Abstract 4372164: cBIN1 Gene Therapy Delivered Intramyocardially in Left Ventricle Attenuates Right Ventricular Structural Remodeling in a Canine Model of Dilated Ischemic Cardiomyopathy

Abstract

Introduction: Myocardial infarction is a common cause of heart failure (HF), leading to scar tissue formation and increased stress on the cardiac muscle, which affects atrial and ventricular remodeling. We recently showed that gene therapy targeting cardiac bridging integrator 1 (cBIN1) improves left ventricular (LV) function by restoring T-tubule integrity in a canine model of dilated ischemic cardiomyopathy (DICM). However, it is still unclear how this improvement impacts the right ventricular (RV) structural remodeling. Hypothesis: cBIN1 gene therapy delivered intramyocardially in the LV improves RV structural remodeling in a canine model of DICM. Methods: A preclinical canine model of DICM was created by ligating the left anterior descending artery, resulting in a left ventricular ejection fraction < 40% and NT-proBNP level > 900 pmol/L. Ten weeks (±2) post-procedure, dogs were divided into three groups: Group 1 (n=3) received no therapy; Group 2 (n=4) received intramyocardial injections of AAV9 carrying Green Fluorescent Protein (negative control); and Group 3 (n=5) received AAV9-cBIN1. Eight weeks (±2) later, RV mechanical dyssynchrony (septal-free wall peak strain time difference) and RV free wall strain were assessed through echocardiography in awake dogs using a 4-chamber apical view. RV free wall muscle samples were analyzed for T-tubule cross-sectional area using electron microscopy and fibrosis via Masson Trichrome staining. Results: cBIN1-treated animals exhibited significantly improved RV septal-free wall peak strain time difference often refers as septal-to-lateral wall delay - SLWD ( Figure A ) and RV free wall strain - FWS ( Figure B ) compared to the other HF groups that received either the control GFP therapy or no treatment. At both the tissue and subcellular levels, there was a significant improvement in RVFW fibrosis ( Figure C ) and T-tubule cross-sectional area ( Figure D ) in the cBIN1 group compared to the GFP-treated and untreated animals. Furthermore, there were no observable differences between the untreated and GFP-treated HF groups. Conclusions: Reducing mechanical stress across the LV segments through intramyocardial delivery of cBIN1 gene therapy significantly decreased fibrosis in the RVFW muscle by restoring the T-tubule membrane architecture, which in turn improved RV strain and reduced electromechanical dyssynchrony. The study provides preclinical data to mitigate negative remodeling of the RV following ischemic events.