Abstract 18729: cBIN1 Gene Therapy Improves Recovery of Peri-Infarction Muscle in a Canine Model of Chronic Ischemic Heart Failure

Abstract

BACKGROUND: Heart failure (HF) due to ischemic dilated cardiomyopathy (IDCM) is a major cause of morbidity and mortality. In failing hearts, loss of T-tubule microdomains is central to impaired calcium transients and loss of cardiac function. Cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein that organizes T-tubule microdomains, is transcriptionally reduced in failing hearts. Hypothesis: cBIN1 gene therapy will improve cardiac function in ischemic cardiomyopathy. AIM: Evaluate the effectiveness of catheter-based delivery of cBIN1 gene therapy in preserving bipolar voltage (an assay of muscle health) and LVEF in a canine model of IDCM. Methods: Nine healthy adult mongrel dogs (30±3 kg) underwent LAD ligation, developing IDCM and HFrEF (LVEF < 40% and NT-proBNP >900 pmol/L) over 3-4 months. Animals received a single treatment at 20 sites by intramyocardial injection of either AAV9-GFP (control, n=3) or AAV9-cBIN1 (n=6) using a MyoStar catheter-mediated subendocardial injection. Low voltage LV regions were quantified as percent of total endocardial area with bipolar voltage <1.5 mV on the day of the treatment (pre-therapy) and the terminal study (5-10 weeks post-therapy). Results: In control-treated dogs, low voltage areas did not change significantly (19.5±3.4 vs. 28.7±9.8%, p=0.143, Figure A ), whereas in the cBIN1-treated cohort, the low voltage areas surrounding infarction zones decreased significantly (18.9±10.9 vs. 13.4±9.1%, p=0.038, Figure B ). Control therapy was associated with an additional 9.2% loss LV myocardium, whereas cBIN1 therapy caused a 6.5% recovery of myocardium (p=0.024, Figure C ). Post-therapy week 5, LVEF decreased in control animals (36±2 vs. 29±3%, p<0.001) yet improved in the cBIN1-treated animals (37±2 vs. 41±3%, P=0.003). CONCLUSION: Intramyocardial injection of cBIN1 gene therapy can halt and reverse expansion of peri-infarction low voltage areas and improve LVEF in a preclinical IDCM model of chronic HF.