Dataset Information

Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil.

ABSTRACT:

Background

Electrocardiographic (ECG) markers of antiarrhythmic drug (AAD) activity could be used to optimize efficacy and minimize toxicity. Vectorcardiographic global electrical heterogeneity (GEH) is associated with ventricular arrhythmias and sudden death, but it is unclear how GEH measurements change in response to AADs.

Objective

The purpose of this study was to characterize acute effects of AADs on GEH measurements.

Methods

We analyzed double-blind placebo-controlled trial data from healthy volunteers given 1 dose of placebo, dofetilide, quinidine, ranolazine, or verapamil on subsequent visits. Serial ECGs and plasma drug concentrations were collected. Vectorcardiographic GEH parameters (spatial ventricular gradient [SVG], spatial QRST angle, sum absolute QRST integral, and SVG-QRS peak angle) were measured. Placebo-corrected change from baseline was regressed on drug concentration stratified by sex using linear mixed effects models.

Results

Among 22 persons (11 (50%) male median age 27 ± 5 years), 5232 ECGs were analyzed. Dofetilide and quinidine were associated with significant changes in more GEH parameters (5) compared with verapamil (2) and ranolazine (1). The most notable change occurred in SVG azimuth, with largest changes (degrees per unit normalized drug concentration) in dofetilide (6.1; 95% confidence interval [CI] 4.2-8.0) and quinidine (9.4; 95% CI 6.7-12.0), and smaller effects in verapamil (4.4; 95% CI 2.9-5.9) and ranolazine (5.4; 95% CI 3.5-7.3). AAD-induced GEH changes significantly differed in men and women.

Conclusion

AADs change GEH measurements. These changes, which differ by sex, are likely driven by alterations in ion channel function and dispersion of depolarization or repolarization. GEH measurement may allow early assessment of favorable or adverse AAD effects.

SUBMITTER: Stabenau HF

PROVIDER: S-EPMC7056537 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil.

Stabenau Hans Friedrich HF Shen Changyu C Tereshchenko Larisa G LG Waks Jonathan W JW

Heart rhythm 20190917 3

<h4>Background</h4>Electrocardiographic (ECG) markers of antiarrhythmic drug (AAD) activity could be used to optimize efficacy and minimize toxicity. Vectorcardiographic global electrical heterogeneity (GEH) is associated with ventricular arrhythmias and sudden death, but it is unclear how GEH measurements change in response to AADs.<h4>Objective</h4>The purpose of this study was to characterize acute effects of AADs on GEH measurements.<h4>Methods</h4>We analyzed double-blind placebo-controlled ...[more]

PMID: 31539628

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Project description:Background:In silico modeling could soon become a mainstream method of pro-arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. Here, we directly compare changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between in silico populations of human ventricular cell models and ex vivo human ventricular trabeculae. Methods and Results:Ex vivo recordings from human ventricular trabeculae in control conditions were used to develop populations of in silico human ventricular cell models that integrated intra- and inter-individual variability in action potential (AP) biomarker values. Models were based on the O'Hara-Rudy ventricular cardiomyocyte model, but integrated experimental AP variability through variation in underlying ionic conductances. Changes to AP duration, triangulation and early after-depolarization occurrence from application of the four drugs at multiple concentrations and pacing frequencies were compared between simulations and experiments. To assess the impact of variability in IC50 measurements, and the effects of including state-dependent drug binding dynamics, each drug simulation was repeated with two different IC50 datasets, and with both the original O'Hara-Rudy hERG model and a recently published state-dependent model of hERG and hERG block. For the selective hERG blockers dofetilide and sotalol, simulation predictions of AP prolongation and repolarization abnormality occurrence showed overall good agreement with experiments. However, for multichannel blockers quinidine and verapamil, simulations were not in agreement with experiments across all IC50 datasets and IKr block models tested. Quinidine simulations resulted in overprolonged APs and high incidence of repolarization abnormalities, which were not observed in experiments. Verapamil simulations showed substantial AP prolongation while experiments showed mild AP shortening. Conclusions: Results for dofetilide and sotalol show good agreement between experiments and simulations for selective compounds, however lack of agreement from simulations of quinidine and verapamil suggest further work is needed to understand the more complex electrophysiological effects of these multichannel blocking drugs.

Project description:BackgroundGlobal electrical heterogeneity (GEH) is associated with sudden cardiac death in the general population. Its utility in patients with systolic heart failure who are candidates for primary prevention (PP) implantable cardioverter-defibrillators (ICDs) is unclear.ObjectiveThe purpose of this study was to investigate whether GEH is associated with sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies in patients with heart failure and PP ICDs.MethodsWe conducted a multicenter retrospective cohort study. GEH was measured by spatial ventricular gradient (SVG) direction (azimuth and elevation) and magnitude, QRS-T angle, and sum absolute QRST integral on preimplant 12-lead electrocardiograms. Survival analysis using cause-specific hazard functions compared the strength of associations with 2 competing outcomes: sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies and all-cause death without appropriate ICD therapies.ResultsWe analyzed 2668 patients (mean age 63 ± 12 years; 624 (23%) female; 78% white; 43% nonischemic cardiomyopathy; left ventricular ejection fraction 28% ± 11% from 6 academic medical centers). After adjustment for demographic, clinical, device, and traditional electrocardiographic characteristics, SVG elevation (hazard ratio [HR] per 1SD 1.14; 95% confidence interval [CI] 1.04-1.25; P = .004), SVG azimuth (HR per 1SD 1.12; 95% CI 1.01-1.24; P = .039), SVG magnitude (HR per 1SD 0.75; 95% CI 0.66-0.85; P < .0001), and QRS-T angle (HR per 1SD 1.21; 95% CI 1.08-1.36; P = .001) were associated with appropriate ICD therapies. Sum absolute QRST integral had different associations in infarct-related cardiomyopathy (HR 1.29; 95% CI 1.04-1.60) and nonischemic cardiomyopathy (HR 0.78; 95% CI 0.62-0.96) (Pinteraction = .022).ConclusionIn patients with PP ICDs, GEH is independently associated with appropriate ICD therapies. The SVG vector points in distinctly different directions in patients with 2 competing outcomes.

Dataset Information

Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil.

Background

Objective

Methods

Results

Conclusion

Publications

Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil.

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