Regional Differences in the Ghrelin-Growth Hormone Secretagogue Receptor Signalling System in Human Heart Disease

The hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR) are expressed in the myocardium, and GHSR binding activates signalling pathways that are coupled to cardiomyocyte survival and contractility. These biological properties have made the ghrelin-GHSR axis an attractive candidate as a biomarker for cardiac function, particularly during the progression of heart disease. The dynamics of ghrelin and GHSR are altered significantly in the later stages of heart failure and cardiomyopathy, when left ventricular function is failing. In this study, we examined the relationship of GHSR with ghrelin in cardiac tissue from patients with valvular disease with no detectable changes in left ventricular function. Biopsy samples from the left ventricle (LV) and right atrium (RA) were obtained from 25 patients with valvular disease (of whom 13 also had coronary artery disease) and preserved left ventricular ejection fraction, and compared to control samples that were obtained via autopsy. Using quantitative confocal fluorescence microscopy, levels of GHSR were determined using a fluorescent peptide analog of ghrelin, Cy5-ghrelin(1-19); ghrelin, the heart failure marker natriuretic peptide type-b (BNP), and contractility marker sarcoplasmic reticulum ATPase pump (SERCA2a) were measured by immunofluorescence. A positive correlation between GHSR and ghrelin was apparent in diseased tissue, but not in control tissue. Ghrelin and BNP significantly correlated in the LV and strongly co-localized to the same intracellular compartment in ventricular cardiomyocytes in both diseased and control tissue. GHSR, ghrelin and BNP all strongly and significantly correlated with SERCA2a in the LV, and there were no significant correlations in control tissue. Our results suggest that the dynamics of the myocardial ghrelin/GHSR axis is altered in cardiovascular disease in the absence of measurable changes in heart function, and may be accompanied by a regional shift in endocrine programming.