Abstract 21353: Ccn5 Gene Therapy Suppresses Arrhythmias by Reversing Fibrosis in Mice With Chronic Angiotensin II Infusion

Background: Increased angiotensin II (ANG) levels elicit profibrotic effects which promote ventricular tachyarrhythmias (VT). Hypothesis: Gene delivery of the matricellular protein CCN5 ameliorates ANG related VT by reversing fibrosis. Methods: 8-10 wk old mice underwent ANG infusion (3mg/Kg/d) for 2wk after which they received 5E11 drp AAV9.CCN5 (ANGII+CCN5, n=8) or empty vector (ANGII, n=8) and were maintained for another 2wk. Optical mapping was performed in hearts that were challenged with right atrial (RA) burst trains (20Hz, 5-20 sec) to determine VT propensity. Fibrosis was assessed using trichrome staining. Results: VT was induced in 6/8 ANG, 2/8 ANG+CCN5, and 1/3 control hearts. A total of 34 trains elicited 13 VT episodes (38.4% rate) in ANG whereas 150 trains yielded only 6 episodes in ANG+CCN5 (4.0%). ANG increased the transepicardial APD gradient by causing selective APD prolongation on the RV side which was partially reversed by CCN5. No differences in the APD gradient were found between VT ...