Cor pulmonale is a common heart disease, which is closely associated with chronic obstructive pulmonary disease (COPD) and the most common cardiac complication in the natural history of COPD. Cor pulmonale has emerged, in recent years, as a leading cause of disability, and death with COPD is becoming increasingly prevalent. The term “cor pulmonale” is generally used to describe the form of right heart dysfunction and hypertrophy.
It is a progressive condition with initial compensatory right ventricular (RV) dysfunction and is becoming overwhelmed by increased RV systolic requirements, while left ventricular function remains relatively preserved. As COPD primarily affects the right side of the heart and leads to cor pulmonale, it was supposed that myostatin levels might be associated with RV dysfunction in cor pulmonale in COPD. Therefore, the present study aimed to determine the potential relationship between circulating myostatin concentrations and RV dysfunction in advanced COPD by measuring plasma myostatin levels in this population. The study also analyzed plasma levels of B-type natriuretic peptide (BNP) as a comparison of myostatin because BNP is established as a biomarker of RV dysfunction in chronic lung disease.
This study was a cross-sectional registry study conducted at a teaching hospital which was affiliated to Guangzhou Medical University. The study protocol was approved by the Ethics Committee of Guangzhou Medical University. Each participant provided a signed informed consent form before recruitment. The study recruited 81 patients with COPD and 40 controls.
All patients were recruited prospectively in the outpatient department of the Guangzhou Institute of Respiratory Disease in the hospital between October 2012 and December 2014. The patients were kept under care in outpatient clinics specialized in respiratory medicine at the time of inclusion in the study. The inclusion criteria were as follows: (1) age > 50 years, (2) clinically and spirometrically confirmed COPD based on the GOLD Guidelines, (3) in GOLD stage III or IV, (4) clinically stable for at least 8 weeks at the time of enrollment, and (5) nonsmokers or ex-smokers who had abstained smoking for at least 3 years.
Pulmonary Function Tests
All participants underwent spirometry and reversibility testing with the inhalation of a short-acting β2-agonist of salbutamol (400 μg). The main parameters of spirometry included forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), ratio of FEV1/FVC, and FEV1 percentage of the predicted value (FEV1%pred) after bronchodilator administration.
Characteristics of Study Subjects
Eighty-one patients with COPD were compared with a group of 40 controls who were determined to be healthy based on clinical, spirometric, biochemical, and imaging investigations. Age was matched among the groups; however, there were significant differences in body mass index (BMI) between the patients and controls though they were recruited by cluster sampling. Among the patients with COPD, spirometry tests identified 29 (35.8%) patients in GOLD stage III and 52 (64.2%) in stage IV, with their mean FEV1 of 35.3% pred and 22.8% pred, respectively. All the patients recruited in this study were on inhaled corticosteroids + long-term bronchodilators (ICS+LABA), with some patients combined on tiotropium bromide. Chi-square test showed that there was no difference in the medication between the patients with or without cor pulmonale.
The present study revealed three main findings. First, plasma myostatin levels were higher in patients with COPD and much higher in those who had cor pulmonale, when compared with controls. Second, plasma myostatin levels were correlated with functional and morphological parameters of the right heart in advanced COPD. Finally, myostatin levels were strongly correlated with indexes for RV dysfunction and hypertrophy compared with BNP levels in advanced COPD, based on the correlation coefficients. The present study was the first to investigate the association between plasma myostatin levels and echocardiographic parameters of the right heart in patients with stable COPD.
One of the key findings in the present study was that myostatin levels increased remarkably in the 39 patients with COPD who had cor pulmonale compared with controls, and the levels were also significantly higher compared with patients who did not have cor pulmonale. This finding was similar to the changes reported in other studies that focused on the left heart failure. Gruson et al reported the elevated plasma myostatin levels in patients with chronic congestive heart failure compared with controls. Also, George et al found that plasma myostatin levels significantly increased in patients with heart failure, although the heart failure was caused by ischemic heart disease or dilated cardiomyopathy.
A further finding of this study was that plasma myostatin levels were significantly correlated with important echocardiographic parameters for RV function (TAPSE values and RVMPI) in COPD patients. The results indicated that the elevated levels of circulating myostatin might be associated with RV dysfunction in advanced COPD. Myostatin, a regulator of skeletal muscle mass, is well known to be mainly expressed in skeletal muscles, while it is also expressed in the myocardium.
Collectively, the finding of this study emphasized the elevated plasma BNP level to be a useful marker for RV stress. Interestingly, a positive correlation between BNP and myostatin levels was found in the COPD group. It is reasonable and predictable to have a positive correlation between plasma BNP and myostatin levels. However, correlation coefficients revealed that BNP levels were not as strongly correlated to RV function as myostatin levels; furthermore, regression analysis revealed that two of the important RV functional parameters (TAPSE and RVMPI) correlated significantly with myostatin levels but not with BNP levels. This is worth noticing because BNP is considered as a biomarker of RV dysfunction associated with chronic lung disease. In addition, no significant correlation was found between BNP levels and RV geometry in the present study. Therefore, this study indicates that, in comparison with BNP, myostatin might be a stronger indicator for cor pulmonale in advanced COPD.
In summary, the present study has shown that plasma myostatin levels are remarkably increased in COPD patients who had cor pulmonale and correlated with RV function and geometry in advanced COPD. In comparison with plasma BNP, myostatin levels had a stronger correlation with the severity of RV dysfunction. These findings suggest that myostatin might be superior to BNP in the early diagnosis of cor pulmonale in COPD.