Dataset Information

Electrocardiographic Predictors of Torsadogenic Risk During Dofetilide or Sotalol Initiation: Utility of a Novel T Wave Analysis Program.

ABSTRACT: Initiation of class III anti-arrhythmic medications requires telemetric monitoring for ventricular arrhythmias and QT prolongation to reduce the risk of torsades de pointes (TdP). Heart rate-corrected QT interval (QTc) is an indicator of risk, however it is imperfect, and subtle abnormalities of repolarization have been linked with arrhythmogenesis.Identification of electrocardiographic predictors of torsadogenic risk through the application of a novel T wave analysis tool.Among all patients admitted to Mayo Clinic for initiation of dofetilide or sotalol, we identified 13 cases who developed drug-induced TdP and 26 age and sex matched controls that did not develop TdP. The immediate pre-TdP ECG of those with TdP was compared to the last ECG performed prior to hospital discharge in controls using a novel T wave program that quantified subtle changes in T wave morphology.The QTc and 12 T wave parameters successfully distinguished TdP cases from controls. The top performing parameters were the QTc in lead V3 (mean case vs control 480 vs 420 msec, p?

SUBMITTER: Sugrue A

PROVIDER: S-EPMC4731047 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Electrocardiographic Predictors of Torsadogenic Risk During Dofetilide or Sotalol Initiation: Utility of a Novel T Wave Analysis Program.

Sugrue Alan A Kremen Vaclav V Qiang Bo B Sheldon Seth H SH DeSimone Christopher V CV Sapir Yehu Y Striemer Bryan L BL Brady Peter P Asirvatham Samuel J SJ Ackerman Michael J MJ Friedman Paul P Noseworthy Peter A PA

Cardiovascular drugs and therapy 20150101 5

<h4>Introduction</h4>Initiation of class III anti-arrhythmic medications requires telemetric monitoring for ventricular arrhythmias and QT prolongation to reduce the risk of torsades de pointes (TdP). Heart rate-corrected QT interval (QTc) is an indicator of risk, however it is imperfect, and subtle abnormalities of repolarization have been linked with arrhythmogenesis.<h4>Purpose</h4>Identification of electrocardiographic predictors of torsadogenic risk through the application of a novel T wave ...[more]

PMID: 26411977

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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.

Dataset Information

Electrocardiographic Predictors of Torsadogenic Risk During Dofetilide or Sotalol Initiation: Utility of a Novel T Wave Analysis Program.

Publications

Electrocardiographic Predictors of Torsadogenic Risk During Dofetilide or Sotalol Initiation: Utility of a Novel T Wave Analysis Program.

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