Abstract 5327: Opposing Influences Of Serca2a Gene Transfer Upon Catecholamine-induced Ventricular Arrhythmias In Normal And Failing Hearts
Sarcoplasmic Reticulum (SR) calcium levels may influence ventricular arrhythmogenesis during catecholamine stimulation. The role of SR Calcium-ATPase 2a (SERCA2a) in modulating isoproterenol (ISO)-induced arrhythmia was evaluated in normal and failing intact hearts. SERCA2a gene transfer was achieved via direct myocardial injection of 3.75×109 Ad.SERCA2a.GFP particles into the normal rat heart (N+SERCA) and the chronically infarcted failing rat heart (HF+SERCA) characterised by reduced SERCA2a levels and increased SR calcium leak. Ad.GFP gene transfer into normal, failing and sham ligated animals plus unoperated cases served as controls (N+GFP, HF+GFP, SHAM+GFP and UNOP). In vivo ventricular arrhythmia (VA) generation was recorded after intraperitoneal ISO injection using ECG telemetry transmitters. HF cases were studied at baseline (HF) and post gene transfer. Hearts were explanted and ventricular arrhythmia thresholds studied ex vivo during perfusion with 100nM ISO. In normal hearts heterogeneous SERCA2a overexpression increased the number of ISO-induced sustained VAs: N+SERCA 3.0 (1.4), N+GFP 0.25 (0.16), UNOP 1.13 (0.44) p<0.05, without changing the total ISO-induced VAs: (log values) N+SERCA 0.90 (0.13), N+GFP 1.16 (0.21), UNOP 1.00 (0.16) p=ns. In contrast restoring normal SERCA2a levels by gene transfer in the failing hearts reduced the total number of ISO-induced VAs in vivo: (log values) SHAM+GFP 1.2 (0.2), HF 2.0 (0.1), HF+SERCA 1.6 (0.2), HF+GFP 2.2 (0.2) p<0.05. SERCA2a also completely protected against ISO-induced ventricular tachycardia (VT) in HF cases in vivo (cases VT/total): Sham 0/8, HF 13/18, HF+SERCA 0/8, HF+GFP 5/8 p<0.01. Ex vivo studies demonstrated similar patterns with increased ISO-induced VT in normal hearts after SERCA2a gene transfer (N+SERCA 5/10 vs UNOP 0/10 and N+GFP 1/10), whereas SERCA2a gene transfer to the failing heart demonstrated a protective trend against ISO-induced VT (VT episodes: HF+SERCA 1.25 (0.45), HF+GFP 3.71 (1.97), SHAM+GFP 0.57 (0.43). SERCA2a gene transfer influences ISO-induced ventricular arrhythmogenesis in the intact heart. Overexpression in the normal heart is proarrhythmic, whereas SERCA2a gene transfer to restore SERCA2a levels in the failing heart is antiarrhythmic.