What are the etiology, symptoms, diagnosis, and management of cor pulmonale, a condition characterized by right-sided heart failure secondary to pulmonary disease?

Cor Pulmonale: Etiology, Symptoms, Diagnosis, and Management

Etiology

Chronic obstructive pulmonary disease (COPD) is the predominant cause of cor pulmonale, accounting for the vast majority of cases, followed distantly by idiopathic pulmonary fibrosis and obesity-hypoventilation syndrome 1.

Primary Pulmonary Causes

• Chronic alveolar hypoxia is the fundamental mechanism driving pulmonary vascular remodeling through hypoxic pulmonary vasoconstriction, which increases pulmonary vascular resistance and leads to right ventricular pressure overload 2, 1.
• Destruction of the pulmonary vascular bed from emphysematous changes mechanically reduces the cross-sectional area available for blood flow 2.
• Extensive remodeling of all layers of pulmonary arterial walls occurs, characterized by intimal thickening, proliferation of smooth muscle cells, and deposition of elastic and collagen fibers 2.
• Restrictive lung diseases, particularly idiopathic pulmonary fibrosis, cause cor pulmonale through similar mechanisms of vascular destruction and hypoxic vasoconstriction 3.

Thromboembolic Disease

• Chronic thromboembolic disease from recurrent or unresolved pulmonary emboli causes persistent elevation in pulmonary vascular resistance 4.
• Acute massive pulmonary embolism represents a primary cause of death from acute right heart failure through sudden right ventricular afterload increase 4.

Other Causes

• Disorders of ventilatory drive, thoracic cage abnormalities, and neuromuscular diseases can eventually lead to cor pulmonale through chronic hypoventilation 3.
• Erythrocytosis in chronic hypoxemic states increases effective pulmonary vascular resistance 2.

Clinical Presentation and Symptoms

Early Symptoms

• Progressive exertional dyspnea with exercise intolerance is the most common presenting symptom, though it is nonspecific 5.
• Fatigue and weakness induced by exertion occur as initial manifestations 5.
• Symptoms at rest occur only in advanced cases 5.

Advanced Disease Manifestations

• Peripheral edema, abdominal distension, and ankle swelling develop with progressing right ventricular failure 5.
• Early satiety and epigastric fullness or pain may occur as the right heart fails 5.
• Angina can result from right ventricular ischemia or, rarely, from compression of the left main coronary artery by dilated pulmonary arteries 5.
• Syncope indicates severe disease 5.
• Dry cough and exercise-induced nausea and vomiting are less common symptoms 5.

Physical Examination Findings

• Physical signs depend on the degree of airflow limitation and severity of pulmonary hypertension, but sensitivity for detecting moderately severe disease is poor 5.
• Left parasternal lift (right ventricular heave) is palpable at the left lower sternal border 5.
• Accentuated pulmonary component of the second heart sound (loud P2) indicates elevated pulmonary artery pressure 5.
• Right ventricular third or fourth heart sound gallop may be auscultated 5.
• Pansystolic murmur of tricuspid regurgitation and diastolic murmur of pulmonary regurgitation may be present 5.
• Elevated jugular venous pressure with large V waveforms, hepatomegaly, ascites, and cool extremities characterize advanced disease 5.
• Central cyanosis indicates significant hypoxemia but has low sensitivity 5.
• Visible activity of accessory muscles or pursed-lip breathing usually implies severe airflow obstruction 5.

Diagnosis

Diagnostic Algorithm

The diagnostic approach must establish three critical elements: presence and severity of pulmonary hypertension, determination of the underlying cause, and assessment of right ventricular function 5, 4.

Step 1: Clinical Suspicion and Initial Testing

• Electrocardiogram may provide supportive evidence but a normal ECG does not exclude the diagnosis 5.
• ECG abnormalities include P pulmonale, right axis deviation, right ventricular hypertrophy, right ventricular strain, right bundle branch block, and QTc prolongation 5.
• Right ventricular strain is more sensitive than right ventricular hypertrophy (which has only 55% sensitivity and 70% specificity) 5.
• Chest radiography is often unrevealing in early stages but may show hilar fullness from enlarged central pulmonary arteries, clear or oligemic lung fields, right ventricular enlargement, and peripheral lung opacities suggestive of previous infarction 5.

Step 2: Echocardiography

• Echocardiography is useful for screening but insufficient for definitive diagnosis of pulmonary hypertension 5.
• Echocardiography plays a central role in the diagnostic work-up, particularly in the acute setting, providing assessment of right ventricular morphology and function 6.
• It provides parameters with prognostic value and can assess treatment efficacy during follow-up 6.

Step 3: Pulmonary Function Testing

• Forced expiratory volume in 1 second (FEV1) is the best measure for assessing severity of airflow limitation in COPD-related cor pulmonale 5.
• The FEV1/vital capacity ratio is a relatively sensitive index of mild COPD 5.
• Arterial blood gases should be obtained to assess hypoxemia and hypercapnia 5.

Step 4: Right Heart Catheterization

• Right heart catheterization is required to definitively establish pulmonary hypertension, requiring mean pulmonary artery pressure >25 mmHg (traditional definition) or >20 mmHg (revised Nice statement), and pulmonary vascular resistance ≥3 Wood units 5, 7.
• Pulmonary capillary wedge pressure ≤15 mmHg is generally required to exclude left-sided heart disease as the cause 5.
• Right heart catheterization provides information necessary for preoperative risk assessment if surgical intervention is considered 5.

Step 5: Imaging for Thromboembolic Disease

• Ventilation-perfusion (V/Q) scanning is important in the evaluation of chronic thromboembolic pulmonary hypertension, as a normal scan excludes the diagnosis 5.
• A relatively normal CT angiogram can be observed in chronic thromboembolic pulmonary hypertension despite substantial V/Q scan abnormalities 5.
• Pulmonary angiography is the gold standard for defining pulmonary vascular anatomy and identifying chronic thromboembolic obstruction 5.
• Evidence of obstruction must persist despite 3 months of therapeutic anticoagulation to diagnose chronic thromboembolic pulmonary hypertension 5.

Severity Assessment in COPD

• Approximately 50% of patients with severe COPD have pulmonary hypertension, but only 1-3% develop "out-of-proportion" severe pulmonary hypertension (mean pulmonary artery pressure >40 mmHg), which carries significantly higher mortality 2.
• Resting pulmonary artery mean pressure in stable COPD usually ranges between 20 and 35 mmHg 1.
• Pulmonary hypertension may worsen during exercise, sleep, and exacerbations of the disease 1.

Management

Oxygen Therapy

Long-term oxygen therapy (LTOT) is the only treatment proven to improve survival in patients with COPD and cor pulmonale 8, 1.

• LTOT stabilizes or attenuates and sometimes reverses the progression of pulmonary hypertension, though pulmonary artery pressure seldom returns to normal 1.
• Supplemental oxygen partially reverses hypoxemia effects by decreasing pulmonary artery pressure, reducing respiratory rate and dynamic hyperinflation, and decreasing lactic acid production 2.
• Statistical proof correlating improvements in pulmonary hemodynamics with increased survival is lacking, but the survival benefit is established 8.

Bronchodilators

• Beta-2 agonists and especially theophylline may have beneficial effects on pulmonary hemodynamics in addition to their effect on respiratory function 8.
• These agents are useful in COPD when right ventricular dysfunction is present 8.

Diuretics

• Diuretics are useful for improving symptoms in patients with fluid overload and should be treated with thiazides, loop diuretics, and aldosterone antagonists as appropriate 5, 8.
• Diuretics improve symptoms in appropriate patients with systemic venous congestion 8.

Phlebotomy

• Phlebotomy is useful in improving symptoms in patients with significant erythrocytosis 8.

Vasodilators: Limited Role

• Vasodilators such as calcium channel blockers and ACE-inhibitors may improve pulmonary hemodynamics acutely but may lower arterial PO2 by worsening ventilation-perfusion matching or blunt the improvement in pulmonary hemodynamics seen with supplemental oxygen 8.
• The long-term benefits of these agents have not been proven and their routine use in patients with cor pulmonale due to COPD cannot be recommended 8.
• Prostacyclin, endothelin receptor antagonists, sildenafil, and nitric oxide could be considered in patients with severe pulmonary hypertension, but controlled studies are presently lacking 1.
• There is no evidence supporting treatment of COPD patients with pulmonary hypertension using drugs approved for pulmonary arterial hypertension, though such drugs may be effective in a selected group whose disease includes pulmonary arterial hypertension-like vascular components 7.

Digoxin

• There are few data to support the efficacy of digoxin in right-sided heart failure from cor pulmonale 5.

Management of Underlying Conditions

• Treatment must address the underlying pulmonary disease to prevent progression 1.
• Maintain optimal lung function through appropriate management of COPD or other underlying respiratory conditions 1.
• Maintain oxygen saturation to prevent chronic hypoxic pulmonary vasoconstriction 1.

Prognosis

• Cor pulmonale is associated with higher mortality rates independent of other prognostic variables 8.
• The risk of death due to right-sided heart failure is correlated with pulmonary artery pressure at diagnosis, with 70% mortality when mean pulmonary artery pressure is ≥40 mmHg, increasing to 90% at ≥50 mmHg 5.
• When present, cor pulmonale limits peripheral oxygen delivery, increases shortness of breath, and reduces exercise endurance 8.