Abstract
Background: Structural & electromechanical remodeling promotes the incidence of ventricular tachycardia (VT) during progression from compensated hypertrophy to heart failure. The multifactorial nature of VT during disease progression presents a major challenge for conventional anti-arrhythmic approaches. Objective: To determine the safety & efficacy of the antifibrotic matricellular protein CCN5 and a novel combinatorial vector carrying CCN5 and SERCA2a (CCN5/S2a) for prevention of VT. Methods: Adult mice (N=15) underwent chronic ANG infusion (3mg/kg/d) for 2 wk. Mice were subsequently randomized for treatment with AAV9 vectors carrying CCN5, CCN5/S2a, or an empty vector and were maintained for another 2 wk. Age matched mice served as controls (Ctrl). Cardiac function was serially assessed by echocardiography. Optical mapping was performed in perfused hearts before & after challenge with isoproterenol and rapid pacing. VT threshold (VT-t) was defined as the pacing frequency required for induction of sustained VT. Results: ANG infusion resulted in a biphasic change in fractional shortening (FS) consistent with an early phase of compensated hypertrophy followed by decompensation. Late decompensation was associated with adverse electrophysiological (EP) remodeling, including action potential prolongation (21.3±2.4ms in ANG vs 17.5±1.9ms in Ctrl), conduction slowing (0.43±0.04m/s in ANG vs 0.57±0.08m/s in Ctrl) and susceptibility for pacing induced VT (VT-t 21.3±1.2Hz in ANG vs 25.8±1.4Hz in Ctrl). At a cut-off frequency of 22Hz, 5/5 ANG vs 0/7 Ctrl heart were prone to VT. Treatment of ANG mice with CCN5 and the combinatorial CCN5/S2a vector suppressed VT susceptibility by increasing VT-t (25.9±2.9Hz for CCN5, 28.4±2.6Hz for CCN5/S2a). Mechanistically, CCN5/S2a delivery reversed EP and structural remodeling, which in turn prevented the formation of the critical lines of block that maintained VT circuits. In addition, CCN5/S2a fully abrogated the late decrease in FS. Conclusion: Delivery of a combinatorial AAV9 vector carrying CCN5/S2a during the early phase of compensated hypertrophy prevents the progression of electrical and structural remodeling, thereby suppressing the incidence of VT while preserving mechanical function.
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