Spatially discordant alternans and arrhythmias in tachypacing-induced cardiac myopathy in transgenic LQT1 rabbits: The importance of IKsand Ca2+ cycling

Emily Lau, Konstantinos Kossidas, Tae Yun Kim, Yukiko Kunitomo, Ohad Ziv, Song Zhen, Chantel Taylor, Lorraine Schofield, Joe Yammine, Gongxin Liu, Xuwen Peng, Zhilin Qu, Gideon Koren, Bum Rak Choi

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Abstract

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 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 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.

Original languageEnglish (US)
Article numbere0122754
JournalPloS one
Volume10
Issue number5
DOIs
StatePublished - May 13 2015

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Lau, E., Kossidas, K., Kim, T. Y., Kunitomo, Y., Ziv, O., Zhen, S., Taylor, C., Schofield, L., Yammine, J., Liu, G., Peng, X., Qu, Z., Koren, G., & Choi, B. R. (2015). Spatially discordant alternans and arrhythmias in tachypacing-induced cardiac myopathy in transgenic LQT1 rabbits: The importance of IKsand Ca2+ cycling. PloS one, 10(5), [e0122754]. https://doi.org/10.1371/journal.pone.0122754