Researchers Suggest Possible Biomarker for Diabetic Cardiomyopathy

Alterations in the myocardial ghrelin-GHSR1a system may predict diabetic cardiomyopathy (DCM), according to a study recently published in the Journal of the Endocrine Society.

Researchers led by Savita Dhanvantari, PhD, of the Lawson Health Research Institute in London, Ontario point out that DCM is characterized by progressive cardiac dysfunction, and that the early stages of DCM represent a latent subclinical phase marked by diastolic dysfunction, oxidative stress, derangements in Ca²⁺ homeostasis, and altered substrate utilization, resulting in myocardial lipotoxicity.

The authors go on to write that ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are new molecules of interest that may track the progression of heart disease and the cardiomyopathy of diabetes, and they hypothesized that GHSR1a could also be a biomarker for DCM.

The researchers used streptozotocin (STZ) to induce DCM in two sets of mice: the first group comprised adult mice treated with 35 mg/kg STZ for three days and the second group comprised neonatal mice treated with double that amount at days 2 and 5 after birth. Group one showed mild fasting hyperglycemia eight weeks after the last injection. Group two showed severe fasting hyperglycemia one to three weeks after the last injection. “In group [one], left ventricular function was slightly impaired as measured by echocardiography, and Western blot analysis showed a significant decrease in myocardial GHSR1a,” the authors write. “In group [two], GHSR1a levels were also decreased as assessed by Cy5-ghrelin(1–19) fluorescence microscopy, and there was a significant negative correlation between GHSR1a levels and glucose tolerance.”

The researchers saw significant positive correlations between GHSR1a and ghrelin and between GHSR1a and sarcoplasmic reticulum (SR) Ca²⁺-ATPase 2a (SERCA2a), a marker for contractility, but not between GHSR1a and B-type natriuretic peptide, a marker for heart failure. “The strong positive correlation suggests that GHSR1a activation by ghrelin may function to regulate cardiomyocyte contractility through control of Ca²⁺ flux from the SR,” the authors write.

The authors note that ghrelin may be a possible biomarker in heart failure. “Our results seem to indicate that cardiac tissue levels of ghrelin, together with GHSR1a, may be more appropriate markers of early cardiac dysfunction and may indicate changes in intracellular Ca²⁺homeostasis in cardiomyocytes,” the authors write.

They go on to cite a study involving tissue biopsies from 12 patients with chronic heart failure that showed that both immunoreactive GHSR1a and GHSR1 mRNA levels were dramatically increased in patients with end-stage heart failure. “Therefore,” the authors conclude, “it appears that myocardial GHSR1a levels are altered differently in early-onset DCM and in end-stage heart failure. We are currently investigating a role for cardiac ghrelin and GHSR1a as an integrated system biomarker for the onset of DCM and heart failure.