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 sildenafil33,34,35 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 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.