having the patient inhale a radionucleotide (typically xenon or technetium) to assess ventilation, whereas perfusion is evaluated by the intravenous injection of another radionucleotide. The two images are then analyzed to determine if there are any mismatched perfusion defects, which is suggestive of a pulmonary embolism.

V/Q scans are typically interpreted as being normal, or having a high, intermediate, or low probability for pulmonary embolism. In CTEPH, the V/Q scan typically demonstrates having a high probability for pulmonary embolism as well as having multiple mismatched perfusion defects which can be visualized.

 

Cardiac Catheterization

Although high-resolution echocardiography and magnetic resonance imaging are accurate methods to measure pulmonary pressure,[21] right heart catheterization is considered the most precise method for diagnosis and quantification of pulmonary hypertension. This procedure is indicated when echocardiography cannot assess the severity of a tricuspid regurgitant jet, thus excluding an assessment of pulmonary hypertension.

In patients with cor pulmonale, right heart catheterization reveals evidence of right ventricular (RV) dysfunction without left ventricular (LV) dysfunction. Hemodynamically, this typically presents as a mean pulmonary artery pressure (PAP) above 25 mmHg, which leads to elevated RV systolic pressures and central venous pressures (CVP). However, these findings are also seen in LV dysfunction. One method of differentiating left-sided from right-sided disease includes measuring the pulmonary capillary wedge pressure (PCWP), which is an estimation of left atrial pressure. Thus, RV dysfunction is also defined as having a PCWP below 15 mmHg, because failure of the LV would result in elevated LV end diastolic pressures and, subsequently, left atrial pressures.[6]

Right heart catheterization is occasionally important for differentiating cor pulmonale from occult left ventricular dysfunction, especially when the presentation is confusing. Another indication is for evaluation of the potential reversibility of pulmonary arterial hypertension with vasodilator therapy or when a left-sided heart catheterization is indicated.

Lung Biopsy

Lung biopsy may occasionally be indicated to determine the etiology of underlying lung disease. This is especially true if interstitial lung disease (ILD) is the suspected etiology for pulmonary hypertension resulting in cor pulmonale.

ILD encompasses a broad range of diagnoses, including but not limited to exposure-related causes (eg, asbestosis, silicosis), complications of connective tissue disorders (eg, rheumatoid arthritis, systemic lupus erythematosus, scleroderma), and idiopathic pneumonia (eg, usual interstitial pneumonia, acute interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia).

Typically, laboratory tests, pulmonary function tests, and imaging studies, including high-resolution computed tomography (HRCT) scanning, are performed before proceeding to invasive lung biopsy. Lung biopsy can sometimes be important in determining prognosis and management, depending on the diagnosis obtained via pathology. Biopsies can be obtained with the use of transbronchial biopsy, thoracotomy, or video-assisted thoracoscopic surgery (VATS). 

Overview of Cor Pulmonale Management

Medical therapy for chronic cor pulmonale is generally focused on treatment of the underlying pulmonary disease and improving oxygenation and right ventricular (RV) function by increasing RV contractility and decreasing pulmonary vasoconstriction.[22] However, the approach might be different to some degree in an acute setting, with priority given to stabilizing the patient.

Cardiopulmonary support for patients experiencing acute cor pulmonale with resultant acute RV failure includes fluid loading and vasoconstrictor (eg, epinephrine) administration to maintain adequate blood pressure. Of course, the primary problem should be corrected, if possible. For example, for massive pulmonary embolism, consider administration of anticoagulation, thrombolytic agents or surgical embolectomy, especially if circulatory collapse is impending; consider bronchodilation and infection treatment in patients with chronic obstructive pulmonary disease (COPD); and consider steroid and immunosuppressive agents in infiltrative and fibrotic lung diseases.

Oxygen therapy, diuretics, vasodilators, digitalis, theophylline, and anticoagulation therapy are all different modalities used in the long-term management of chronic cor pulmonale.

Patient education

Patient education regarding the importance of adherence to medical therapy is vital because appropriate treatment of both hypoxia and underlying medical illness can improve mortality and morbidity.

Complications

Complications of cor pulmonale include syncope, hypoxia, pedal edema, passive hepatic congestion, and death.

Oxygen Therapy

Oxygen therapy is of great importance in patients with underlying chronic obstructive pulmonary disease (COPD),[23] particularly when administered on a continuous basis. With cor pulmonale, the partial pressure of oxygen (PaO2) is likely to be below 55 mm Hg and decreases further with exercise and during sleep.

Oxygen therapy relieves hypoxemic pulmonary vasoconstriction, which then improves cardiac output, lessens sympathetic vasoconstriction, alleviates tissue hypoxemia, and improves renal perfusion. The multicenter, randomized Nocturnal Oxygen Therapy Trial (NOTT) showed that continuous low-flow oxygen therapy for patients with severe COPD resulted in significant reduction in the mortality rate.[24]

In general, in patients with COPD, long-term oxygen therapy is recommended when the PaO2 is less than 55 mm Hg or the O2 saturation is less than 88%. However, in the presence of cor pulmonale or impaired mental or cognitive function, long-term oxygen therapy can be considered even if the PaO2 is greater than 55 mm Hg or the O2 saturation is greater than 88%.

Although the impact of oxygen therapy on survival in patients with cor pulmonale due to pulmonary disorders other than COPD is unclear, it may provide some degree of symptomatic relief and improvement in functional status. Therefore, oxygen therapy plays an important role in both the immediate setting and long-term management, especially in patients who are hypoxic and have COPD.

Pharmacotherapy

Diuretics are used to decrease the elevated right ventricular (RV) filling volume in patients with chronic cor pulmonale. Calcium channel blockers are pulmonary artery vasodilators that have some efficacy in the long-term management of chronic cor pulmonale secondary to primary pulmonary arterial hypertension (PAH).[25]

US Food and Drug Administration (FDA)–approved prostacyclin analogues and endothelin-receptor antagonists are available for treatment of pulmonary arterial hypertension (PAH). The beneficial role of cardiac glycosides, namely digitalis, on the failing right ventricle are controversial; these agents may improve RV function but must be used with caution and should be avoided during acute episodes of hypoxia.

The main indication for oral anticoagulants in the management of cor pulmonale is in the setting of an underlying thromboembolic event or PAH.

Methylxanthines, like theophylline, can be used as an adjunctive treatment for chronic cor pulmonale secondary to chronic obstructive pulmonary disease (COPD). Besides the moderate bronchodilatory effect of methylxanthine, this agent improves myocardial contractility, causes a mild pulmonary vasodilatory effect, and enhances diaphragmatic contractility.

Diuretic agents

Diuretics are used in the management of chronic cor pulmonale, particularly when the RV filling volume is markedly elevated and in the management of associated peripheral edema. These agents may result in improvement of the function of both the right and left ventricles; however, diuretics may produce hemodynamic adverse effects if they are not used cautiously. Excessive volume depletion can lead to a decline in cardiac output.

Another potential complication of diuresis is the production of a hypokalemic metabolic alkalosis, which diminishes the effectiveness of carbon dioxide stimulation on the respiratory centers and lessens ventilatory drive. The adverse electrolyte and acid-base effect of diuretic use can also lead to cardiac arrhythmia, which can diminish cardiac output. Therefore, diuresis, while recommended in the management of chronic cor pulmonale, needs to be used with great caution.

Vasodilator drugs

Vasodilators have been advocated in the long-term management of chronic cor pulmonale with modest results. Calcium channel blockers, particularly oral sustained-release nifedipine[26] and diltiazem, can lower pulmonary pressures, although these agents appear more effective in primary rather than secondary pulmonary hypertension.[27]

Other classes of vasodilators, such as beta agonists, nitrates, and angiotensin-converting enzyme (ACE) inhibitors have been tried but, in general, vasodilators have failed to show sustained benefit in patients with COPD, and they are not routinely used. A trial of vasodilator therapy may be considered only in patients with COPD with disproportionately high pulmonary hypertension.

Beta-selective agonist drugs

Beta-selective agonists have an additional advantage of bronchodilator and mucociliary clearance effect. Right heart catheterization has been recommended during initial administration of vasodilators to objectively assess the efficacy and detect the possible adverse hemodynamic consequences of vasodilators.

Prostacyclin analogues and receptor agonists

Epoprostenol, treprostinil, and bosentan are prostacyclin (PGI2) analogues and have potent vasodilatory properties.[28] Epoprostenol is administered intravenously (IV). Treprostinil can be administered IV and subcutaneously (SC); the FDA has approved oral and inhaled formulations. Iloprost is commonly inhaled but requires frequent dosing.

Of these prostacyclin analogues, epoprostenol has been the most studied; it has been shown to improve survival in idiopathic pulmonary arterial hypertension as well as some benefit in other types of World Health Organization (WHO) classification group 1 pulmonary hypertension, particularly in patients with more severe functional status.[29]

Selexipag is a prostacyclin receptor agonist, which acts to vasodilate the pulmonary vasculature. It is administered orally and has been shown to reduce disease progression in PAH.[30]

Endothelin receptor antagonists

Bosentan and macitentan are mixed endothelin-A and endothelin-B receptor antagonists, whereas ambrisentan is a selective endothelin-A receptor antagonist. Endothelins are peptides that act via vasoconstriction; thus, endothelin receptor antagonists indicated result in subsequent vasodilation. In clinical trials, bosentan improved exercise capacity, decreased rate of clinical deterioration, and improved hemodynamics.[28]

The endothelin receptor antagonists are indicated in idiopathic pulmonary artery hypertension as well as pulmonary hypertension secondary to connective tissue disorders (group I pulmonary hypertension). Common side effects include elevated liver function test findings.

Phosphodiesterase type 5 (PDE5) inhibitors

The PDE5 inhibitors function by preventing the degradation of cyclic GMP and subsequently prolonging the vasodilatory effect of nitric oxide. Of these, sildenafil has been intensively studied[31, 32, 33] and was approved by the FDA for treatment of pulmonary hypertension. Sildenafil promotes selective smooth muscle relaxation in lung vasculature.[34]  Tadalafil and vardenafil are other PDE5 inhibitors also approved by the FDA for the treatment of PAH to improve exercise ability.[35]

There are not enough data available yet regarding the efficacy of these drugs in patients with secondary pulmonary hypertension, such as in patients with COPD.

Guanylate cyclase stimulants

Riociguat is a soluble guanylate cyclase stimulant that mimics the function of nitric oxide as well as acts synergistically with it to promote vasodilation. Unlike other advanced therapies, riociguat has been FDA approved for the treatment of group I pulmonary hypertension as well as group 4 pulmonary hypertension (chronic thromboembolic pulmonary hypertension). It was shown to improve exercise tolerance as well as reduce symptoms.[36]

Cardiac glycoside agents

The use of cardiac glycosides, such as digitalis, in patients with cor pulmonale has been controversial, and the beneficial effect of these drugs is not as obvious as in the setting of left heart failure. Nevertheless, studies have confirmed a modest effect of digitalis on the failing right ventricle in patients with chronic cor pulmonale.[37] This drug must be used cautiously, however, and should not be used during the acute phases of respiratory insufficiency when large fluctuations in levels of hypoxia and acidosis may occur. Patients with hypoxemia or acidosis are at increased risk of developing arrhythmias due to digitalis through different mechanisms, including sympathoadrenal stimulation.

Theophylline

In addition to bronchodilatory effects, theophylline has been reported to reduce pulmonary vascular resistance and pulmonary arterial pressures acutely in patients with chronic cor pulmonale secondary to COPD.[38] Theophylline has a weak inotropic effect and thus may improve right and left ventricular ejection. Low doses of theophylline have also been suggested to have anti-inflammatory effects that help to control underlying lung diseases such as COPD.[39] As a result, considering the use of theophylline as adjunctive therapy in the management of chronic or decompensated cor pulmonale is reasonable in patients with underlying COPD. Theophylline has a narrow therapeutic index, and adverse effects include seizures, tachycardia, and other cardiac arrhythmias.

Warfarin

Anticoagulation with warfarin is recommended in patients at high risk for thromboembolism. The beneficial role of anticoagulation in improving the symptoms and mortality in patients with primary PAH has been demonstrated in several studies.[40, 41, 42] The evidence of benefit, however, has not been established in patients with secondary PAH. Therefore, anticoagulation therapy may be used in patients with cor pulmonale secondary to thromboembolic phenomena and with underlying primary PAH.

Thrombolytic therapy

Thrombolytic therapy is indicated in patients with acute cor pulmonale due to a pulmonary embolism resulting in hemodynamic instability. In some cases, thrombolytic therapy may be indicated in patients with severe RV dysfunction without resultant hypotension to prevent further decompensation.[43] Thrombolytic agents, including tissue plasminogen activator (tPA), result in accelerated lysis of clots and can be administered systemically or via a catheter. As always, the risk of bleeding must be a strong consideration when using thrombolytic therapy.

Surgical Management of Cor Pulmonale

Phlebotomy is indicated in patients with chronic cor pulmonale and chronic hypoxia causing severe polycythemia, defined as hematocrit of 65% or more. Phlebotomy results in a decrease in mean pulmonary artery pressure, a decrease in mean pulmonary vascular resistance,[44] and an improvement in exercise performance in such patients. However, no evidence suggests improvement in survival.

Generally, phlebotomy should be reserved as an adjunctive therapy for patients with acute decompensation of cor pulmonale and patients who remain significantly polycythemic despite appropriate long-term oxygen therapy. Replacement of the acute volume loss with a saline infusion may be necessary to avoid important decreases in systemic blood pressure.

Uvulopalatopharyngoplasty (UPPP) in selected patients with sleep apnea and hypoventilation may relieve cor pulmonale.[45]

Pulmonary embolectomy is indicated in patients with acute pulmonary embolism and hemodynamic instability when thrombolytic therapy is contraindicated. Catheter-directed embolectomy can be accomplished with a variety of modalities, including suction embolectomy, rotational embolectomy, and rheolytic embolectomy, which involves the injection of pressured saline and concurrent aspiration of the macerated thrombus. 

Surgical embolectomy may be also be indicated in similar patients or in patients whose previous thrombolytic therapy failed, particularly if the location of the thrombus is in a more proximal location. 

Single-lung, double-lung, and heart-lung transplantation are all used to salvage the terminal phases of several diseases (eg, PPH, emphysema, idiopathic pulmonary fibrosis, cystic fibrosis) complicated by cor pulmonale. Lung transplantation may lead to a reversal of right ventricular dysfunction from the chronic stress of pulmonary hypertension. However, strict selection criteria for lung transplant recipients must be met because of the limited availability of organ donors.

Outpatient Monitoring

Patients with cor pulmonale generally require close attention in the outpatient setting. It is appropriate to regularly assess the patient’s oxygen needs and pulmonary function. Consider a formal program of pulmonary rehabilitation, as many patients benefit from this therapy.

Prognosis of Cor Pulmonale

The prognosis of cor pulmonale is variable depending upon the underlying pathology. Development of cor pulmonale as a result of a primary pulmonary disease usually heralds a poorer prognosis. For example, patients with chronic obstructive pulmonary disease (COPD) who develop cor pulmonale have a 30% chance of surviving 5 years. However, whether cor pulmonale carries an independent prognostic value or is simply reflecting the severity of underlying COPD or other pulmonary disease is not clear.

Prognosis in the acute setting due to massive pulmonary embolism or acute respiratory distress syndrome (ARDS) has not previously been shown to be dependent on the presence or absence of cor pulmonale. However, a prospective, multicenter cohort study by Volschan et al indicated that in cases of pulmonary embolism, cor pulmonale may be a predictor of inhospital mortality.[46] The authors collected demographic, comorbidity, and clinical manifestation data on 582 patients admitted to emergency or intensive care units and diagnosed with pulmonary embolism. Assessing the information using logistic regression analysis, the investigators built a prediction model. Their results indicated that in hemodynamically stable patients with pulmonary embolism, the following factors may be independent predictors of inhospital mortality[46] :

A Chinese study indicated that chronic cor pulmonale is one of the major risk factors for early hospital readmission in patients following hospitalization for acute exacerbation of COPD. The study, by Lin et al, of 692 patients, included 63 patients who were readmitted to the hospital within 31 days after discharge. Through multivariate analysis, the investigators found that risk factors for early readmission included, in order of significance, chronic cor pulmonale (odds ratio [OR], 2.14), hypoproteinemia (OR, 2.02), and an elevated partial pressure of CO2 (Pa CO2 [OR, 1.03]).[47]

What is cor pulmonale?What is the pathophysiology of cor pulmonale?What are the WHO classifications of pulmonary hypertension leading to cor pulmonale?What is the pathophysiology of decreased output in cor pulmonale?What is the role of right ventricle (RV) and left ventricular (LV) morphogenesis in the pathophysiology of cor pulmonale?What is the role of right ventricle (RV) pressure and overload in the pathophysiology of cor pulmonale?What is the prevalence of cor pulmonale?What is the clinical presentation of cor pulmonale?What are the symptoms of cor pulmonale?What are symptoms of advanced cor pulmonale?What are the physical findings characteristic of cor pulmonale?What is included in the evaluation for cor pulmonale?Which conditions are in the differentials for cor pulmonale?What is the role of lab testing in the diagnosis of cor pulmonale?How does arterial blood gas analysis aid in diagnosing cor pulmonale?What is the role of brain natriuretic peptide (BNP) measurement in the diagnosis of cor pulmonale?What is the role of chest radiography in the diagnosis of cor pulmonale?What is the role of electrocardiography in the diagnosis of cor pulmonale?What is the role of echocardiography in the diagnosis of cor pulmonale?What is the role of angiography in the diagnosis of cor pulmonale?What is the role of ECG-gated CT scanning for the diagnosis of cor pulmonale?What is the role of MRI in the diagnosis of cor pulmonale?What is the role of nuclear imaging in the diagnosis of cor pulmonale?What is the role of cardiac catheterization in the diagnosis of cor pulmonale?What is the role of lung biopsies in the diagnosis of cor pulmonale?What are the treatment options for cor pulmonale?What is included in patient education for cor pulmonale?What are the complications of cor pulmonale?What is the role of oxygen therapy in the treatment of cor pulmonale?What is the role of drug treatment for cor pulmonale?What is the role of diuretics in the treatment of cor pulmonale?What is the role of vasodilators in the treatment of cor pulmonale?What is the role of beta-selective agonists in the treatment of cor pulmonale?What is the role of prostacyclin analogues and receptor agonists in the treatment of cor pulmonale?What is the role of endothelin receptor antagonists in the treatment of cor pulmonale?What is the role of phosphodiesterase type 5 (PDE5) inhibitors in the treatment of cor pulmonale?What is the role of guanylate cyclase stimulants in the treatment of cor pulmonale?What is the role of cardiac glycoside agents in the treatment of cor pulmonale?What is the role of theophylline in the treatment of cor pulmonale?What is the role of warfarin in the treatment of cor pulmonale?What are the indications for thrombolytic therapy in the treatment of cor pulmonale?What is the role of surgery in the treatment of cor pulmonale?What is included in long-term monitoring of cor pulmonale?What is the prognosis of cor pulmonale?

Author

Derek Leong, MD, Resident Physician, Department of Internal Medicine, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Abraham G Kocheril, MD, FACC, FACP, FHRS, Professor of Medicine, University of Illinois College of Medicine

Disclosure: Nothing to disclose.

Ali A Sovari, MD, FACP, FACC, Attending Physician, Cardiac Electrophysiologist, Cedars Sinai Medical Center and St John's Regional Medical Center

Disclosure: Nothing to disclose.

Ravi H Dave, MD, Associate Professor of Medicine, University of California at Los Angeles David Geffen School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Steven J Compton, MD, FACC, FACP, FHRS, Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals

Disclosure: Nothing to disclose.

Chief Editor

Henry H Ooi, MD, MRCPI, Director, Advanced Heart Failure and Cardiac Transplant Program, Nashville Veterans Affairs Medical Center; Assistant Professor of Medicine, Vanderbilt University School of Medicine

Disclosure: Nothing to disclose.

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This ECG shows some typical abnormalities that may be seen in cor pulmonale and other chronic pulmonary diseases: (1) R/S ratio >1 in V1 and <1 in V6 suggestive of right ventricular hypertrophy/enlargement, (2) right superior axis deviation, (3) left atrial type of p wave with increased width of the p wave and biphasic p wave in V1, and (4) right bundle branch block pattern with wide QRS and RsR1 pattern in V1 and slurred s wave in V6.This ECG also presents a sinus bradycardia rhythm with first-degree AV block and left anterior fascicular block.

This ECG shows some typical abnormalities that may be seen in cor pulmonale and other chronic pulmonary diseases: (1) R/S ratio >1 in V1 and <1 in V6 suggestive of right ventricular hypertrophy/enlargement, (2) right superior axis deviation, (3) left atrial type of p wave with increased width of the p wave and biphasic p wave in V1, and (4) right bundle branch block pattern with wide QRS and RsR1 pattern in V1 and slurred s wave in V6.This ECG also presents a sinus bradycardia rhythm with first-degree AV block and left anterior fascicular block.