Dataset Information

Voltage/Calcium Uncoupling Underlies Sustained Torsade de Pointes Ventricular Tachyarrhythmia in an Experimental Model of Long QT Syndrome.

ABSTRACT:

Background

Clinical experience showed that the majority of Torsade de Pointes (TdP) ventricular tachyarrhythmia (VT) in patients with long QT syndrome (LQTS) are self-terminating (ST), but the few that are non-self-terminating (NST) are potentially fatal. A paramount issue in clinical arrhythmology is to understand the electrophysiological mechanism of ST vs. NST TdP VT.

Methods

We investigated the electrophysiological mechanism of ST vs. NST TdP VT in the guinea pig Anthopleurin-A experimental model of LQTS, a close surrogate model of congenital LQT3. We utilized simultaneous optical recordings of membrane voltage (V _m ) and intracellular calcium (Ca _i ) and a robust analytical method based on spatiotemporal entropy difference (E _d ) to investigate the hypothesis that early V _m /Ca _i uncoupling during TdP VT can play a primary role in perpetuation of VT episodes.

Results

We analyzed a total of 35 episodes of TdP VT from 14 guinea pig surrogate models of LQTS, including 23 ST and 12 NST VTs. E _d values for NST VT were significantly higher than E _d values for ST VT. Analysis of wave front topology during the early phase of ST VT showed the Ca _i wave front following closely V _m wave front consistent with a lower degree of E _d . In contrast, NST VT was associated with uncoupling of V _m /Ca _i wave fronts during the first 2 or 3 cycles of VT associated with early wave break propagation pattern.

Conclusions

Utilizing a robust analytical method we showed that, in comparison to ST TdP VT, NST VT was consistently predated by early uncoupling of V _m /Ca _i that destabilized wave front propagation and can explain a sustained complex reentrant excitation pattern.

SUBMITTER: Himel HD

PROVIDER: S-EPMC7876465 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Voltage/Calcium Uncoupling Underlies Sustained Torsade de Pointes Ventricular Tachyarrhythmia in an Experimental Model of Long QT Syndrome.

Himel Herman D HD Cupelli Michael M Boutjdir Mohamed M El-Sherif Nabil N

Frontiers in physiology 20210128

<h4>Background</h4>Clinical experience showed that the majority of Torsade de Pointes (TdP) ventricular tachyarrhythmia (VT) in patients with long QT syndrome (LQTS) are self-terminating (ST), but the few that are non-self-terminating (NST) are potentially fatal. A paramount issue in clinical arrhythmology is to understand the electrophysiological mechanism of ST vs. NST TdP VT.<h4>Methods</h4>We investigated the electrophysiological mechanism of ST vs. NST TdP VT in the guinea pig Anthopleurin- ...[more]

PMID: 33584347

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Project description:BackgroundDrug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known.MethodsWe tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration.ResultsThe genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81; P=0.02), 23% in response to quinidine (r=0.48; 95% confidence interval, -0.03 to 0.79; P=0.06), and 27% in response to ranolazine (r=0.52; 95% confidence interval, 0.05-0.80; P=0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2=12%, P=1×10-7).ConclusionsWe demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950.

Dataset Information

Voltage/Calcium Uncoupling Underlies Sustained Torsade de Pointes Ventricular Tachyarrhythmia in an Experimental Model of Long QT Syndrome.

Background

Methods

Results

Conclusions

Publications

Voltage/Calcium Uncoupling Underlies Sustained Torsade de Pointes Ventricular Tachyarrhythmia in an Experimental Model of Long QT Syndrome.

Similar Datasets

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