Abstract Background Ischemic cardiomyopathy and resultant heart failure (HF) is a significant cause of morbidity and mortality worldwide.Downregulation of cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein responsible for organizing t-tubules and organizing the calcium handing apparatus, occurs in progressive HF.Therefore, gene therapy upregulating cBIN1 production may rescue failing muscle and clinical HF.
Methods Adult mongrel dogs underwent ligation of the left anterior descending artery and developed progressive dilated cardiomyopathy and chronic HF.When left ventricular ejection fraction (LVEF) dropped below 40%, the animals received a one-time series of endocardial injections of either of low dose gene therapy composed of either adeno-associated virus serotype 9 packaged cBIN1 (AAV9-cBIN1, n = 6) or AAV9-GFP (green fluorescent protein, n = 4).Animals were followed up to 7 weeks after therapy delivery with laboratory, echocardiography, and endocardial mapping assessment.
Results Post injection of the negative control, animals develop progressive symptomatic HF requiring early termination of all but one animal prior to the end of the study.In contrast, the AAV9-cBIN1-treated group reveals a significant improvement in LV function, with a noticeable improvement in LVEF (29 ± 3% vs.
Enhanced Perception for Autonomous Vehicles at Obstructed Intersections: An Implementation of Vehicle to Infrastructure (V2I) Collaboration
.42 ± 2%, p = 0.
0095) and global longitudinal strain (−7.1 ± 0.9% vs.
−12.
Comparison of circulating metabolite concentrations in dogs and cats when allowed to freely choose macronutrient intake
.5 ± 1.6%, p = 0.
0095).Compared to the control animals, the AAV9-cBIN1-treated group displays improved T-tubule morphology, left ventricular chamber size, plasma biomarkers, and endocardial voltage, and survives the study period.Conclusions Chronic HF from ischemic cardiomyopathy can be successfully treated with low dose AAV9-cBIN1 gene therapy.
This study indicates that myocardial specific therapy can dramatically reverse HF progression