Cor pulmonale: an overview

Chronic cor pulmonale involves the enlargement of the right ventricle as a result of pulmonary hypertension due to pulmonary disorders involving the lung parenchyma, bellows function, or ventilatory drive. The right ventricular hypertrophy that occurs in chronic cor pulmonale is a direct result of chronic hypoxic pulmonary vasoconstriction and subsequent pulmonary artery hypertension, leading to increased right ventricular work and stress. We discuss methods by which hypoxic vasoconstriction and reduction in the pulmonary vascular bed lead to the development of pulmonary artery hypertension. This article reviews the interaction of the pulmonary vasculature and right ventricle in the non-diseased state as well as during disease exacerbations. Ventricular dependence and its contribution to the pathophysiology of right ventricular failure are also reviewed. In addition, we provide an overview of specific disease states that can result in the development of chronic cor pulmonale including chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep apnea, alveolar hypoventilation disorders, and primary pulmonary hypertension. We also review the current diagnostic studies used to evaluate and study cor pulmonale.     

Pulmonary diseases and heart function

The most severe cardiac sequel to lung disease is the load on the right ventricle due to pulmonary hypertension with the development of a cor pulmonale. This is characterized by hypertrophy and/or dilatation of the right ventricle because of a primary impairment of lung function and/or lung structure. The most important pathomechanisms for the development of pulmonary hypertension are vessel obliteration, mechanical lesions, primary vascular or extra-vascular inflammation and hypoxic vasoconstriction. Chronic obstructive pulmonary disease (COPD) is one of the most important reasons for chronic cor pulmonale. A further very common reason is obstructive sleep apnea syndrome, especially if combined with a COPD. In this case, the prevalence of cor pulmonale can reach 80%. The development of a chronic cor pulmonale is the most striking negative prognostic factor for these patients. Only 30% of COPD patients with cor pulmonale survive longer than 5 years, and only early detection of the disturbances to respiration which might potentially lead to cor pulmonale and their subsequent therapy are able to improve the patient's prognosis. Furthermore, pulmonary diseases may also have an impact on the left heart side in terms of an impairment of left heart function or by inducing severe arrhythmias . Thus, lung diseases may have both a significant impact on right and left heart performance.     

Lungenerkrankungen und Herzfunktion

The most severe cardiac sequel to lung disease is the load on the right ventricle due to pulmonary hypertension with the development of a cor pulmonale. This is characterized by hypertrophy and/or dilatation of the right ventricle because of a primary impairment of lung function and/or lung structure. The most important pathomechanisms for the development of pulmonary hypertension are vessel obliteration, mechanical lesions, primary vascular or extra-vascular inflammation and hypoxic vasoconstriction. Chronic obstructive pulmonary diesease (COPD) is one of the most important reasons for chronic cor pulmonale. A further very common reason is obstructive sleep apnea syndrome, especially if combined with a COPD. In this case, the prevalence of cor pulmonale can reach 80%. The development of a chronic cor pulmonale is the most striking negative prognostic factor for these patients. Only 30% of COPD patients with cor pulmonale survive longer than 5 years, and only early detection of the disturbances to respiration which might potentially lead to cor pulmonale and their subsequent therapy are able to improve the patient’s prognosis. Furthermore, pulmonary diseases may also have an impact on the left heart side in terms of an impairment of left heart function or by inducing severe arrhytmias. Thus, lung diseases may have both a significant impact on right and left heart performance.     

Hypoxia- and non-hypoxia-related pulmonary hypertension - established and new therapies

Pulmonary hypertension can occur as an isolated disease affecting the lung vessels only, in association with underlying hypoxic lung disorders, or due to chronic thromboembolic disease. Pulmonary hypertension caused by pulmonary venous congestion will not be focused on in this review. Regardless of the underlying disease, chronic cor pulmonale is associated with progressive clinical deterioration and a poor prognosis in most cases. The aim of specific therapies for pulmonary hypertension is to reduce pulmonary vascular resistance and thereby improve right ventricular function. Currently, three classes of drugs (prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors) are approved for the treatment of pulmonary arterial hypertension (PAH) in a defined patient population (group I according to the recent WHO classification). However, these medications may also lower pulmonary vascular resistance in patients with associated lung diseases (e.g. chronic obstructive pulmonary disease or lung fibrosis) and significant pulmonary hypertension, for whom these drugs are not yet approved. As non-selective vasodilators may induce gas-exchange disturbances, which preclude their long term use in these patients, such substances should be avoided in the hypoxemic patient. In this article we provide an update of the current understanding of hypoxia- and non-hypoxia-related pulmonary hypertension, addressing both the pathophysiological understanding of different disease aetiologies as well as the therapeutic options currently available.     

Primary pulmonary hypertension and cor pulmonale

Primary pulmonary hypertension and cor pulmonale represent forms of precapillary pulmonary hypertension due to intrinsic lung disease. In the case of primary pulmonary hypertension, this is due to disease of the pulmonary vasculature while cor pulmonale is related to diseases of the pulmonary vasculature, airways, or interstitium. Patients present with signs and symptoms of right ventricular dysfunction and low cardiac output including dyspnea, chest pain and peripheral edema. Therapy is directed at the underlying disease and may include supplemental oxygen for diseases causing chronic hypoxemia and anticoagulation for thrombotic disease. Vasodilator therapy has variable efficacy for pulmonary vascular disorders. Postacyclin by continuous infusion has been a major advance in the therapy of primary pulmonary hypertension and has prolonged survival and delayed the need for lung transplantation. Bosentan, an endothelin receptor blocking agent is the first oral medication approved for the therapy of pulmonary hypertension.     

Pneumococcal Vaccine and Patients with Pulmonary Diseases

Chronic pulmonary diseases are chronic diseases that affect the airways and lung parenchyma. Examples of common chronic pulmonary diseases include asthma, bronchiectasis, chronic obstructive lung disease, lung fibrosis, sarcoidosis, pulmonary hypertension, and cor pulmonale. Pulmonary infection is considered a significant cause of mortality in patients with chronic pulmonary diseases. Streptococcus pneumoniae is the leading isolated bacteria from adult patients with community-acquired pneumonia, the most common pulmonary infection. Vaccination against S. pneumoniae can reduce the risk of mortality, especially from more serious infections in both immunocompetent and immunocompromised patients. Patients with chronic pulmonary diseases who take steroids or immunomodulating therapy (eg, methotrexate, anti-tumor necrosis factor inhibitors), or who have concurrent sickle cell disease or other hemoglobinopathies, primary immunodeficiency disorders, human immunodeficiency virus infection/acquired immunodeficiency syndrome, nephrotic syndrome, and hematologic or solid malignancies should be vaccinated with both 13-valent pneumococcal conjugate vaccine and the pneumococcal polysaccharide vaccine 23-valent.     

Lung function and cardiovascular disease: A link

The relationship between lung and heart diseases has long been recognized, with necropsy studies demonstrating silent myocardial infarctions or coronary artery calcification in patients with advanced emphysema as the death cause. Improvements in non-invasive techniques and epidemiologic approaches established that lung and cardiovascular diseases frequently coexist in mid and late life. Even among those without diagnosed lung disease, lower than expected forced vital capacity, forced expiratory volume in 1 s, and their ratio each portend greater risk of developing cardiovascular risk factors including hypertension, obesity, and metabolic syndrome, and for incident cardiovascular diseases including left heart failure, atrial fibrillation and stroke. Greater longitudinal declines in these spirometric measures are further associated with cardiovascular morbidity and mortality. While obstructive ventilatory patterns are more common, restrictive ventilatory patterns seem to demonstrate an independent and more robust association with cardiovascular diseases such as heart failure. These subclinical alterations in pulmonary function also relate to subclinical abnormalities of cardiac structure and function. Although the biologic pathways linking pulmonary and cardiovascular dysfunction are not clear, chronic systemic inflammation appears to be one important underlying pathophysiologic link. Despite the growing evidence of lung dysfunction as a cardiovascular risk factor, spirometric evaluation is still underutilized in clinical practice, particularly among cardiac patients, and optimal therapeutic and preventive strategies are still unclear. In this review, we address the current knowledge and controversies regarding the links between lung function and cardiovascular disease.     

Chronic obstructive pulmonary disease and the early stage of cor pulmonale: A perspective in treatment with pulmonary arterial hypertension-approved drugs

Cor pulmonale is right ventricular hypertrophy and/or dilation caused by pulmonary hypertension (PH) due to diseases affecting the lung function and structure. Recently, the definition of PH was revised from a mean pulmonary arterial pressure (mPAP) >25 mmHg to an mPAP >20 mmHg based on the Nice statement; this might expedite the detection of cor pulmonale. However, the only treatment for cor pulmonale for the past 3 decades has been to maintain the lung function and oxygen saturation.Chronic obstructive pulmonary disease (COPD) is the leading cause of cor pulmonale. Cor pulmonale in COPD is generally known to occur due to loss of vascular bed and chronic hypoxic pulmonary vasoconstriction (HPV) due to alveolar wall destruction. However, a recent study suggested that in some patients with COPD, the pulmonary vascular alterations include components that are primary lesions of the pulmonary artery. These alterations may be similar to the remodeling that occurs in pulmonary arterial hypertension (PAH). Although, there is no evidence supporting the treatment of COPD patients with PH using drugs approved for PAH, such drugs may be effective in the treatment of a selected group of COPD patients, whose disease includes PAH-like vascular components.To distinguish these patients, it is necessary to understand the histopathology of COPD and renew our understanding of the concept of cor pulmonale, which treats the heart and lung as a single unit. Herein, we review the recent histopathological concepts of COPD with respect to the progression of cor pulmonale.     

Pulmonary hypertension and cor pulmonale in COPD

Pulmonary artery hypertension (PAH) is the primary cardiovascular complication encountered in chronic obstructive pulmonary disease (COPD). Cor pulmonale can range clinically from mild changes in right ventricular function to frank right heart failure. The prevalence of PAH increases as COPD worsens, and the development of PAH and cor pulmonale appears to affect survival of patients with COPD. Potential causes proposed to explain the development of PAH in COPD include gas exchange abnormalities, destruction of the pulmonary vascular bed, alterations in respiratory mechanics, changes in intrinsic pulmonary vessel tone, and increased blood viscosity. Standard clinical evaluation, including history, physical examination, spirometry, electrocardiography, and chest radiography, is generally inadequate in identifying right ventricular dysfunction. Noninvasive techniques, such as echocardiography, radionuclide ventriculography, and magnetic resonance imaging, have largely replaced invasive pulmonary artery catheterization in the initial assessment of cor pulmonale. The goals of therapy consist of attenuation of PAH, enhancement of right ventricular function, alleviation of clinical symptoms, and improvement in survival. The agents that have been most extensively evaluated for these purposes include oxygen, vasodilators, theophylline, and inotropic medications.     

Severe pulmonary hypertension in histiocytosis X

Diminished exercise capacity in advanced pulmonary histiocytosis X does not appear to be related to ventilatory limitation but may be related to pulmonary vascular dysfunction. Pulmonary hemodynamics and respiratory function were studied in 21 consecutive patients with advanced pulmonary histiocytosis X, and compared with parameters of patients with other severe chronic lung diseases (29 patients with chronic obstructive pulmonary disease and 14 patients with idiopathic pulmonary fibrosis). All patients with pulmonary histiocytosis X displayed severe pulmonary hypertension: mean pulmonary arterial pressure, 59 +/- 4 mm Hg; cardiac index, 2.6 +/- 0.8 L/min/m(2); and total vascular pulmonary resistance, 25 +/- 3 IU/m(2) (p < 0.05, as compared with patients with other chronic lung diseases). Pa(O(2)) was similar in the three groups, whereas FEV(1) was lower in patients with other chronic lung diseases (p < 0.05). In contrast to other chronic lung diseases, the degree of pulmonary hypertension was not related to variables of pulmonary function in pulmonary histiocytosis X. Histopathology was available for 12 patients with pulmonary histiocytosis X and revealed proliferative vasculopathy involving muscular arteries and veins, with prominent venular involvement. Two consecutive lung samples (taken before and after the occurrence of pulmonary hypertension) were available for six patients with pulmonary histiocytosis X, and showed that pulmonary vasculopathy worsened, whereas parenchymal and bronchiolar lesions remained relatively unchanged. These results indicate that pulmonary hypertension in pulmonary histiocytosis X might be related to an intrinsic pulmonary vascular disease, in which the pulmonary circulation is involved independent of small airway and lung parenchyma injury.     

Pulmonary hypertension and right ventricular failure. Part IV. Chronic lung disease

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary hypertension, its modern classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. In the forth lecture they present literature data on prevalence of chronic cor pulmonale among patients with congestive heart failure and its value for prognosis. The authors consider peculiarities of pathogenesis of pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD) and interstitial lung diseases. Attention is paid to the fact that chronic cor pulmonale develops mainly in bronchitic type of COPD and rarely is met in patients with emphysematous type of COPD. Pathogenetic mechanisms of right ventricular failure in COPD and the role of interaction of hemodynamic, renal, and neuro-humoral factors in pathogenesis of edematous syndrome in patients with chronic cor pulmonal are presented. The article also contains discussion of possibilities and limitations of clinical and instrumental diagnostics of pulmonary hypertension and right ventricular failure in patients with COPD.     

Pulmonary artery dissection: an emerging cardiovascular complication in surviving patients with chronic pulmonary hypertension

Pulmonary arterial dissection is an extremely rare and usually lethal complication of chronic pulmonary hypertension. The condition usually manifests as cardiogenic shock or sudden death and is therefore typically diagnosed at postmortem examination rather than during life. However, recent isolated reports have described pulmonary artery dissection in surviving patients. The first case of pulmonary artery dissection in a surviving patient with cor pulmonale caused by chronic obstructive pulmonary disease is presented. The aetiology, pathophysiology, and clinical presentation of pulmonary artery dissection are reviewed and factors that may aid diagnosis during life are discussed.     

Cheyne-Stokes respiration as an additional risk factor for pulmonary hypertension in a boy with trisomy 21 and atrioventricular septal defect

Central ventilation disorders(1) and airway obstruction(2) with chronic hypoxemia are causally related to cor pulmonale. Pulmonary vascular resistance is often reversible, and hypoxic pulmonary hypertension often responds to treatment with supplemental oxygen. Oxygen therapy during sleep may be useful as a temporary palliative treatment in children with obstructive sleep apnea syndrome (3) and Cheyne-Stokes respiration (CSR) in congestive heart failure(4). This type of sleep-related breathing disorder is characterized by periodic crescendo-decrescendo alterations in tidal volume. Proposed mechanism include an increased central nervous system sensitivity to changes in arterial PCO2 and PO2, a decrease in total body stores of CO2 and O2 with resulting instability in arterial blood gas tensions in response to changes in ventilation, and an increased circulatory time. Clinical features of obstructive and central sleep-related breathing disorders include daytime somnolence, unusual breathing patterns, failure to thrive, and cyanosis masquerading as cyanotic congenital heart disease(2). Down syndrome is often associated with cardiac malformations, left to right shunt, and the development of pulmonary hypertension(5). However, this may be exacerbated by sleep-related breathing disorders, as illustrated in the following case report.     

The effects of long term methyldopa in patients with hypoxic cor pulmonale

Methyldopa (alpha-methyldopa) was given to patients with cor pulmonale secondary to chronic obstructive airways disease (COAD) to determine its effect on pulmonary haemodynamics. Twenty-five patients were randomly allocated to methyldopa (750 mg daily) or placebo. Pulmonary haemodynamics were measured twice, 12 months apart. Conventional therapies were continued unchanged. The effects of the drug on pulmonary haemodynamics were inconclusive when considered overall, but total pulmonary vascular resistance (TPVR) fell in all patients on active therapy in whom measurements were obtained both at rest and upon exercise. Only one patient in the placebo group achieved this. Over the trial period there was one death in the active but five in the placebo group. Survival was unrelated to abnormalities in pulmonary haemodynamics at the commencement of the trial in this study although the numbers of patients was small. Postural hypotension developed in patients receiving methyldopa and limited the dose that could be administered. The problems involved in long term trials of vasodilators in hypoxic cor pulmonale are discussed.     

Pulmonary arterial hypertension and chronic obstructive bronchopneumopathy

Sooner or later, chronic obstructive lung disease becomes complicated with pulmonary arterial hypertension, largely responsible for chronic cor pulmonale. Its principal cause is an increase in pulmonary resistance due to chronic hypoxia. There is no non-invasive method that can be used to measure pulmonary arterial pressure (PAP) with accuracy. In the course of chronic obstructive lung disease PAP increases slowly, by about 0.5 to 0.6 mmHg per year. As mortality factor, it is the second major variable after FEV1. The usefulness of specific vasodilators has not yet been demonstrated.     

Should patients have cardiac catheterization prior to long-term oxygen treatment?

Pulmonary arterial pressure predicts survival in patients with hypoxic chronic obstructive pulmonary disease as does the presence of cor pulmonale. Thus, cardiac catheterization has been performed prior to treatment for long-term oxygen therapy (LTOT) in order to 1) assess the suitability of patients for LTOT, 2) predict survival in patients receiving LTOT and 3) for research in cor pulmonale. In this review I will submit the evidence which suggests that these indications for measurement of pulmonary haemodynamics are not justified, and measurements of arterial blood gas values and assessment of airflow limitation are all that is necessary prior to LTOT.     

醛固酮与慢性肺源性心脏病肺动脉高压的相关性研究

目的 探讨血浆醛固酮与慢性肺源性心脏病肺动脉高压的关系。方法 选择90例慢性阻塞性肺病（COPD）患者分为COPD合并肺动脉高压组（n=30）、慢性肺源性心脏病肺心功能代偿期组（n=30）、慢性肺源性心脏病肺心功能失代偿期组（n=30）,采用放射免疫分析法测定3组患者的血醛固酮水平、多普勒超声检测肺动脉压力。结果 慢性肺源性心脏病肺心功能失代偿组血浆醛固酮浓度为（124.78±27.64）pg/ml,显著高于COPD合并肺动脉高压组（79.91±20.76）pg/ml及慢性肺源性心脏病肺心功能代偿期组（83.56±28.45）pg/ml,P〈0.05;血浆醛固酮浓度与肺动脉高压呈线性正相关（r=0.514,P〈0.05）,与血氧分压呈负相关（r=-0.248,P=0.019）。结论 醛固酮参与慢性肺源性心脏病患者肺动脉高压的发展。     

OP-1206, a prostaglandin E1 derivative. Effects of oral administration to patients with chronic lung disease

In order to assess the clinical effectiveness of an oral prostaglandin E1 derivative, OP-1206, five patients with chronic obstructive pulmonary disease and two with pulmonary fibrosis were studied from the standpoint of hemodynamics and nine others with chronic lung disease from the standpoint of respiratory function. Oral intake of OP-1206 resulted in a significant decrease in the pulmonary arterial pressure (p less than 0.01), total pulmonary vascular resistance (p less than 0.01), pulmonary arteriole resistance (p less than 0.01), and total systemic vascular resistance (p less than 0.05), and an increase in the cardiac index (p less than 0.05) and oxygen delivery (p less than 0.01) with insignificant changes of PaCO2, PaO2 and pH. There was no clinical improvement of lung function after OP-1206 intake. OP-1206 is a potent vasodilator, improving cardiac performance in patients with chronic lung disease and possibly preventing the progress of cor pulmonale in this kind of patient.     

Hemodynamic effect of hydralazine in advanced, stable chronic obstructive pulmonary disease with cor pulmonale. Immediate and short-term evaluation at rest and during exercise

Hydralazine was administered to eight patients (mean age, 69 +/- 2 years) who had stable, advanced chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (mean pulmonary arterial pressure, 31 +/- 3 mm Hg), and cor pulmonale. All of the patients were studied at rest and during exercise. After intravenous administration of hydralazine at rest, there were statistically significant increases in pulmonary arterial pressure (p less than 0.05), cardiac index (p less than 0.005), arterial oxygen saturation (p less than 0.01), and mixed venous saturation (SvO2) (p less than 0.005). Pulmonary vascular resistance did not change, and systemic resistance decreased (p less than 0.005). During exercise, pulmonary arterial pressure increased in all patients, and this increase was not blunted by hydralazine; however, cardiac index (p less than 0.005), arterial oxygen pressure (p less than 0.005), and SvO2 (p less than 0.001) increased further during exercise. The increase in pulmonary vascular resistance was significantly blunted by hydralazine (p less than 0.005). Therapy with the drug was continued orally in seven patients because one patient showed a deleterious response in pulmonary hemodynamics. After seven days of oral hydralazine, pulmonary arterial pressure and pulmonary vascular resistance were not statistically different from control. There were statistically significant increases in cardiac index (p less than 0.005) and SvO2 (p less than 0.05), systemic resistance decreased (p less than 0.01). The same condition was found during exercise; however, only two patients showed pulmonary gas exchange and pulmonary hemodynamic benefit at rest and during exercise with hydralazine therapy. Our results suggest that it is unlikely that vasodilator therapy with hydralazine will be useful in patients with advanced stable COPD and cor pulmonale who seem to have fixed pulmonary vascular disease.     

Current clinical aspects of cor pulmonale

Two main types of cor pulmonale have been distinguished. In asphyxial cor pulmonale the cardiac disorder is consequent upon respiratory failure. Hypervolemia and polycythemia determine the high venous pressure, and fluid retention follows the development of hypercapnia. The cardiac output remains high, pulmonary hypertension follows and augments but does not initiate heart failure.

In obliterative cor pulmonale, heart failure follows obstruction of the pulmonary vascular bed and pulmonary hypertension. The cardiac output falls, but the blood gases may be normal. Sometimes hypocapnia results from hyperventilation and slight hypoxemia from shunts within the lung or across a patent foramen ovale.

Principles of management have been outlined in the light of the pathophysiology of the various etiologic types of cor pulmonale.