Adrenergic stimulation promotes T-wave alternans and arrhythmia inducibility in a TNF- genetic mouse model of congestive heart failure

Shusterman V, McTiernan CF, Goldberg A, Saba S, Salama G, London B. Adrenergic stimulation promotes T-wave alternans and arrhythmia inducibility in a TNFgenetic mouse model of congestive heart failure. Am J Physiol Heart Circ Physiol 298: H440–H450, 2010. First published November 25, 2009; doi:10.1152/ajpheart.01024.2008.— T-wave alternans (TWA) is a proarrhythmic repolarization instability that is common in congestive heart failure (CHF). Although transgenic mice are commonly used to study the mechanisms of arrhythmogenesis in CHF, little is known about the dynamics of TWA in these species. We hypothesized that TWA is present in a TNFmodel of CHF and can be further promoted by adrenergic stimulation. We studied 16 TNFmice and 12 FVB controls using 1) in vivo intracardiac electrophysiological testing and 2) ambulatory telemetry during 30 min before and after an intraperitoneal injection of isoproterenol. TWA was examined using both linear and nonlinear filtering applied in the time domain. In addition, changes in the mean amplitude of the T wave and area under the T wave were computed. During intracardiac electrophysiological testing, none of the animals had TWA or inducible arrhythmias before the injection of isoproterenol. After the injection, sustained TWA and inducible ventricular tachyarrhythmias were observed in TNFmice but not in FVB mice. In ambulatory telemetry, before the isoproterenol injection, the cardiac cycle length (CL) was longer in TNFmice than in FVB mice (98 9 and 88 3 ms, P 0.04). After the injection of isoproterenol, the CL became 8% and 6% shorter in TNFand FVB mice (P 10 ); however, the 2% difference between the groups in the magnitude of CL changes was not significant. In TNFmice, the magnitude of TWA was 1.5–2 times greater than in FVB mice both before and after the isoproterenol injection. The magnitude of TWA increased significantly after the isoproterenol injection compared with the baseline in TNFmice (P 0.003) but not in FVB mice. The mean amplitude of the T wave and area under the T wave increased 60% and 80% in FVB mice (P 0.006 and 0.009) but not in TNFmice. In conclusion, TWA is present in a TNFmodel of CHF and can be further promoted by adrenergic stimulation, along with the enhanced susceptibility for ventricular arrhythmias.