Heart-directed expression of junction and triadin causes catecholamine-induced ventricular tachycardias, shortening of cardiac action potentials and prolonged calcium transients

摘要

Catecholaminergic ventricular tachycardias (CVT) have been associated with mutations in the genes coding for the cardiac ryanodine receptor or calsequestrin. In vivo, the ryanodine receptor and calsequestrin form a quarternary protein complex with junctin (JCN) and triadin (TRD). We investigated the electrophysiological function of these proteins in mice with heart-directed expression of JCN (1.5-fold), TRD (3.5-fold), or both proteins (JCNxTRD).Telemetric ECG recordings showed repetitive incessant ventricular tachycardias (VT) in unrestrained mice during and after defined stress tests. Orciprenaline (l.7muM) provoked similar VT episodes in isolated, Langendorff-perfused hearts. Orciprenaline excessively shortened right and left ventricular monophasic action potentials in JCNxTRD mice (33+-2ms in JCNxTRD, p<0.05 vs. WT (36+-2ms)). Action potentials were even shorter in JCNxTRD hearts with VT (APD90: 30+-2 ms, p<0.05 vs. JCNxTRD without VT (40+-2 ms)). Left ventricular contractility was normal, while relaxation times and E/A ratios showed signs of slight diastolic dysfunction. Calcium transients were prolonged in INDO-loaded ventricular myocytes isolated from JCNxTRD mice during orciprenaline superfusion. Calcium transient amplitude remained normal.