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

Abstract

BackgroundRemodeling 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 I ks remodeling in VF susceptibility using a tachypacing HF model of transgenic rabbits with Long QT Type 1 (LQT1) syndrome.Methods and ResultsLQT1 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.ConclusionsCompared 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.

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

“…KCNQ1-KCNE1 complexes generate the I Ks current that helps to repolarize ventricular cardiomyocytes. I Ks is down-regulated in heart failure, which is suggested to contribute to increased risk of ventricular fibrillation in heart failure (50). It is fascinating, then, that cilantro extract was recently found to improve left ventricular function in heart failure (51).…”

Alternans in atria: Mechanisms and clinical relevance

“…Also, electrical restitution is determined by inactivation and recovery thereof of different ion channels (Na + , LCCs, slow rectifier K + channels and others), each of which has individual properties and kinetics and consequently experimentally measured restitution curves rarely follow a simple mathematical function [48]. Furthermore, APD restitution curves may also be poor predictors of alternans occurrence because AP morphology is strongly influenced by intracellular Ca 2+ dynamics [18,49,50], and Ca 2+ alternans can be initiated independently of V m alternans [17,51] (see discussion below). While the question whether V m → [Ca 2+ ] i or [Ca 2+ ] i →V m coupling plays a leading role in the initiation of alternans is still debatable, there is little doubts that V m → [Ca 2+ ] i coupling is critical for development and sustainability of atrial alternans.…”

“…Additional support for Ca 2+ -dependent development of discordant alternans comes from computational models, demonstrating that discordant APD alternans can be induced if [Ca 2+ ] i →V m coupling results in APD shortening [107] or, alternatively, by SR Ca 2+ accumulation during rapid pacing [108]. Furthermore, suppression of intracellular Ca 2+ release from SR by ryanodine significantly reduces development of spatially discordant alternans during tachypacing induced cardiomyopathy in transgenic rabbits with Long QT type-1 syndrome [49]. The aforementioned insights come from ventricular tissue, however experimental evidence that heterogeneity in Ca 2+ cycling underlies generation of discordant alternans also in atria is still lacking.…”

Turing Bifurcation and Pattern Formation of Stochastic Reaction-Diffusion System

“…and , in the Appendix. Using the Fredholm solubility condition again, we can obtain And then we substitute system (28) and (33) into (24) to simplify [32]; we obtain the expressions of the coefficients of 0 , , and in the Appendix. And…”

“…A stochastic version of the Brusselator model is proposed and studied via the system size expansion [20] and the mesoscopic equations governing the dynamics were derived and used to special models [21]. Many studies have been presented in these research areas [22][23][24][25][26][27][28], as practice shows that theory on Turing bifurcation and pattern formation in dynamical system was rarely studied.…”