Proarrhythmia as a pharmacogenomic entity: a critical review and formulation of a unifying hypothesis.
Proarrhythmia represents an extreme example of the phenomenon that drug effects vary widely among individuals. Studies of mechanisms leading to proarrhythmia have had important implications for understanding arrhythmogenesis, rational use of antiarrhythmic therapies, selection of patients for specific therapies, and drug development. In addition, because proarrhythmia often seems to develop in the absence of clear risk predictors, a role for genetics in predisposing to this adverse drug reaction has been postulated. This review presents mechanisms whereby genetic factors may contribute to variable drug responses and describes our current understanding of how these mechanisms play a role in proarrhythmia. A unifying hypothesis is presented: physiologic processes (such as drug elimination or cardiac repolarization) include multiple redundancies, and congenital or acquired absence of such redundancies--due to disease, interacting drugs, or genetic makeup--may confer no baseline phenotype, but nevertheless enhance susceptibility to unusual drug responses.
Roden
Dan M
DM
Department of Medicine, and Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, 532 Medical Research Building I, Nashville, TN 37232, United States. dan.roden@vanderbilt.edu
D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D010597:Pharmacogenetics; D026941:Sodium Channel Blockers / Q000009:adverse effects; D016171:Torsades de Pointes / Q000139:chemically induced
D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers