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Expression of the Growth Hormone Secretagogue Receptor and Ghrelin in Human Heart Failure

The following abstract was presented as part of London Health Research Day 2017.

Research Areas: Circulatory; Prevention of diseases and health conditions and promotion of well-being
First Author: Rebecca Sullivan
Supervisor(s): Dr. Savita Dhanvantari

The leading cause of mortality in Canada is heart disease (HD), which impacts nearly 1.6 million people, with over 500,000 affected by heart failure (HF). HF is a specific condition that occurs when the heart is unable to provide adequate blood flow and oxygen to organs across the body. Current prognosis for HF is poor as the current biomarkers used to detect HF are in the circulation, not specifically in cardiac tissue. A novel biomarker of interest is the growth hormone secretagogue receptor-1a (GHSR-1a) and its ligand ghrelin. Both ghrelin and GHS-R1a are present in cardiomyocytes and may have therapeutic potential in chronic HF. Our group has developed a fluorescent analog of ghrelin, Cy5ghrelin(1-18), which incorporates the first 18 amino acids of ghrelin attached to the Cy5 fluorescent probe. We have previously shown that this analog specifically binds to GHSR-1a in cardiac tissue in situ and can be used to detect changes in GHSR-1a during cardiomyocyte differentiation. My study is focused on characterizing GHS-R1a, ghrelin and other biomarker levels in human cardiac tissue and correlating corresponding levels to the stage of HF.

I expect GHS-R1a, BNP and fibrosis expression levels to increase in end stage heart failure.

Materials and Methods:
Samples of cardiac tissue were obtained from the cardiology unit of London Health Sciences Center (LHSC) including cardiac transplant patients (n=10) with samples obtained from the explanted heart and biopsies of the healthy heart at various weeks post-transplant. GHSR-1a levels were measured using Cy5-ghrelin(1-18) and ghrelin and natriuretic peptide Type B (BNP), a known biomarker of HF, were measured using fluorescent antibodies. Quantitative fluorescence microscopy was used to test for the levels of ghrelin, GHS-R1a and BNP using NIS Elements Software (Nikon) and image analyses was conducted using ImageJ FIJI version 1.46h with set parameters. Fibrosis, a biomarker of HF that measures the presence of fibrotic tissue, was measured using Masson’s trichrome stain and quantified using ImageJ FIJI with an online script. Levels of ghrelin, GHS-R1a, BNP and fibrosis of the explanted heart were compared to the healthy biopsies using two-tailed t-test, two-way ANOVA and Tukey’s test, where significance was set at p<0.05. These levels will then be correlated to the clinical data for each patient (obtained from LHSC). This information will lead to the establishment of clinical parameters for classification of HF severity.

Overall there was an increase in GHS-R1a and fibrosis levels in tissue samples from explanted hearts when compared to the healthy implanted heart biopsies. Ghrelin and BNP expression levels were slightly elevated in end stage HF. Within individual patients there were significant differences in GHS-R1a levels between the explanted heart and healthy heart biopsies where GHS-R1a was significantly elevated in end stage HF.

Discussion and Conclusions:
GHSR-1a’s elevated expression levels in the explanted heart biopsies indicate the potential of GHS-R1a as a cardiac specific biomarker for HF. While fibrosis and BNP, clinically established markers of HF, did show elevation in end stage HF patients, GHS-R1a expression levels showed a more drastic change in expression. Ultimately the establishment of GHS-R1a as a cardiac specific biomarker can greatly impact the diagnosis of HF and will help with individual or personalized medicine.