Abstract
Background:
Growth hormone-releasing hormone receptor agonists (GHRH-A) stimulate cardiac repair following myocardial infarction (MI) through the activation of the GHRH signaling pathway within the heart. We tested the hypothesis that the administration of GHRH-A prevents ventricular remodeling in a swine sub-acute MI model.
Methods:
Twelve female Yorkshire swine (25-30 Kg) underwent transient occlusion of the LAD coronary artery (MI). Two-weeks post-MI, swine were randomized to receive injections of either 30 μg/Kg GHRH-A (MR-409) (GHRH-A group; n=6) or vehicle (placebo group; n=6). Cardiac MRI, pressure volume loops and measures of endothelial function were obtained at multiple time points. Infarct-, border- and remote- (non-infarcted) zones were assessed by immunohistochemistry for the growth hormone-releasing hormone receptor (GHRHR).
Results:
Four-weeks of GHRH-A treatment resulted in reduced scar mass (GHRH-A group: –21.9±6.42%; p=0.02; placebo group: 10.9±5.88%; p=0.25; Two-way ANOVA; p=0.003), and reduced scar size (percent of left ventricle mass) (GHRH-A group: –38.38±4.63; p=0.0002; placebo group: –14.56± 6.92; p=0.16; Two-way ANOVA; p=0.02). Moreover, peripheral endothelial function was significantly increased compared to baseline values in the GHRH-A group (paired t-test; p=0.006) but not in the placebo group (p=0.99). Unlike in rats, this reduced infarct size in swine was not accompanied by improved cardiac function as measured by serial hemodynamic pressure-volume analysis. GHRH receptors were abundant in cardiac tissue, with a greater density in the border zone of the GHRH-A group compared to the placebo group. These data support the concept of direct post-infarction activation of cardiac signal transduction, and of enhancing this activation with systemic treatment by GHRH.
Conclusions:
Daily subcutaneous administration of GHRH-A is feasible and safe in female swine. Furthermore, GHRH-A therapy significantly reduced infarct size and increased endothelial function, suggesting that a local activation of the GHRH pathway leads to the regenerative process and preservation of peripheral endothelial function.