Cardiac ventricular repolarization reserve: a principle for understanding drug-related proarrhythmic risk
Year: 2011
Type: article
Abstract: Cardiac repolarization abnormalities can be caused by a wide range of cardiac and non-cardiac compounds and may lead to the development of life-threatening Torsades de Pointes (TdP) ventricular arrhythmias. Drug-induced torsades de pointes is associated with unexpected and unexplained sudden cardiac deaths resulting in the withdrawal of several compounds in the past. To better understand the mechanism of such unexpected sudden cardiac deaths, the concept of repolarization reserve has recently emerged. According to this concept, pharmacological, congenital or acquired impairment of one type of transmembrane ion channel does not necessarily result in excessive repolarization changes because other repolarizing currents can take over and compensate. In this review, the major factors contributing to repolarization reserve are discussed in the context of their clinical significance in physiological and pathophysiological conditions including drug administration, genetic defects, heart failure, diabetes mellitus, gender, renal failure, hypokalaemia, hypothyroidism and athletes' sudden deaths. In addition, pharmacological support of repolarization reserve as a possible therapeutic option is discussed. Some methods for the quantitative estimation of repolarization reserve are also recommended. It is concluded that repolarization reserve should be considered by safety pharmacologists to better understand, predict and prevent previously unexplained drug-induced sudden cardiac deaths.
Source: British Journal of Pharmacology
Authors: András Varró, István Baczkó
Institutions: University of Szeged, Hungarian Academy of Sciences
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1545972634