Objectives

1. Describe the epidemiology and natural history of cor pulmonale secondary to COPD.
2. Review the changes in pulmonary artery circulation and right ventricular function resulting from COPD.
3. Identify the causes of pulmonary artery hypertension in COPD.
4. Describe the evaluation of cardiac function in patients with cor pulmonale.
5. Review the role of oxygen therapy and pharmacologic agents in the treatment of cor pulmonale secondary to COPD.

Abbreviations

ACE = angiotensin-converting enzyme; CI = cardiac index; CO = cardiac output; LV = left ventricle; PA = pulmonary artery; PAH = pulmonary artery hypertension; Ppa = pulmonary artery pressure; PVR = pulmonary vascular resistance; RV = right ventricle; RVEF = right ventricular ejection fraction

Definition and Epidemiology

Pulmonary artery hypertension (PAH) is described hemodynamically as a resting mean pulmonary artery pressure (Ppa) >20 mm Hg. Cor pulmonale was defined in 1963 by the World Health Organization as "hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs, except when these pulmonary alterations are the result of diseases that primarily affect the left side of the heart, as in congenital heart disease."¹ It may be secondary to diseases of the pulmonary parenchyma and/or the pulmonary vasculature between the proximal main pulmonary artery (PA) and the distal pulmonary veins. Cor pulmonale can range clinically from mild changes in right ventricular (RV) function to frank right heart failure.

COPD is the most common cause of chronic cor pulmonale in North America. Other common causes of cor pulmonale are listed in Table 1.

COPD was the cause in 84% of the 100 cases of chronic cor pulmonale studied by Ben Jrad et al,² with restrictive lung disease and thromboembolic diseases accounting for the remaining 14% and 2% of the cases, respectively. Vizza et al³ identified RV dysfunction [right ventricular ejection fraction (RVEF) <45%] in 267 of 434 patients (66%) with severe pulmonary disease. The prevalence was higher in patients with pulmonary vascular disease (94%) than among patients with COPD (59%) or cystic fibrosis (66%). In contrast, dysfunction of the left ventricle (LV), defined as a left ventricular ejection fraction <45%, was present in only 6.4% overall and in 3.6% of patients with parenchymal or airway disease.³

The prevalence of PAH generally increases as COPD worsens and patients with hypoxemia, hypercapnia, and polycythemia appear to be more likely to present with cor pulmonale as well.

Pulmonary Circulation and the Right Ventricle in COPD

The walls of the large pulmonary arteries are thinner than those of the systemic arteries and are designed to distend. The surface area of the pulmonary capillaries is extensive and can increase further with hyperinflation as well as during exercise owing to passive dilatation of the functional vessels and recruitment of previously underperfused vessels. The pulmonary vascular bed has less than one tenth the resistance of its systemic counterparts and can accommodate increases in blood flow with only mild elevations in pressure. Significant PAH develops only in patients with considerable abnormality of the pulmonary vessels because the pulmonary circuit is normally a low-resistance, highly compliant system. As COPD worsens, Ppa and pulmonary vascular resistance (PVR) may become elevated at rest and increase further with exercise. Nonetheless, PAH, even in severe COPD, is generally mild.

The adult RV is a thin-walled, crescent-shaped chamber bounded by the RV free wall and the interventricular septum. Compared with the LV, it is less able to generate pressure and it is more of a volume pump than a pressure pump. The RV adapts better to changing preloads but not to acute increases in afterload. An augmentation of the right ventricular afterload, resulting from increases in Ppa and PVR, is the most common cause of impaired RV function. In addition, RV compliance can decrease secondary to RV free wall hypertrophy and impairment of RV diastolic filling. While there is compelling evidence that RV contractility is well preserved in persons with PAH secondary to COPD, some investigators have found a reduced RVEF.^4,5

Etiology of PAH in COPD

Potential causes proposed to explain the development of PAH in COPD are listed in Table 2. The increase in Ppa and PVR in patients with COPD arises mainly from hypoxic vasoconstriction, destruction of the lung parenchyma, impaired vasomotor tone, and reduced ability to recruit underperfused vessels. If unchecked, these factors eventually lead to RV hypertrophy and failure.

Evaluation of the Patient With Cor Pulmonale

Standard clinical evaluation (history, physical examination, ECG, and chest radiography) is generally insensitive in identifying the presence and quantifying the severity of cor pulmonale, and has been replaced by noninvasive techniques such as echocardiography, radionuclide ventriculography, and MRI in the initial assessment of cor pulmonale secondary to COPD. Nonetheless, these noninvasive methods, although capable of detecting the presence of PAH, cannot accurately measure Ppa (Table 3). Right heart catheterization remains the gold standard for diagnosing PAH.

Chest Radiography

Comparing chest radiographic features with the Ppa obtained during cardiac catheterization in persons with COPD, Matthay et al⁶ observed that an increase in the diameter of the right descending PA to >16 mm on posteroanterior projection combined with an increase in the diameter of the left descending PA to >18 mm on left lateral projection correctly identified PAH in 45 of 46 patients.

Electrocardiography

Kilcoyne et al⁷ performed ECGs on 200 patients with COPD, hypoxemia (arterial oxygen saturation <85%), and cor pulmonale (Ppa >25 mm Hg), and noted at least one of the following changes: (1) a rightward shift of the mean QRS axis of 30 degrees or more from its previous position; (2) inverted, biphasic, or flattened T waves in the precordial leads; (3) depressed ST segments in leads II, III, and aVF; and (4) incomplete or complete right bundle branch block. These ECG changes disappeared when arterial oxygen saturation improved.

Echocardiography

An estimate of the systolic Ppa can be made using pulsed Doppler by determining the blood flow velocity in the main PA or in the regurgitant jet from the tricuspid valve. The tricuspid valve regurgitant jet can be used to determine the RV-atrial gradient using the modified Bernoulli equation, P = 4V 2 (P = peak pressure difference between the RV and the atrium; V = peak velocity of the tricuspid regurgitant jet). The systolic Ppa is obtained by adding this pressure to the mean right atrial pressure.

Echocardiography has greater sensitivity than ECG in diagnosing cor pulmonale. Putnik et al⁸ evaluated 60 patients with COPD and clinical symptoms of cardiac decompensation using the two methods. The diagnosis of cor pulmonale was established by ECG in 43 patients (78.18%) and by echocardiography in 57 patients (95%).

MRI

The mean RV wall mass in persons with COPD is greater than that in healthy control individuals, and there is a positive correlation between RV free wall volume determined by MRI and the Ppa and PVR in persons with COPD.⁹

Therapy for Cor Pulmonale Secondary to COPD

The goals of therapy for cor pulmonale are enumerated in Table 4.

The agents that have been most extensively evaluated for these purposes include oxygen, vasodilators, theophylline, and inotropic medications (Table 5). With the exception of supplemental oxygen, no therapy has demonstrated consistent and long-term benefits.

Oxygen

Long-term oxygen therapy has been shown to improve pulmonary hemodynamics and survival in hypoxic COPD patients.

In the Medical Research Council Working Party trial, 87 patients were randomly assigned to receive either oxygen for 15 h daily or placebo. Mortality within 5 years was 45% in the oxygen-treated group and 67% in the group that did not receive oxygen. Mean Ppa and PVR, determined at the time of entry and again after 1 year, remained unchanged in patients receiving long-term oxygen therapy but increased in control subjects.¹⁰

In the Nocturnal Oxygen Therapy Trial ( NOTT) study in North America, patients with COPD were randomized to receive either nocturnal oxygen therapy (averaging 12 h/d) or continuous oxygen therapy (averaging 17 h/d).¹⁰ The mortality rates after a year were 20.6% and 11.9% in the nocturnal oxygen group and the continuous oxygen group, respectively. After 6 months of therapy, Ppa decreased slightly in patients receiving continuous oxygen therapy but increased slightly in the nocturnal oxygen therapy group. In addition, PVR increased by 6.5% in the group receiving nocturnal oxygen therapy but fell by 11.1% in the continuous oxygen therapy group.¹²

Weitzenblum et al¹³ also reported a reversal in the progression of PAH in patients given continuous oxygen therapy. Prior to the initiation of long-term oxygen therapy, patients with COPD and severe hypoxemia had been experiencing an average increase in Ppa of 1.47 mm Hg yearly. In contrast, there was a significant decrease in Ppa of 2.5 mm Hg annually when oxygen therapy was provided 15 to 18 h/d for 1 to 6 years.

Two possible reasons for the beneficial effects on pulmonary hemodynamics and survival include (1) the relief of pulmonary vasoconstriction and reduction of Ppa and PVR; and (2) enhanced oxygen delivery to the brain, heart, and other vital organs.

The acute oxygen-induced reversibility of PAH might predict the outcome from long-term oxygen therapy. Ashutosh et al¹⁴ classified 43 patients with COPD and cor pulmonale as oxygen responders if they had a fall in Ppa of ≥5 mm Hg during a 24-h administration of 28% oxygen, and oxygen nonresponders if the decrease in Ppa was smaller. Continuous long-term oxygen therapy was then prescribed for all patients, who were monitored for 3 years or until their death. Compared to nonresponders, the oxygen responders had a markedly higher survival at 1, 2, and 3 years.

It remains uncertain, however, whether the salutary hemodynamic effects contribute to the improved survival associated with oxygen therapy. In the NOTT study, continuous oxygen therapy resulted in improved survival only in patients whose baseline PVR was low and not in those who had a high PVR.¹²

Phlebotomy

In polycythemic patients who undergo phlebotomy, the mean Ppa and PVR decrease but the cardiac output is generally unaffected. In a study by Weisse et al,¹⁵ 12 patients with stable cor pulmonale and polycythemia (hematocrit >55%) underwent serial phlebotomies resulting in three mean hematocrit levels of 61%, 50%, and 44%, with no change in blood volume. The reduction in hematocrit from 61% to 50% was accompanied by significant reductions in mean Ppa and PVR with no change in cardiac output (CO). Reduction in hematocrit to 44% did not lead to any additional changes. Although rarely indicated as the sole therapy for cor pulmonale, phlebotomy might be considered for acute decompensation of cor pulmonale accompanied by severe polycythemia, or for patients who remain markedly polycythemic even after continuous oxygen therapy. Nonetheless, it is not known whether repeated phlebotomies lead to any definite long-term benefits in pulmonary hemodynamics.

Pharmacologic Agents

Almitrine: Almitrine, a respiratory stimulant, has a salutary effect on gas exchange, including an increase in Pao₂ and decrease in Paco₂. Possible mechanisms for almitrine's beneficial effects on arterial blood gases may be due, in part, to alterations in breathing pattern, an improved peripheral chemoreceptor responsiveness to hypoxia, or a reduction in ventilation-perfusion mismatching secondary to enhanced hypoxic pulmonary vasoconstriction. The latter action may, in turn, give rise to detrimental long-term consequences, including the progression of PAH.

Angiotensin-Converting Enzyme Inhibitors: Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, enalapril, and losartan, have been tried in the therapy of cor pulmonale secondary to COPD. In a double-blind, crossover trial, Kiely et al¹⁶ randomly assigned nine COPD patients with PAH to receive either 50 mg of oral losartan or placebo. Significant reductions in mean Ppa, PVR, systemic vascular resistance, and mean arterial blood pressure were noted with losartan administration compared with placebo. The use of losartan was also associated with a significant increase in CO. Other investigators have failed to detect any improvement in exercise tolerance or RV function despite reductions in mean Ppa and PVR following long-term administration of enalapril.¹⁷

Calcium-Channel Blockers: Sturani et al¹⁸ evaluated the short-term (30 and 60 min) and long-term (average of 55 days) hemodynamic effects of orally administered nifedipine (20 mg) in 12 patients with PAH related to COPD. PVR decreased and cardiac index (CI) and oxygen delivery increased after nifedipine administration. Only one third of the patients demonstrated any reduction in Ppa. The improvements in PVR and CI were sustained during long-term treatment with nifedipine.

Digitalis: The cardiac glycosides have been used to manage cor pulmonale for many years. The evidence, however, does not support the use of digoxin in patients with cor pulmonale unless they have concurrent LV failure. Mathur et al¹⁹ studied the effects of 8 weeks of digoxin therapy on RV function in patients with severe COPD. Digoxin therapy improved RV function only in those with a reduced initial left ventricular ejection fraction.

Hydralazine: Hydralazine has variable effects on Ppa and RV performance in patients with COPD. Although many studies have demonstrated favorable hemodynamic effects with the use of this agent, others have shown detrimental results. V asodilators that, like hydralazine, primarily reduce afterload and thus improve right ventricular performance might be more beneficial than vasodilators that, like nitroglycerin and nitroprusside, reduce preload and thus potentially cause a fall in the CI and Pao₂.²⁰

Nitrates: Studies using the cardiac preload-reducing agents, nitroglycerin and nitroprusside, demonstrated significant improvements in Ppa and PVR in patients with PAH. Konietzko et al²¹ noted a reduction in PVR and an increase in the alveolar-arterial oxygen gradient following administration of isosorbide dinitrate to 10 patients with chronic cor pulmonale.

Nitric Oxide: Germann et al²² measured oxygenation and hemodynamic indices in 18 patients with COPD receiving long-term oxygen therapy at baseline and 1 h after sequential additions of 5, 10, and 20 ppm nitric oxide to the inspired oxygen. Hemodynamic indices improved (decrease in mean Ppa and PVR and increase in RVEF) in a dose-dependent fashion, reaching a maximal change at 20 ppm nitric oxide. Maximal improvement in oxygenation (increased Pao₂/fraction of inspired oxygen ratio) was achieved at 5 ppm nitric oxide.

Prostaglandins: The prostaglandins E₁ and I₂ have pronounced vasodilator effects on the pulmonary circulation. Naeije et al²³ administered prostaglandin E₁ IV to 26 patients with decompensated COPD and noted a decrease in Ppa and an increase in both the CO and oxygen delivery.

Theophylline: Theophylline modestly lowers both Ppa and PVR, and enhances right and left cardiac systolic pump function. Matthay et al²⁴ noted that oral theophylline improved RVEF significantly after 72 h of therapy in 15 patients with COPD. RVEF normalized in 7 of 10 patients with depressed baseline RV function, including two patients with cor pulmonale. The improvement in RVEF was sustained after an average of 4 months of therapy in 11 patients treated with oral theophylline.²⁴ These beneficial effects are postulated to be secondary to a reduction in ventricular afterload and a positive ventricular inotropic effect.

Prognosis

PAH in COPD typically progresses slowly, with Ppa increasing an average of 0.5 mm Hg annually.²⁵ However, the rise in Ppa can be sudden and marked during episodes of acute respiratory failure, exercise, and sleep. The development of PAH and cor pulmonale appears to affect survival of patients with COPD, with Ppa being inversely related to survival rate. Weitzenblum et al²⁶ reported that in 175 patients with moderate to severe COPD (mean FEV₁/vital capacity, 40.2 ± 11.1%), survival rates after 4 and 7 years were significantly lower in the subgroup with Ppa >20 mm Hg. Nevertheless, PAH may merely reflect the severity of the underlying COPD and might not be directly responsible for its increased mortality. Finally, cor pulmonale is associated with increased mortality and risk of hospital readmission, and influences the length of hospital stay during acute exacerbations of COPD.^27,28

Summary

References

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