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Cor Pulmonale
Ali A Sovari, MD, Clinical and Research Fellow in Cardiovascular Medicine, Section of Cardiology, University of Illinois at Chicago Ravi H Dave, MD, Associate Professor of Medicine, University of California at Los Angeles David Geffen School of Medicine; Abraham G Kocheril, MD, FACC, FACP, FHRS, Professor of Medicine, Director of Clinical Electrophysiology, University of Illinois at Chicago Updated: Jul 22, 2010

Introduction
Background
Cor pulmonale is defined as an alteration in the structure and function of the right ventricle caused by a primary disorder of the respiratory system. Pulmonary hypertension is 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 ]

Pathophysiology
Several different pathophysiologic mechanisms can lead to pulmonary hypertension and, subsequently, to cor pulmonale. These pathogenetic mechanisms include (1) pulmonary vasoconstriction due to alveolar hypoxia or blood acidemia, (2) anatomic compromise of the pulmonary vascular bed secondary to lung disorders (eg, emphysema, pulmonary thromboembolism, interstitial lung disease, adult respiratory distress syndrome, and rheumatoid disorders), (3) increased blood viscosity secondary to blood disorders (eg, polycythemia vera, sickle cell disease, macroglobulinemia), (4) increased blood flow in pulmonary vasculature, and (5) idiopathic primary pulmonary hypertension. The result is increased pulmonary arterial pressure. The right ventricle (RV) is a thin-walled chamber that is more a volume pump than a pressure pump. It adapts better to changing preloads than afterloads. With an increase in afterload, the RV increases systolic pressure to keep the gradient. At a point, a further increase in the degree of pulmonary arterial pressure produces significant RV dilation, an increase in RV end-diastolic pressure, and RV circulatory collapse. A decrease in RV output with a decrease in diastolic left ventricle (LV) volume results in decreased LV output. Since the right coronary artery, which supplies the RV free wall, originates from the aorta, decreased LV output diminishes blood pressure in the aorta and decreases right coronary blood flow. What ensues is a vicious cycle between decreases in LV and RV output. Genetic investigations have confirmed that morphogenesis of the right and left ventricle originated from different sets of progenitor cells and sites. This polymorphism could explain the differing rates of hypertrophy of the right and left ventricles.[2 ] Right ventricular overload is associated with septal displacement toward the left ventricle. Septal displacement, which is seen on echocardiography, can be another factor that decreases LV volume and output in the setting of cor pulmonale and right ventricular enlargement. Several pulmonary diseases cause cor pulmonale, which may involve interstitial and alveolar tissues with a secondary effect on pulmonary vasculature or may primarily involve pulmonary vasculature. Chronic obstructive pulmonary disease (COPD) is the most common cause of cor pulmonale in the United States. Cor pulmonale usually presents chronically, but 2 main conditions can cause acute cor pulmonale: massive pulmonary embolism (more common) and acute respiratory distress syndrome (ARDS). The underlying pathophysiology in massive pulmonary embolism causing cor pulmonale is the sudden increase in pulmonary resistance. In ARDS, 2 factors cause RV overload: the pathologic features of the syndrome itself and mechanical ventilation. Mechanical ventilation, especially higher tidal volume, requires a higher transpulmonary pressure. In chronic cor pulmonale, right ventricular hypertrophy (RVH) generally predominates. In acute cor pulmonale, right ventricular dilatation mainly occurs. In the case of ARDS, cor pulmonale is associated with increased possibility of right to left shunt through patent foramen ovale and caries poorer prognosis.[3 ]

Frequency
United States

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. At present, cor pulmonale accounts for 10-30% of decompensated heart failure related admissions in the United States.[4 ] Although the prevalence of COPD in the United States is about 15 million, the exact prevalence of cor pulmonale is difficult to determine because it does not occur in all cases of COPD, and the physical examination and routine tests are relatively

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insensitive for the detection of pulmonary hypertension.

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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. In the United States, 50,000 deaths are estimated to occur per year from pulmonary emboli and about half occur within the first hour due to acute right heart failure.

International

The incidence of cor pulmonale varies among different countries depending on the prevalence of cigarette smoking, air pollution, and other risk factors for various lung diseases.

Mortality/Morbidity
Development of cor pulmonale as a result of a primary pulmonary disease usually heralds a poorer prognosis. For example, patients with 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 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 indicates that in cases of pulmonary embolism, cor pulmonale may be a predictor of inhospital mortality.[5 ]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:
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Age over 65 years Bed rest for longer than 72 hours Chronic cor pulmonale Sinus tachycardia Tachypnea

Clinical
History
Clinical manifestations of cor pulmonale generally are nonspecific. The symptoms may be subtle, especially in early stages of the disease, and mistakenly may be attributed to the underlying pulmonary pathology.
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The patient may complain of fatigue, tachypnea, exertional dyspnea, and cough. Anginal chest pain also can occur and may be due to right ventricular ischemia (it usually does not respond to nitrates) or pulmonary artery stretching. Hemoptysis may occur because of rupture of a dilated or atherosclerotic pulmonary artery. 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. A variety of neurologic symptoms may be seen due to decreased cardiac output and hypoxemia. In advanced stages, passive hepatic congestion secondary to severe right ventricular failure may lead to anorexia, right upper quadrant abdominal discomfort, and jaundice. Syncope with exertion, which may 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 hypotheses explain this symptom, especially in a fraction of patients with COPD who do not show increase in right atrial pressure. A decrease in glomerular filtration rate (GFR) and filtration of sodium and stimulation of arginine vasopressin (which decreases free water excretion) due to hypoxemia play important

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pathophysiologic roles in this setting and may even have a role for peripheral edema in patients with cor pulmonale who have elevated right atrial pressure.[6 ]

Physical
Physical findings may reflect the underlying lung disease or pulmonary hypertension, RVH, and RV failure.
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On inspection, 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[7 ]may be heard as systolic bruits in the lungs. Splitting of the second heart sound with accentuation of the pulmonic component can be heard in early stages. A systolic ejection murmur with 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 third and fourth sounds of the heart and 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. On percussion, hyperresonance of the lungs may be a sign of underlying COPD; ascites can be seen in severe disease. Examination of the lower extremities reveals evidence of pitting edema. Edema in cor pulmonale is strongly associated with hypercapnia.[8 ]

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Causes
Etiologies of cor pulmonale can mechanistically be categorized in 5 groups. 1. Pulmonary vasoconstriction due to alveolar hypoxia or blood academia: This can result in pulmonary hypertension and if the hypertension is severe enough, it causes cor pulmonale. 2. Various lung disorders: Parenchymal or alveolar lung disorders may anatomically compromise the vasculature beds and cause elevated pulmonary blood pressure. Chronic obstructive pulmonary disorder is the most common cause of cor pulmonale. Other lung disorders that may cause cor pulmonale are pulmonary thromboembolism, interstitial lung disease, and adult respiratory distress syndrome. Also, some connective tissue disorders with pulmonary involvement may result in pulmonary hypertension and cor pulmonale. 3. Blood disorders that are associated with increased blood viscosity such as polycythemia vera, sickle cell disease, macroglobulinemia 4. Increased blood flow in the pulmonary vasculature 5. Idiopathic primary pulmonary hypertension

Differential Diagnoses
Other Problems to Be Considered
Congestive (biventricular) heart failure Primary pulmonic stenosis Primary pulmonary hypertension Right-sided heart failure due to congenital heart diseases Right heart failure due to right ventricular infarction Ventricular septal defect Constrictive pericarditis High-output heart failure Infiltrative cardiomyopathies Atrial myxoma

Workup
Laboratory Studies
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Laboratory investigations are directed toward defining the potential underlying etiologies as well as evaluating complications of cor pulmonale. In specific instances, appropriate lab studies may include the following: hematocrit for polycythemia (which can be a consequence of underlying lung disease but can also increase pulmonary arterial pressure by increasing viscosity), serum alpha1-antitrypsin if deficiency is suspected, and antinuclear antibody level for collagen vascular disease such as scleroderma. Hypercoagulability states can be evaluated by serum levels of proteins S and C, antithrombin III, factor V

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Leyden, anticardiolipin antibodies, and homocysteine.

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Arterial blood gas tests may provide important information about the level of oxygenation and type of acid-base disorder. Elevated brain natriuretic peptide (BNP) level alone is not adequate to establish presence of cor pulmonale, but it helps to diagnose cor pulmonale in conjunction with other noninvasive tests and in appropriate clinical settings. An elevated BNP level may actually be a natural mechanism to compensate for elevated pulmonary hypertension and right heart failure by promoting diuresis and natriuresis, vasodilating systemic and pulmonary vessels, and reducing circulating levels of endothelin and aldosterone.

Imaging Studies
A general approach to diagnose cor pulmonale and to investigate its etiology starts with routine laboratory tests, chest radiography, and electrocardiography. Echocardiography gives valuable information about the disease and its etiology. Pulmonary function tests may become necessary to confirm the underlying lung disease. Ventilation/perfusion (V/Q) scan or chest CT scan may be performed if history and physical examination suggest pulmonary thromboembolism as the cause or if other diagnostic tests do not suggest other etiologies. Right heart catheterization is the most accurate but invasive test to confirm the diagnosis of cor pulmonale and gives important information regarding the underlying diseases. Any abnormal result in each of these tests may need further diagnostic evaluation in that specific direction. Imaging studies may show evidence of underlying cardiopulmonary diseases, pulmonary hypertension, or its consequence, right ventricular enlargement.
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Chest roentgenography: 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. Echocardiography: Two-dimensional echocardiography usually demonstrates signs of chronic 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 cavity during diastole resulting in decreased diastolic volume of LV and reduction of LV output. Doppler echocardiography is now used to estimate pulmonary arterial pressure, taking advantage of the functional tricuspid insufficiency that is usually present in pulmonary hypertension. Doppler echocardiography is considered the most reliable noninvasive technique to estimate pulmonary artery pressure. 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. Ventilation/perfusion (V/Q) lung scanning, pulmonary angiography, and chest CT scanning may be indicated to diagnose pulmonary thromboembolism as the underlying etiology of cor pulmonale. These tests may be performed early in the diagnostic workup if any evidence of pulmonary embolism appears in history and physical examination. The test may also be considered later in the workup if other tests are not suggestive of any other etiology. 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. Ultrafast, ECG-gated CT scanning has been evaluated to study RV function. In addition to estimating right ventricular ejection fraction (RVEF), it can estimate RV wall mass. Its use is still experimental, but with further improvement, it may be used to evaluate the progression of cor pulmonale in the near future. Magnetic resonance imaging (MRI) of the heart is another modality that can provide valuable information about RV mass, septal flattening, and ventricular function.[9 ] Radionuclide ventriculography can determine RVEF noninvasively. Myocardial perfusion may also show a permanent increase in brightness of the right ventricle.[10 ]

Other Tests
Electrocardiography (ECG) abnormalities in cor pulmonale reflect the presence of RVH, RV strain, or underlying pulmonary disease. These electrocardiographic changes may include the following:
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Right axis deviation

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R/S amplitude ratio in V1 greater than 1 (increase in anteriorly directed forces may be a sign of posterior infarct) R/S amplitude ratio in V6 less than 1 P-pulmonale pattern (an increase in P wave amplitude in leads 2, 3, and aVF) S1 Q3 T3 pattern and incomplete (or complete) right bundle branch block, especially if pulmonary embolism is the underlying etiology

Low-voltage QRS because of underlying COPD with hyperinflation

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.

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 LV, small changes in RV forces may be lost in the ECG). 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.

Procedures
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Cardiac catheterization: Although high-resolution echocardiography and MRI are accurate methods to measure pulmonary pressure[11 ], right-heart catheterization is considered the most precise method for diagnosis and quantification of pulmonary hypertension. It is indicated when echocardiography cannot assess the severity of a tricuspid regurgitant jet, thus excluding an assessment of pulmonary hypertension. 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 heart catheterization is indicated. Lung biopsy may occasionally be indicated to determine the etiology of underlying lung disease.

Treatment
Medical Care

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Medical therapy[12 ]for chronic cor pulmonale is generally focused on treatment of the underlying pulmonary disease and improving oxygenation and RV function by increasing RV contractility and decreasing pulmonary vasoconstriction. 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 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 longterm management of chronic cor pulmonale. Oxygen therapy Oxygen therapy is of great importance in patients with underlying COPD[13 ], particularly when administered on a continuous basis. With cor pulmonale, the partial pressure of oxygen (PO2) 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 Nocturnal Oxygen Therapy Trial (NOTT), a multicenter randomized trial, showed that continuous low-flow oxygen therapy for patients with severe COPD resulted in significant reduction in the mortality rate.[14 ]In general, in patients with COPD, long-term oxygen therapy is recommended when PaO2 is less than 55 mm Hg or 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 PaO2 is greater than 55 mm Hg or O2 saturation is greater than 88%. Although whether oxygen therapy improves survival in patients with cor pulmonale due to pulmonary disorders other than COPD is not clear, 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. Diuretics Diuretics are used in the management of chronic cor pulmonale, particularly when the right ventricular filling volume is markedly elevated and in the management of associated peripheral edema. Diuretics 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 Vasodilator drugs have been advocated in the long-term management of chronic cor pulmonale with modest results. Calcium channel blockers, particularly oral sustained-release nifedipine[15 ]and diltiazem, can lower pulmonary pressures, although they appear more effective in primary rather than secondary pulmonary hypertension.[16 ]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 blood pressure. Beta-selective agonists 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. The Food and Drug Administration (FDA) has approved epoprostenol, treprostinil, bosentan, and iloprost for treatment of primary pulmonary hypertension. Epoprostenol, treprostinil, and iloprost are prostacyclin (PGI2) analogues and have potent vasodilatory properties.[17 ]Epoprostenol and treprostinil are administered intravenously and iloprost is an inhaler. Bosentan is a mixed endothelin-A and endothelin-B receptor antagonist indicated for pulmonary arterial hypertension (PAH), including primary pulmonary hypertension (PPH). In clinical trials, it improved exercise capacity, decreased rate of clinical deterioration, and improved hemodynamics.[17 ] The PDE5 inhibitor sildenafil has been intensively studied[18,19,20 ]and approved by the FDA for treatment of pulmonary hypertension. Sildenafil promotes selective smooth muscle relaxation in lung vasculature.[21 ]Tadalafil, another PDE5 inhibitor, was also recently

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approved by the FDA for the treatment of PAH to improve exercise ability.[22 ] Not enough data are available regarding the efficacy of these drugs in patients with secondary pulmonary hypertension such as in patients with COPD. Cardiac glycosides 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.[23 ]It 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 effect, theophylline has been reported to reduce pulmonary vascular resistance and pulmonary arterial pressures acutely in patients with chronic cor pulmonale secondary to COPD.[24 ]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.[25 ]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. 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 pulmonary arterial hypertension has been demonstrated in several studies.[26,27,28,29 ]The evidence of benefit, however, has not been established in patients with secondary pulmonary arterial hypertension. Therefore, anticoagulation therapy may be used in patients with cor pulmonale secondary to thromboembolic phenomena and with underlying primary pulmonary arterial hypertension.

Surgical Care
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,[30 ]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. No surgical treatment exists for most diseases that cause chronic cor pulmonale. Pulmonary embolectomy is efficacious for unresolved pulmonary emboli, which contribute to pulmonary hypertension. Uvulopalatopharyngoplasty in selected patients with sleep apnea and hypoventilation[31 ]may relieve cor pulmonale. Single-lung, double-lung, and heart-lung transplantation are all used to salvage the terminal phases of several diseases (eg, primary pulmonary hypertension, 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.

Medication
Diuretics are used to decrease the elevated right ventricular filling volume in patients with chronic cor pulmonale. Calcium channel blockers are pulmonary artery vasodilators that have proven efficacy in the long-term management of chronic cor pulmonale secondary to primary pulmonary arterial hypertension. New FDA-approved prostacyclin analogues and endothelin-receptor antagonists are available for treatment of PPH. The beneficial role of cardiac glycosides, namely digitalis, on the failing right ventricle are somewhat controversial; they can improve right ventricular function but must be used with caution and should be avoided during acute episodes of hypoxia. In the management of cor pulmonale, the main indication for oral anticoagulants is in the setting of an underlying thromboembolic event or primary pulmonary arterial hypertension. Methylxanthines, like theophylline, can be used as an adjunctive treatment for chronic cor pulmonale secondary to COPD. Besides the moderate bronchodilatory effect of methylxanthine, it improves myocardial contractility, causes a mild pulmonary vasodilatory effect, and enhances diaphragmatic contractility.

Diuretics
Are used to decrease the elevated right ventricular filling volume in patients with chronic cor pulmonale.

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Furosemide (Lasix)

Example of diuretic agents used in the management of chronic cor pulmonale. Furosemide is a powerful loop diuretic that works on thick ascending limb of Henle loop, causing a reversible block in reabsorption of sodium, potassium, and chloride.
Dosing
Adult

20-80 mg/d PO/IV/IM; may titrate to maximum dose of 600 mg/d

Pediatric

1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; do not administer more frequent than q6h 1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg
Interactions

Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently with this medication
Contraindications

Documented hypersensitivity; hepatic coma; anuria; concurrent severe electrolyte depletion

Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Calcium channel blockers

These agents inhibit movement of calcium ions across the cell membrane, depressing both impulse formation (automaticity) and conduction velocity.

Nifedipine (Procardia)

Especially in the sustained-release form, nifedipine is a calcium channel blocker that has proven to be fairly effective in the management of chronic cor pulmonale caused by primary pulmonary hypertension. Modifies the entry of calcium into the cells by blocking the slow or voltage-dependent calcium channels, resulting in vasodilation, which improves myocardial oxygen delivery. Sublingual administration generally is safe, despite theoretical concerns.
Dosing
Adult

10-30 mg SR cap PO tid; not to exceed 120-180 mg/d 30-60 mg SR tab PO qd; not to exceed 90-120 mg/d
Pediatric

Not recommended
Interactions

Monitor oral anticoagulants when used concomitantly; coadministration with any agent that can lower BP, including beta-blockers and opioids, can result in severe hypotension; H2 blockers (cimetidine) may increase toxicity
Contraindications

Documented hypersensitivity
Precautions

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Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Aortic stenosis; angina; congestive heart failure; pregnancy; nursing mothers; may cause lower extremity edema; allergic hepatitis has occurred but is rare

Cardiac glycosides
These agents decrease AV nodal conduction primarily by increasing vagal tone.

Digoxin (Lanoxin)

Has a positive inotropic effect on failing myocardium. Effect is achieved via inhibition of the Na+/K+-ATPase pump, leading to increase in intracellular sodium concentration along with concomitant increase in intracellular calcium concentration by means of calcium-sodium exchange mechanism. Net result is augmentation of myocardial contractility.
Dosing
Adult

0.125-0.375 mg PO qd; may be administered qod; available in PO/IV/IM preparations

Pediatric

8-10 mcg/kg/d PO/IV/IM; maximum dose 100-150 mcg/kg/d

Interactions

Medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil; medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (eg, carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid
Contraindications

Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome
Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce arrhythmias in digitalized patients; hypercalcemia predisposes patient to digitalis toxicity; hypocalcemia can make digoxin ineffective until serum calcium levels are normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients diagnosed with incomplete AV block may progress to complete block when treated with digoxin; exercise caution in hypothyroidism, hypoxia, and acute myocarditis

Anticoagulants
These agents may reduce incidence of embolisms when used fast, effectively, and early.

Warfarin (Coumadin)

Most commonly used oral anticoagulant. Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.
Dosing
Adult

2-10 mg/d PO qd; adjust dose to an INR of 1.5:2 or higher depending on the condition requiring anticoagulation

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Pediatric

Administer weight-based dose of 0.05-0.34 mg/kg/d PO/IV; adjust dose according to desired INR
Interactions

Griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate may decrease anticoagulant effects; oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac may increase anticoagulant effects
Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds; GI ulcers

Precautions
Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Dose needs to be adjusted to INR; caution in bleeding tendency and hazardous active hemorrhagic conditions, malignant hypertension, patients at high risk of recurrent trauma, (eg, people with alcoholism or psychosis, unsupervised patients who are senile); warfarin anaphylaxis, hepatic, renal, thyroid, allergic, and hematologic hypocoagulable conditions and disorders; do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis

Methylxanthines
Potentiate exogenous catecholamines and stimulate endogenous catecholamine release and diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation.

Theophylline (Aminophyllin, Theo-24, Theolair, Theo-Dur)

Mechanism of action is not well defined yet. Was formerly thought that this drug increases intracellular cyclic AMP by causing inhibition of phosphodiesterase; however, current data do not support that.
Dosing
Adult

Loading dose: 5.6 mg/kg IV over 20 min (based on aminophylline) Maintenance dose: IV infusion at 0.5-0.7 mg/kg/h; also available in oral preparation
Pediatric

<6 weeks: Not established 6 weeks to 6 months: 0.5 mg/kg/h loading dose IV in first 12 h (based on aminophylline), followed by maintenance infusion of 12 mg/kg/d thereafter; may administer continuous infusion by dividing total daily dose by 24 h 6 months to 1 year: 0.6-0.7 mg/kg/h loading dose IV in first 12 h, followed by maintenance infusion of 15 mg/kg/d; may administer as continuous infusion as above >1 year: Administer as in adults
Interactions

Effects may decrease with aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics; effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon
Contraindications

Documented hypersensitivity; uncontrolled arrhythmias; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders
Precautions
Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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Precautions

Has low serum therapeutic-to-toxicity ratio, and, therefore, serum level monitoring is important; peptic ulcer; hypertension; tachyarrhythmias; hyperthyroidism; compromised cardiac function; do not inject IV solution faster than 25 mg/min; patients diagnosed with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance

Endothelin receptor antagonists

Competitively bind to endothelin-1 (ET-1) receptors ETA and ETB causing reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP).

Bosentan (Tracleer)

Endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with WHO Class II-IV symptoms, to improve exercise ability and decrease rate of clinical worsening. Inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index (CI) associated with significant reduction in pulmonary artery pressure (PAP), mean right atrial pressure (RAP), pulmonary vascular resistance (PVR), and, to a lesser extent, systemic vascular resistance (SVR). Due to teratogenic potential, can only be prescribed through the Tracleer Access Program (1-866-228-3546).
Dosing
Adult

<40 kg: 62.5 mg PO bid; not to exceed 125 mg/d >40 kg: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid
Pediatric

Not established; 62.5 mg PO bid recommended if <40 kg, or >12 years; not to exceed 125 mg/d
Interactions

Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, and cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450 3A4 causing decrease in plasma concentrations of drugs metabolized by these enzymes including glyburide as well as other hypoglycemics, cyclosporine A, hormonal contraceptives, simvastatin, and possibly other statins; hepatotoxicity increases with concomitant administration of glyburide
Contraindications

Documented hypersensitivity; coadministration with cyclosporine A or glyburide

Precautions
Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Causes at least 3-fold elevation of liver aminotransferases (ie, ALT, AST) in about 11% of patients; may elevate bilirubin (serum aminotransferase levels must be measured prior to initiation of treatment and then monthly); caution in patients with mildly impaired liver function (avoid in patients with moderate or severe liver impairment); not recommended while breastfeeding; monitor hemoglobin levels after 1 and 3 mo of treatment and every 3 mo thereafter; exclude pregnancy before initiating treatment and prevent thereafter by use of reliable contraception; headache and nasopharyngitis may occur

Ambrisentan (Letairis)

Endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. Improves exercise ability and decreases progression of clinical symptoms. Inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in pulmonary artery pressure, mean right atrial pressure, pulmonary vascular resistance, and, to a lesser extent, systemic vascular resistance (SVR). Because of the risks of hepatic injury and teratogenic potential, only available through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).
Dosing

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Adult

5 mg PO qd initially; may increase to 10 mg PO qd if 5 mg/d tolerated; do not chew, crush, or split tab
Pediatric

Not established
Interactions

Glycoprotein-P, OATP, UGTs (ie, 1A9S, 2B7S, 1A3S), CYP2C19, and CYP3A substrate; coadministration with CYP3A (eg, cyclosporine, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or 2C19 inhibitors (eg, omeprazole) may decrease elimination and therefore increase serum levels; CYP3A and 2C19 inducers (eg, rifampin) may increase metabolism and therefore decrease serum levels
Contraindications

Pregnancy
Precautions
Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include peripheral edema, nasal congestion, sinusitis, and facial flushing; caution with mild hepatic impairment or history of moderate-to-severe hepatic impairment; hepatic injury may occur (monitor bilirubin, ALT, and AST values at baseline and then monthly); may use in women of childbearing potential only after negative pregnancy test result and must use 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A or LNg 20 IUD inserted); may decrease hemoglobin and hematocrit values (monitor at baseline, 1 mo, and then periodically)

Follow-up
Further Inpatient Care
Appropriate treatment is directed both at the underlying etiology and at correction of hypoxia when present.

Further Outpatient Care

z z z

Patients with cor pulmonale generally require close attention in the outpatient setting. Regular assessment of oxygen needs and pulmonary function are appropriate. Many patients benefit from a formal program of pulmonary rehabilitation.

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

Prognosis
z z

The prognosis of cor pulmonale is variable depending upon underlying pathology. Patients with cor pulmonale due to COPD have a high 2-year mortality.

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.

Miscellaneous
Medicolegal Pitfalls
z

Making a diagnosis of cor pulmonale should be followed by further investigation to determine the underlying lung pathology. Sometimes a common lung disease such as COPD is not the only lung pathology as the cause of cor pulmonale; other lung diseases may coexist.

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When diagnosing cor pulmonale, considering the possibility of thromboembolic disease and primary pulmonary hypertension as possible etiologies is important. Note the importance of continuous supplemental oxygen therapy in appropriate patients, as well as the dangers of cigarette smoking while using supplemental oxygen. Elevation of carboxyhemoglobin in the blood due to smoking can significantly decrease the effect of O2 on arterial O2 content.

Multimedia

Media file 1: 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.

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33. Kingman MS, Thompson BS, Newkirk T, Torres F. Nesiritide for pulmonary arterial hypertension with decompensated cor pulmonale. Prog Cardiovasc Nurs. Fall 2005;20(4):168-72. [Medline]. 34. Klinger JR, Hill NS. Right ventricular dysfunction in chronic obstructive pulmonary disease. Evaluation and management. Chest. Mar 1991;99(3):715-23. [Medline]. 35. Lee-Chiong Jr TL, Matthay RA. Pulmonary hypertension and cor pulmonale in COPD. Semin Respir Crit Care Med. Jun 2003;24(3):263-72. [Medline]. 36. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part One. Am J Respir Crit Care Med. Sep 1994;150(3):833-52. [Medline]. 37. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part two. Am J Respir Crit Care Med. Oct 1994;150(4):1158-68. [Medline]. 38. Mahler DA, Matthay RA, Snyder PE, Wells CK, Loke J. Sustained-release theophylline reduces dyspnea in nonreversible obstructive airway disease. Am Rev Respir Dis. Jan 1985;131(1):22-5. [Medline]. 39. Ringbaek TJ, Fabricius P, Lange P. The effect of home oxygen therapy on hospitalization in moderate hypoxaemic COPD. Chron Respir Dis. 2005;2(2):107-8. [Medline]. 40. Wiedemann HP, Matthay RA. The management of acute and chronic cor pulmonale. In: Scharf SM, Cassidy SS, eds. HeartLung Interactions in Health and Disease. New York, NY: Marcel Dekker; 1989:915.

Keywords
cor pulmonale, pulmonary hypertension, cardiopulmonary disease, COPD, chronic obstructive pulmonary disease, ARDS, acute respiratory distress syndrome, right heart failure, right ventricular failure, right ventricular hypertrophy, RVH, pulmonary thromboembolism, interstitial lung disease, polycythemia vera, macroglobulinemia, pulmonary embolism, pulmonary emboli, diastolic pulmonary regurgitation murmur

Contributor Information and Disclosures

Author

Ali A Sovari, MD, Clinical and Research Fellow in Cardiovascular Medicine, Section of Cardiology, University of Illinois at Chicago Ali A Sovari, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart Rhythm Society Disclosure: Nothing to disclose.
Coauthor(s)

Ravi H Dave, MD, Associate Professor of Medicine, University of California at Los Angeles David Geffen School of Medicine Disclosure: Nothing to disclose. Abraham G Kocheril, MD, FACC, FACP, FHRS, Professor of Medicine, Director of Clinical Electrophysiology, University of Illinois at Chicago Abraham G Kocheril, MD, FACC, FACP, FHRS is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, Cardiac Electrophysiology Society, Central Society for Clinical Research, Heart Failure Society of America, and Illinois State Medical Society Disclosure: Nothing to disclose.
Medical Editor

Gregory J Dehmer, MD, Director, Division of Cardiology, Scott & White Healthcare; Professor of Medicine, Texas A&M Health Science Center College of Medicine Gregory J Dehmer, MD is a member of the following medical societies: American College of Cardiology, American Heart Association, Society for Cardiac Angiography and Interventions, and Society of Cardiac Angiography and Interventions Disclosure: Nothing to disclose.
Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine Disclosure: eMedicine Salary Employment
Managing Editor

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Steven J Compton, MD, FACC, FACP, Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals Steven J Compton, MD, FACC, FACP is a member of the following medical societies: Alaska State Medical Association, American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart Rhythm Society Disclosure: Nothing to disclose.
CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions Disclosure: Nothing to disclose.
Chief Editor

Henry H Ooi, MBBCh, BAO, MRCPI, Director, Advanced Heart Failure and Cardiac Transplant Program, Nashville Veterans Affairs Medical Center; Cardiologist, Heart Failure and Cardiac Transplant Program, Vanderbilt University Medical Center Henry H Ooi, MBBCh, BAO, MRCPI is a member of the following medical societies: American College of Cardiology, American Heart Association, Heart Failure Society of America, and International Society for Heart and Lung Transplantation Disclosure: Nothing to disclose.
Acknowledgments The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Robert S Crausman, MD, MMS and Nidal A Yunis, MD to the development and writing of this article. Further Reading Clinical trials Educational and Supportive Interventions to Prevent Cardiopulmonary Rehospitalization Identification of Genetic Markers for Cardiopulmonary Diseases (Genotype) 1994- 2010 by Medscape. All Rights Reserved (http://www.medscape.com/public/copyright)

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