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  • Review Article
  • Published:

Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms

Nature Reviews Cardiology volume 13, pages 36–47 (2016)Cite this article

Subjects

Key Points

  • Various cardiovascular and noncardiovascular drugs can induce proarrhythmic adverse effects

  • Pharmacokinetic risk factors and genetic predisposition can enhance proarrhythmia

  • Antiarrhythmic, antimicrobial, antipsychotic, and antidepressant drugs are important drug classes with an associated risk of proarrhythmia

  • Monitoring the QT interval might not be sufficient to assess the risk of proarrhythmia

  • Spatial and temporal dispersion of repolarization, action-potential configuration, and occurrence of early afterdepolarizations are additional predictors of proarrhythmia

Abstract

Drug-induced ventricular tachyarrhythmias can be caused by cardiovascular drugs, noncardiovascular drugs, and even nonprescription agents. They can result in arrhythmic emergencies and sudden cardiac death. If a new arrhythmia or aggravation of an existing arrhythmia develops during therapy with a drug at a concentration usually considered not to be toxic, the situation can be defined as proarrhythmia. Various cardiovascular and noncardiovascular drugs can increase the occurrence of polymorphic ventricular tachycardia of the 'torsade de pointes' type. Antiarrhythmic drugs, antimicrobial agents, and antipsychotic and antidepressant drugs are the most important groups. Age, female sex, and structural heart disease are important risk factors for the occurrence of torsade de pointes. Genetic predisposition and individual pharmacodynamic and pharmacokinetic sensitivity also have important roles in the generation of arrhythmias. An increase in spatial or temporal dispersion of repolarization and a triangular action-potential configuration have been identified as crucial predictors of proarrhythmia in experimental models. These studies emphasized that sole consideration of the QT interval is not sufficient to assess the proarrhythmic risk. In this Review, we focus on important triggers of proarrhythmia and the underlying electrophysiological mechanisms that can enhance or prevent the development of torsade de pointes.

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Figure 1: Spatial dispersion of repolarization.
Figure 2: Temporal dispersion of repolarization.
Figure 3: Representative Poincaré plots obtained from analysis of 30 MAPs under baseline conditions, under the influence of a | erythromycin or b | veratridine, and after additional infusion of DHA.
Figure 4: Action-potential configuration.
Figure 5: Early afterdepolarizations leading to torsades de pointes in a rabbit whole-heart model.

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  1. Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Albert-Schweitzer Strasse 33, Münster, D-48149, Germany

    Gerrit Frommeyer & Lars Eckardt

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Frommeyer, G., Eckardt, L. Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms. Nat Rev Cardiol 13, 36–47 (2016). https://doi.org/10.1038/nrcardio.2015.110

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