Abstract 4358648: Prokaryotic Voltage-Gated Sodium Channel (BacNav) Gene Therapy Restores Contractile and Electrical Function in a Rat Model of Chronic Ischemia-Reperfusion Heart Failure

Abstract

Introduction: Following infarction, heart often undergoes pathological remodeling and dysregulation of sodium and calcium homeostasis, predisposing patients to heart failure and arrhythmias. While current pharmacological therapies can slow disease progression, they are not aimed to directly address deficits in both cardiac contraction and action potential conduction. Previously, we have demonstrated that AAV-mediated gene therapy with the prokaryotic voltage-gated sodium channel (BacNav) can restore cardiac electrical and mechanical function in a setting of pressure-overload heart failure. Hypothesis: We hypothesized that AAV-BacNav gene therapy could rescue contractile and electrical dysfunction in a clinically relevant setting of chronic post-myocardial infarction. Method: 8-to-10-week-old male rats underwent a 45-min left anterior descending artery ligation followed by reperfusion. Two weeks after the ischemia/reperfusion surgery, we delivered a total of 1E12 viral genomes of either myo2A-cTnT-BacNav-HA-mScarlet (BacNav group) or myo2A-cTnT-mScarlet (mock group) via direct injection around the scar area in the left ventricle (a total of 200uL, split into 6-8 sites) (n=3 for BacNav group, n=5 for mock group). Cardiac contractile and electrical function was non-invasively monitored over the following four weeks using echocardiography and electrocardiography, respectively, followed by ex vivo epicardial voltage mapping in Langendorff-perfused hearts. Results: At 2 weeks post-surgery, all rats exhibited left ventricular ejection fraction (LVEF) reduction (BacNav: 46.45+/-3.81%; mock: 50.92+/-2.50%). The LVEF continued to deteriorate in the mock group during the following 4 weeks, while in the BacNav group it significantly improved (BacNav: 54.71+/-3.26%; mock: 42.66+/-3.34%). While both groups exhibited rare incidences of spontaneous arrhythmias in ECG, the BacNav group had reduced cardiac axis deviation (BacNav: 37.53-69.18°; mock: -152.14-135.54°). Ex vivo epicardial voltage mapping to test for arrhythmia vulnerability revealed spontaneous reentry in 100% of mock group hearts, compared to only 33.3% in the BacNav group. Conclusion: AAV-BacNav therapy significantly improved both contractile and electrical function in a rat model of ischemia-reperfusion heart failure, providing foundation for the future translational studies.