A Phase II

Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients

Abstract 214: Reduction of Scar Tissue after GHRH-A Treatment in a Swine Model of Sub-acute Ischemic Cardiomyopathy

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

Abstract 18122: Reduction of Scar Tissue after GHRH-Agonist Treatment in a Swine Model of Sub-acute Ischemic Cardiomyopathy

Introduction: Growth hormone-releasing hormone receptor agonists (GHRH-A) stimulate cardiac repair following myocardial infarction (MI) in rats through the activation of the GHRH signaling pathway within the heart. Hypothesis: 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 for growth hormone-releasing hormone receptor (GHRHR) by immunohistochemistry. Results: Four-weeks of GHRH-A treatment resulted in reduced scar mass (GHRH-A: –21.9±6.42%; p=0.02; placebo: 10.9±5.88%; p=0.25; Two-way ANOVA; p=0.003..