Spatially Discordant Alternans and Arrhythmias in Tachypacing-Induced Cardiac Myopathy in Transgenic LQT1 Rabbits: The Importance of IKs and Ca2+ Cycling

Background Remodeling of cardiac repolarizing currents, such as the downregulation of slowly activating K+ channels (I-Ks), could underlie ventricular fibrillation (VF) in heart failure (HF). We evaluated the role of I-Ks remodeling in VF susceptibility using a tachypacing HF model of transgenic rabbits with Long QT Type 1 (LQT1) syndrome. Methods and Results LQT1 and littermate control (LMC) rabbits underwent three weeks of tachypacing to induce cardiac myopathy (TICM). In vivo telemetry demonstrated steepening of the QT/RR slope in LQT1 with TICM (LQT1-TICM; pre: 0.26 +/- 0.04, post: 0.52 +/- 0.01, P<0.05). In vivo electrophysiology showed that LQT1-TICM had higher incidence of VF than LMC-TICM (6 of 11 vs. 3 of 11, respectively). Optical mapping revealed larger APD dispersion (16 +/- 4 vs. 38 +/- 6 ms, p<0.05) and steep APD restitution in LQT1-TICM compared to LQT1-sham (0.53 +/- 0.12 vs. 1.17 +/- 0.13, p<0.05). LQT1-TICM developed spatially discordant alternans (DA), which caused conduction block and higher-frequency VF (15 +/- 1 Hz in LQT1-TICM vs. 13 +/- 1 Hz in LMC-TICM, p<0.05). Ca2+ DA was highly dynamic and preceded voltage DA in LQT1-TICM. Ryanodine abolished DA in 5 out of 8 LQT1-TICM rabbits, demonstrating the importance of Ca2+ in complex DA formation. Computer simulations suggested that HF remodeling caused Ca2+-driven alternans, which was further potentiated in LQT1-TICM due to the lack of I-Ks. Conclusions Compared with LMC-TICM, LQT1-TICM rabbits exhibit steepened APD restitution and complex DA modulated by Ca2+. Our results strongly support the contention that the down-regulation of I-Ks in HF increases Ca2+ dependent alternans and thereby the risk of VF.