Katz M. G., Eliyahu E. , Gubara S. M., Bridges C. R., Fargnoli A. S., Fuster V.
Mount Sinai School of Medicine;
Purpose Progress in molecular biology has led to the development of multiple gene constructs, which have the potential to greatly improve the surgical treatment of ischemic heart failure. Our molecular cardiac surgery method with gene delivery provides intimate access to the myocardium via complete cardiac isolation during cardio-pulmonary bypass, leveraging high concentration of vector and favorable perfusion gradients. We hypothesized that gene overexpression effects would be retained at 6 months post-myocardial infarction. The purpose of the study was to evaluate cardiac function pre and post gene therapy in a long term large animal MI model, validate robust, cardiac-specific expression profile via molecular biology assays, and demonstrate how superior delivery kinetics result in long term myocardial salvage in ischemic heart failure. Methods Eighteen ovine subjects were induced with myocardial infarction following baseline magnetic resonance tomography and were divided into two groups: control (n=9) and treated (n=9) with a gene construct including adeno-associated virus and calcium handling protein. Functional assessments were performed at 3 months and at 6 months thereafter. Molecular biology assays for genome copy transduction was performed post mortem normalized to non-treated controls. Statistical assessment was done based on the Anova and Tukey comparison tests. Results Cardiac function was in the same range at baseline and 1-month post-myocardial infarction. After gene therapy, however, the gene group versus control demonstrated superior retention of ejection fraction at 3 months [14±2 vs. -21±2%, p<0.01] and at 6 months [16±3 vs. -24±3%, p<0.001]. Treated animals also scored higher systolic stroke volume index [39±2 vs. 11±2 ml/m], improved geometry [1.8±0.06 vs. 1.0±0.03], and enhanced border zone contractility [24±4 vs. 5±2], all p<0.001. Infarct size was the same for both groups. Polymerase chain reaction revealed significant cardiac-specific expression in the heart vs. liver [69379±48828 vs. 6485±4629 genome copies per 100 nanograms DNA] in the majority of cardiac regions. Myocyte specific calcium handling protein was found 2.5 times more overexpressed in treated versus the control group (p<0.01). Apoptosis assay revealed significantly reduced the onset of programmed death in the border zone of myocardial infarction. Conclusions This study demonstrates that gene therapy is safe and efficacious with no toxic effect on organ systems. Our new cardiac circulatory system with gene transfer leads to markedly improved left ventricular dysfunction and arrests ventricular remodeling. We believe that cardiac gene delivery could be clinically applicable for patients with ischemic heart failure who would normally undergo cardiac operations for coronary revascularization or other reasons, and patients in whom percutaneous coronary intervention is contraindicated.
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