Spatially discordant alternans and arrhythmias in tachypacing-induced cardiac myopathy in transgenic LQT1 rabbits: The importance of I_Ksand 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 Hzin 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 downregulation of I_Ks in HF increases Ca²⁺ dependent alternans and thereby the risk of VF.