Key result
Transgenic LQT1 rabbits with tachypacing-induced cardiomyopathy exhibited a higher incidence of ventricular fibrillation (6 of 11 vs 3 of 11) and higher-frequency VF compared to littermate controls.
Absolute Event Rate: 54.5% vs 27.3%
Downregulation of IKs in a heart failure model increases Ca2+-dependent spatially discordant alternans and the risk of ventricular fibrillation.
May signal elevated VF risk in LQT1 cardiomyopathy; leaves open human translation.
BACKGROUND: Remodeling of cardiac repolarizing currents, such as the downregulation of slowly activating K+ channels (IKs), could underlie ventricular fibrillation (VF) in heart failure (HF). We evaluated the role of Iks 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 IKs. 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 IKs in HF increases Ca2+ dependent alternans and thereby the risk of VF.
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Lau et al. (2015) studied Tachypacing-induced cardiomyopathy (Heart Failure) (n=34). Tachypacing-induced cardiomyopathy in LQT1 rabbits vs. Tachypacing-induced cardiomyopathy in littermate control (LMC) rabbits was evaluated on Incidence of ventricular fibrillation (VF) during in vivo electrophysiology. Transgenic LQT1 rabbits with tachypacing-induced cardiomyopathy exhibited a higher incidence of ventricular fibrillation (6 of 11 vs 3 of 11) and higher-frequency VF compared to littermate controls.
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