CHAPTER 76: COR PULMONALE: THE HEART IN PARENCHYMAL LUNG DISEASE

Cor pulmonale, or “pulmonary heart,” describes the pathological changes and associated signs and symptoms of right ventricular failure resulting from pulmonary hypertension (PH) in the setting of parenchymal lung disease such as chronic obstructive pulmonary disease (COPD).¹

The pulmonary circulation (with the exception of the bronchial arteries, which deliver oxygenated blood from the left heart) is characterized not only by the delivery of venous deoxygenated blood to the alveoli for oxygen uptake, but also by low resistance and large capacitance. The pulmonary circulation in the absence of right-to-left shunts has to accept the entire cardiac output, approximately 5 L/min at rest and up to fivefold during maximal exercise. Normal mean pulmonary pressure is less than 20 mm Hg at rest, with a level greater than 25 mm Hg diagnostic of PH.² Although pulmonary pressures do rise with exercise, pulmonary vascular resistance (PVR) normally drops further with exercise to accommodate the marked increase in cardiac output. In PH, although there is an exaggerated increase in pulmonary pressures during exercise without an appropriate decrease in PVR, criteria for exercise-induced PH have not been established.² To accommodate the large amount of blood flow, the pulmonary circulation provides a large cross-sectional area. Reduction in the cross-sectional area by up to 50%, as with a pneumonectomy, is well tolerated without PH at rest. Further reductions, as may occur with advanced pulmonary disease, can lead to PH both on exertion and at rest with resultant pressure overload on the right ventricle.

The term cor pulmonale originated over two centuries ago and has been applied variably in the past to right heart failure as a result of various lung conditions, both parenchymal and vascular in origin, as well as a result of pulmonary emboli. Indeed, from a pathophysiologic and clinical standpoint, any disease in which pulmonary arterial pressures increase sufficiently to affect right ventricular function results in a similar clinical syndrome of right heart failure. In 1963, the World Health Organization (WHO) defined cor pulmonale as “hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs.”³ Strictly speaking, therefore, the term should be applied only to group III PH and excludes group I (pulmonary arterial hypertension, including idiopathic pulmonary arterial hypertension, connective tissue diseases, and congenital heart disease), group II (secondary to left heart failure), group IV caused by chronic thromboembolic disease, and group V (miscellaneous conditions such as sarcoidosis) based on the 2013 Updated Clinical Classification of Pulmonary Hypertension.⁴ PH is discussed in detail in Chap. 74.

Chronic cor pulmonale is typically a manifestation of various parenchymal lung diseases. Acute pulmonary embolism, if large, leads to acute right heart failure, which has been termed by some as acute cor pulmonale. Pulmonary embolism is not an intrinsic lung disease, and as such, the term is not strictly within the definition used here for cor pulmonale. The cardiac response to “acute cor pulmonale” also differs from the typical cor pulmonale syndrome, which is characterized by right ventricular hypertrophy with right ventricular dilatation as a late phenomenon. In contrast, in acute pulmonary embolism, the right ventricle dilates acutely without intervening hypertrophy, leading to a volume overload rather than pressure overload right ventricular failure.

The sine qua non of cor pulmonale is the presence of significant PH. Lung diseases that are associated with PH include the obstructive lung diseases, with COPD being by far the most prevalent; restrictive lung diseases, including pulmonary fibrosis and kyphoscoliosis; and diseases associated with hypoventilation, such as obstructive sleep apnea (OSA). A listing of lung diseases that have been associated with cor pulmonale is provided in Table 76–1. All of these have chronic hypoxemia in common, and indeed without significant hypoxemia, cor pulmonale does not typically develop.

Given the worldwide smoking epidemic, COPD is by far the most important disease causing cor pulmonale. COPD risk factors include not only smoking, however, but also outdoor, occupational, and indoor air pollution, with burning of wood and other biofuels being a major risk factor, and nonsmokers accounted for 23.3% of COPD with moderate or greater disease severity in the Burden of Obstructive Lung Disease (BOLD) study.⁵ COPD is also a disease of aging, with a higher prevalence among men. COPD is considered the fourth leading cause of death in the world and is predicted to become the third leading cause by 2020. There is significant underdiagnosis of COPD as well as different criteria used for diagnosis, creating uncertainty as to the burden of disease. The BOLD study reported a prevalence of 10.1% for moderate or above disease (11.8% for men and 8.5% for women), a higher disease burden than previously appreciated, with every decade of life associated with almost a doubling in the odds ratio of having the disease.⁶

The presence of cor pulmonale markedly increases the risk of death in COPD, but its exact contribution is difficult to separate from the almost invariable severe COPD and respiratory failure found in patients at the stage when cor pulmonale is diagnosed.

Various mechanisms contribute to increased pulmonary vascular disease in parenchymal lung disease, including inflammation, destruction of lung parenchyma as in emphysema, obliteration as a result of fibrosis as in idiopathic pulmonary fibrosis, endothelial dysfunction, and hypoxemia⁷ (Fig. 76–1). In COPD, hypoxia plays a central role and is usually manifest when patients become symptomatic with cor pulmonale, but it is preceded in the pathogenesis of PH by a much earlier inflammatory process. In the case of COPD, this inflammatory process is even induced by smoking itself, even while lung function is still normal.^8,9

Inflammation

Changes in the structure and function of the arterial wall (arterial remodeling) have been studied extensively in smokers and patients with COPD. Intimal thickening, with an increase in both cellular proliferation with smooth muscle cell migration and proliferation, as well as an increase in extracellular matrix, occur early in the disease process and are present even in patients with mild COPD, whereas the severity of pulmonary vascular remodeling correlates with the severity of inflammation.⁹ Remodeling occurs in arteries of different sizes, although it affects small muscular arteries the most, with intimal thickening being the most pronounced pathologic abnormality, while the muscular layer does not show significant changes. The resultant decrease in cross-sectional area and vasodilatory capacity leads to an increase in PVR.

The inflammatory process in COPD is characterized by an increase in activated T lymphocytes, mostly CD8⁺ cells,¹⁰ and correlates with the extent of airflow obstruction. Even smokers with normal lung function have an increased number of CD8⁺ T cells in their pulmonary arteries, with a reduction in the CD4⁺/CD8⁺ ratio, similar to patients with COPD.¹¹

Endothelial Dysfunction

As in the systemic circulation, the endothelium plays a key role in mediating vascular dilation. Unlike the systemic circulation, endothelial cells in the pulmonary circulation respond to hypoxia with signaling leading to vasoconstriction as opposed to vasodilation, so that the endothelium may also mediate the response to hypoxia, which is a major contributor to development of PH. COPD and other lung diseases associated with PH have been shown to have impairment in the three major pathways that regulate pulmonary vascular tone: the two vasodilatory pathways, the nitric oxide pathway and the prostacyclin pathway, and the vasoconstrictive pathway, the endothelin pathway. Impairment of nitric oxide synthesis (reduction in endothelial nitric oxide synthase) as well as prostacyclin synthase has been shown in patients with COPD along with upregulation in the expression of endothelin-1 receptors.

Hypoxia

Hypoxia has been considered as a key mediator in PH associated with various parenchymal lung diseases, including COPD. That hypoxemia can indeed be a cause of PH is seen in both subacute mountain sickness (seen in sea-level dwellers who move to high altitude) and in chronic mountain sickness (seen after many years at high altitude). In both conditions, the PH is relieved by relief of the hypoxia. In COPD patients, when cor pulmonale develops, significant hypoxia is usually evident with arterial partial pressure of oxygen (PO₂) < 55 mm Hg, but whether the hypoxemia is the key mediator in causing the PH or simply a marker of more advanced disease is controversial. Although oxygen therapy does ameliorate the associated PH, its effect is limited. Most importantly, changes in the pulmonary vasculature, specifically pulmonary vascular remodeling and endothelial dysfunction, have been documented in early COPD without overt hypoxemia and even in smokers with normal lung function.^12,13

The acute effects of hypoxia on the pulmonary vasculature also need to be distinguished from chronic effects. Acute hypoxemia causes vasoconstriction in the resistance pulmonary vessels. When caused by localized (eg, a segmental or lobar pneumonia) hypoxemia, this vasoconstriction may serve to improve the matching of ventilation and perfusion. In contrast, in the presence of diffuse lung disease, such vasoconstriction is deleterious because it increases right ventricular afterload.

The clinical manifestations of cor pulmonale are nonspecific and reflect the signs and symptoms of right heart failure. Typically, the underlying lung disease is long-standing and has been diagnosed already, and although subtle changes in the pulmonary vasculature may have occurred much earlier in the disease process, overt signs and symptoms of cor pulmonale are a late phenomenon and often overshadowed by the signs and symptoms of the underlying pulmonary disease. Thus, a patient with severe COPD may present with an exacerbation with respiratory failure, which appropriately becomes the focus of treatment.

Signs and symptoms attributable to cor pulmonale include peripheral edema, hepatic congestion presenting as early satiety, presyncope and, when pulmonary pressures are significantly elevated, frank syncope. On physical exam, the patient may appear plethoric as a result of accompanying polycythemia (a response to chronic hypoxemia). The cardiac exam may reveal jugular venous distention, a prominent jugular V wave caused by tricuspid regurgitation, a parasternal lift caused by right ventricular hypertrophy (this may be obscured by significant hyperinflation in the COPD patient), and a prominent P₂ sound. As PH progresses, pulmonic valve regurgitation may develop (Graham-Steele murmur), along with a right-sided third heart sound. Signs of right-sided volume overload include hepatojugular reflux, ascites, and in severe cases, anasarca.

Electrocardiographic findings in cor pulmonale include evidence of right axis deviation, right ventricular hypertrophy, right ventricular strain, P pulmonale secondary to right atrial enlargement, and hypertrophy. Common accompanying arrhythmias include atrial fibrillation, atrial flutter, and multifocal atrial tachycardia in addition to premature atrial and ventricular contractions.¹⁴

Echocardiography

Echocardiography is particularly useful for the detection of cor pulmonale and its antecedent PH. Because of the anterior location of the right ventricle, transthoracic echocardiography is sufficient and often superior to transesophageal echocardiography in assessing the right ventricle. The assessment of right ventricular function differs from assessment of left ventricular function as a result of the complex crescent-like shape of the right ventricle, different fiber orientation, and contraction (the septum normally contracting toward the left ventricle). The salient features on transthoracic echocardiography include right ventricular hypertrophy, right ventricular enlargement, elevated tricuspid regurgitation velocity indicative of increased gradient between the right ventricle and right atrium, increased right ventricular/left ventricular ratio and eccentricity index, and decreased tricuspid annular plane systolic excursion (TAPSE), as detailed further below.

Because cor pulmonale is invariably preceded by PH, assessment of pulmonary artery pressure is an essential part of the evaluation of patients with suspected cor pulmonale. Although right heart catheterization is the gold standard for measurement of pulmonary artery pressures, the presence of tricuspid regurgitation, which is almost universally present in patients with PH, allows the calculation of the gradient between the right ventricle and right atrium by measuring the peak tricuspid regurgitation velocity by Doppler and adding the estimated right atrial pressure. The latter can be obtained from physical examination or from echocardiographic assessments. Since the description of the technique by Yock and Popp,¹⁵ it has become the standard for assessing PA pressures noninvasively, but various correlations with invasive measurements have been reported, with correlations varying from a low of r = 0.23¹⁶ to a high of r = 0.97.¹⁷ A recent comprehensive assessment of the correlation in 307 patients who underwent echocardiography and right heart catheterization within 5 days of each other showed a strong correlation when the tricuspid regurgitation signal was interpretable (which was found in approximately two-thirds), with an area under the curve for classifying PH of 0.97 for right ventricular systolic pressure. When tricuspid regurgitation signals were uninterpretable, eccentricity index and right ventricular size were independently associated with PH classification (area under the curve, 0.77).

TAPSE reflects the longitudinal myocardial shortening of the right ventricle and accurately represents global right ventricular function. TAPSE is assessed with M-mode in the apical four-chamber view, with normal value being at least 16 mm and severe RV dysfunction when TAPSE is less than 10 mm.

Right ventricular dimensions are increased in cor pulmonale and are accompanied by increases in wall thickness, usually assessed by the long-axis view on the subcostal view. Normally the right ventricle appears to be smaller than the left ventricle on the four-chamber view, with the apex being formed by the left ventricle. With the development of cor pulmonale, the right ventricle enlarges, the right ventricular/left ventricular ratio increases to greater than 1, and the right ventricle forms the apex. When pressure and volume overload of the right ventricle develop, the left ventricle assumes a D shape as the intraventricular septum flattens. This leads to an abnormal ratio (> 1; sometimes significantly > 1, normal ~1) between the left ventricular anteroposterior and septolateral dimensions (eccentricity index). Other parameters of right ventricular function include right ventricular dP/dt assessed by measuring the time required for the tricuspid regurgitation jet to increase in velocity from 1 to 2 m/s on continuous wave Doppler and right ventricular fractional area change, a measure of the right ventricular ejection fraction in the apical four-chamber view.

The assessment of ventricular myocardial function (for the left ventricle, but particularly for the right ventricle) by two-dimensional echocardiography is limited by high subjectivity as well as the inability to accurately differentiate movement from contraction. Newer techniques that assess deformation of the muscle (tissue Doppler imaging and two-dimensional speckle tracking) can provide strain and strain rate data. Assessment of myocardial strain can provide early evidence of myocardial dysfunction, is often abnormal in the early stages of the development of cor pulmonale, and can better predict hemodynamic abnormalities than traditional echocardiography parameters.^18,19,20

Radiography, Nuclear Scan, Computed Tomography, and Magnetic Resonance Imaging

Beyond the characteristic findings of the underlying lung diseases (eg, honeycombing in pulmonary fibrosis and hyperinflation in emphysema) and skeletal abnormalities (eg, kyphoscoliosis) that lead to cor pulmonale, the characteristic radiologic findings are of right ventricular hypertrophy, which is best assessed in the lateral projection with filling of the retrosternal space. This sign, however, may be obscured by the vertical emphysematous heart. PH may be suspected when there is enlargement of the descending pulmonary arteries (> 16 mm in the right pulmonary artery and > 18 mm in the left pulmonary artery). Nuclear scanning and magnetic resonance imaging may be used to assess right ventricular function and obtain an accurate ejection fraction.

Computed tomography scans are particularly useful to screen for associated lung abnormalities such as pulmonary fibrosis, bronchiectasis, and chronic thromboembolic PH. Perfusion/ventilation nuclear scans are also helpful in excluding chronic thromboembolic PH and predicting response to pulmonary thromboendarterectomy surgery.

Magnetic resonance imaging of the heart (cardiac magnetic resonance) and of the lung vasculature has emerged as a useful tool in the assessment of PH and, by extension, cor pulmonale. Magnetic resonance assessments of patients with PH has shown close correlations with findings on invasive right heart catheterization.²¹ In addition, magnetic resonance imaging can assess pulmonary arterial compliance. Increased pulmonary artery stiffness is not only a characteristic and relatively early sign of PH, but may also play a role in the progression of the disease.^22,23

Chronic Obstructive Pulmonary Disease

COPD is an inflammatory disease characterized by a combination of small airway disease (obstructive bronchiolitis) and destruction of the parenchyma (emphysema), with variable contribution of each component in an individual patient.²⁴ The hallmark of the disease is a chronic limitation in airflow, which can be objectively quantified by spirometry. Smoking is the most recognized and studied risk factor, but the disease can also occur in nonsmokers. Genetic factors (eg, α₁-antitrypsin deficiency), age, male gender, impaired lung growth and development, and exposure to various air pollutants (both indoor and outdoor) have been clearly linked to the development of COPD, whereas asthma, bronchial hyperreactivity, and chronic bronchitis have been variably linked.

In the majority of COPD patients, PH is present only during exercise, but resting PH is almost invariably present in Global Initiative for Chronic Obstructive Lung Disease stage IV disease, with up to 5% of patients having mean pulmonary artery pressure (mPAP) > 35 mm Hg.^25,26,27

The effect of PH in COPD has been controversial. Vonbank et al²⁸ studied 42 patients with moderate-to-very-severe COPD. Resting mPAP was elevated in 32 patients with PH (mPAP = 26.8 ± 5.9 mm Hg) and normal in 10 nonhypertensive patients (mPAP = 16.8 ± 2 mm Hg). Exercise capacity was evaluated by maximum oxygen uptake during exercise and was significantly lower in PH patients (785 ± 244 mL/min) than in nonhypertensive patients (1052 ± 207 mL/min, P = .004). Similar findings were found by Sims et al,²⁹ who evaluated 362 patients with severe COPD being evaluated for lung transplantation with both 6-minute walk test and right heart catheterization. They documented a decrease in 6-minute walk test of 11 m for every 5-mm Hg rise in mPAP. In contrast, a smaller study by Pynnaert et al³⁰ did not demonstrate a correlation between PH and exercise parameters in COPD, with respiratory exhaustion being the key variable.

The traditional “blue bloater” phenotype, in contrast with the “pink puffer,” has traditionally been associated with cor pulmonale. A recent analysis from the Multi-Ethnic Study of Atherosclerosis (MESA)³¹ investigating COPD surprisingly found lower right ventricular end-diastolic volumes (RVEDV) with no change in right ventricular mass in COPD patients compared with controls. The findings may have been mediated partly by more emphysema rather than chronic bronchitis in the population, perhaps reflecting a shift in the presentation of COPD in the United States. Indeed, a greater percentage of emphysema and presence of centrilobular and paraseptal emphysema were associated with lower RVEDV. Possible mechanisms for this lack of overt cor pulmonale (termed parvus cor pulmonale by the MESA authors) in these patients include decreased venous return as a result of lung hyperinflation and compression of the inferior vena cava. Alternatively, the decreased RVEDV may be a reflection of right ventricular diastolic dysfunction accompanying concentric hypertrophy, akin to the small left ventricular volume often seen in aortic stenosis³² with marked left ventricular hypertrophy.

The treatment of cor pulmonale in COPD is geared to addressing hypoxia when arterial PO₂ is below 60 mm Hg and treating the underlying inflammatory process that may exacerbate arterial thickening and PH. Loop diuretics are appropriate when edema develops. Attention needs to be paid to potential acid-base alterations. The associated contraction alkalosis with loop diuretics may be beneficial to counteract the respiratory acidosis caused by carbon dioxide retention in COPD, but may lead to significant alkalosis if the patient is ventilated with correction of the carbon dioxide retention.

Small studies have evaluated the role of specific PH treatments such as the phosphodiesterase-5 inhibitor sildenafil^33,34,35 and the endothelin receptor antagonist bosentan.^36,37 A meta-analysis demonstrated significant increases in exercise capacity and reductions in pulmonary pressures with these targeted therapies, but hypoxemia and quality of life were not affected.²⁵

Sleep Apnea and Obesity Hypoventilation Syndrome

OSA and central sleep apnea have been associated with cor pulmonale. OSA is common and underdiagnosed, with moderate-to-severe OSA affecting up to 10% of the adult population in the United States.³⁸ Abnormalities in right ventricular function, decreased strain and ejection fraction, increased dyssynchrony,³⁹ right ventricular dilatation, hypertrophy of the interventricular septum, and reduced tissue Doppler–determined systolic and diastolic velocities⁴⁰ have been documented in patients with OSA. Importantly, improvements in all these parameters have been observed with treatment of the OSA with continuous positive airway pressure during sleep.⁴¹

Although OSA is characterized by hypoventilation during sleep and is associated with obesity, morbid obesity is associated by alveolar hypoventilation during both sleep and wakefulness as a result of the obesity hypoventilation syndrome, previously termed the Pickwickian syndrome (named after the character in the Charles Dickins novel The Pickwick Papers). The disorder involves a complex interaction between impaired respiratory mechanics, decreased ventilatory drive, and OSA and is associated with significant mortality and morbidity. Continuous positive airway pressure treatment and bariatric surgery are the mainstays of therapy.

Sarcoidosis

Sarcoidosis is a disease characterized by the presence of noncaseating granulomas in multiple organs, with the lungs being most commonly affected. Overt cardiac involvement, clinically manifest with heart failure, conduction system disease, and arrhythmias is relatively uncommon, and autopsy data suggest cardiac involvement in up to a quarter of cases.⁴² The right ventricle may be affected both directly with sarcoidosis and indirectly as a result of lung involvement. Right ventricular function by free wall longitudinal strain was found to be abnormal in over half of patients with pulmonary sarcoidosis,⁴³ with PH being a common finding. Overt cor pulmonale, however, is uncommon. Therapy of sarcoidosis is mainly anti-inflammatory with steroids.

Cor Pulmonale in Interstitial Lung Disease Including Pulmonary Fibrosis

Interstitial lung disease, also known as diffuse parenchymal lung disease, is a heterogeneous group of lung diseases affecting the interstitium of the lung and is characterized by a restrictive pattern on pulmonary testing. Interstitial lung disease may be associated with inhaled substances such as asbestos or beryllium, hypersensitivity pneumonitis, drugs, or connective tissue diseases, as well as idiopathic presentations. In idiopathic pulmonary fibrosis (IPF), typical radiographic (basal and pleural-based fibrosis with honeycombing) and pathologic (temporally and spatially heterogeneous fibrosis findings) findings accompany an often progressive clinical course. PH is found in a third of patients with severe IPF and is associated with worse prognosis.⁴⁴ There is no specific treatment for PH in IPF, with oxygen therapy being the mainstay of therapy. Recently both pirfenidone, a small-molecule anti-inflammatory drug, and nintedanib, a tyrosine kinase inhibitor, were approved for treatment of IPF. Although a rare disease, IPF is now the leading cause for lung transplantation.⁴⁵ A trial (Randomized Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF [ARTEMIS]) using the endothelin-1 antagonist ambrisentan for IPF, including a subset with PH (ARTEMIS-PH), was halted prematurely⁴⁶ because of an increase in disease progression. An increase in ventilation/perfusion mismatch may be the underlying cause for the adverse effects of ambrisentan.

Right ventricular dysfunction is common in patients with lung diseases, but overt cor pulmonale is relatively uncommon. Therapy (Table 76–2) is mostly aimed at the underlying lung disease with oxygen therapy when arterial oxygen is below 60 mm Hg. Diuretic therapy is indicated in volume overload. The role of specific PH therapies remains inadequately studied and should be used judiciously with attention to possible ventilation/perfusion mismatch and increasing hypoxemia.