Dataset Information

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

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 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.

SUBMITTER: Lau E

PROVIDER: S-EPMC4430457 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

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

Lau Emily E Kossidas Konstantinos K Kim Tae Yun TY Kunitomo Yukiko Y Ziv Ohad O Song Zhen Z Taylor Chantel C Schofield Lorraine L Yammine Joe J Liu Gongxin G Peng Xuwen X Qu Zhilin Z Koren Gideon G Choi Bum-Rak BR

PloS one 20150513 5

<h4>Background</h4>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.<h4>Methods and results</h4>LQT1 and littermate control (LMC) rabbits underwent three weeks of tachypacing to induce cardiac myopathy (TICM). In vivo tel ...[more]

PMID: 25970695

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Project description:AimsLong QT syndrome 1 (LQT1) mutations in KCNQ1 that decrease cardiac IKs (slowly activating delayed rectifier K(+) current) underlie ventricular arrhythmias and sudden death. LQT1 mutations may suppress IKs by preventing KCNQ1 assembly, disrupting surface trafficking, or inhibiting gating. We investigated mechanisms underlying how three LQT1 mutations in KCNQ1 C-terminus assembly domain (R555H/G589D/L619M) decrease IKs in heterologous cells and cardiomyocytes.Methods and resultsIn Chinese hamster ovary (CHO) cells, mutant KCNQ1 + KCNE1 channels either produced no currents (G589D/L619M) or displayed markedly reduced IKs with a right-shifted voltage-dependence of activation (R555H). When co-expressed with wild-type (wt) KCNQ1, the mutant KCNQ1s displayed varying intrinsic dominant-negative capacities that were affected by auxiliary KCNE1. All three mutant KCNQ1s assembled with wt KCNQ1 as determined by fluorescence resonance energy transfer (FRET). We developed an optical quantum dot labelling assay to measure channel surface density. G589D/R555H displayed substantial reductions in surface density, which were either partially (G589D) or fully (R555H) rescued by wt KCNQ1. Unexpectedly, L619M showed no trafficking defect. In adult rat cardiomyocytes, adenovirus-expressed homotetrameric G589D/L619M + KCNE1 channels yielded no currents, whereas R555H + KCNE1 produced diminished IKs with a right-shifted voltage-dependence of activation, mimicking observations in CHO cells. In contrast to heterologous cells, homotetrameric R555H channels showed no trafficking defect in cardiomyocytes.ConclusionDistinct LQT1 mutations in KCNQ1 assembly domain decrease IKs using unique combinations of biophysical and trafficking mechanisms. Functional deficits in IKs observed in heterologous cells are mostly, but not completely, recapitulated in adult rat cardiomyocytes. A 'methodological chain' combining approaches in heterologous cells and cardiomyocytes provides mechanistic insights that may help advance personalized therapy for LQT1 mutations.

Project description:Background Ventricular tachyarrhythmias are often preceded by short sequences of premature ventricular complexes. In a previous study, a restitution-based computational model predicted which sequences of stimulated premature complexes were most likely to induce ventricular fibrillation in canines in vivo. However, the underlying mechanism, based on discordant-alternans dynamics, could not be verified in that study. The current study seeks to elucidate the mechanism by determining whether the spatiotemporal evolution of action potentials and initiation of ventricular fibrillation in in vitro experiments are consistent with model predictions. Methods and Results Optical mapping voltage signals from canine right-ventricular tissue (n=9) were obtained simultaneously from the entire epicardium and endocardium during and after premature stimulus sequences. Model predictions of action potential propagation along a 1-dimensional cable were developed using action potential duration versus diastolic interval data. The model predicted sign-change patterns in action potential duration and diastolic interval spatial gradients with posterior probabilities of 91.1%, and 82.1%, respectively. The model predicted conduction block with 64% sensitivity and 100% specificity. A generalized estimating equation logistic-regression approach showed that model-prediction effects were significant for both conduction block ( P<1×10-15, coefficient 44.36) and sustained ventricular fibrillation ( P=0.0046, coefficient, 1.63) events. Conclusions The observed sign-change patterns favored discordant alternans, and the model successfully identified sequences of premature stimuli that induced conduction block. This suggests that the relatively simple discordant-alternans-based process that led to block in the model may often be responsible for ventricular fibrillation onset when preceded by premature beats. These observations may aid in developing improved methods for anticipating block and ventricular fibrillation.

Project description:Rationale: Discordant alternans, a phenomenon in which the action potential duration (APDs) and/or intracellular calcium transient durations (CaDs) in different spatial regions of cardiac tissue are out of phase, present a dynamical instability for complex spatial dispersion that can be associated with long-QT syndrome (LQTS) and the initiation of reentrant arrhythmias. Because the use of numerical simulations to investigate arrhythmic effects, such as acquired LQTS by drugs is beginning to be studied by the FDA, it is crucial to validate mathematical models that may be used during this process. Objective: In this study, we characterized with high spatio-temporal resolution the development of discordant alternans patterns in transmembrane voltage (Vm) and intracellular calcium concentration ([Cai]+2) as a function of pacing period in rabbit hearts. Then we compared the dynamics to that of the latest state-of-the-art model for ventricular action potentials and calcium transients to better understand the underlying mechanisms of discordant alternans and compared the experimental data to the mathematical models representing Vm and [Cai]+2 dynamics. Methods and Results: We performed simultaneous dual optical mapping imaging of Vm and [Cai]+2 in Langendorff-perfused rabbit hearts with higher spatial resolutions compared with previous studies. The rabbit hearts developed discordant alternans through decreased pacing period protocols and we quantified the presence of multiple nodal points along the direction of wave propagation, both in APD and CaD, and compared these findings with results from theoretical models. In experiments, the nodal lines of CaD alternans have a steeper slope than those of APD alternans, but not as steep as predicted by numerical simulations in rabbit models. We further quantified several additional discrepancies between models and experiments. Conclusions: Alternans in CaD have nodal lines that are about an order of magnitude steeper compared to those of APD alternans. Current action potential models lack the necessary coupling between voltage and calcium compared to experiments and fail to reproduce some key dynamics such as, voltage amplitude alternans, smooth development of calcium alternans in time, conduction velocity and the steepness of the nodal lines of APD and CaD.

Dataset Information

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

Background

Methods and results

Conclusions

Publications

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

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