Torsades de Pointes in the Guinea-Pig Heart

Abstract

It is increasingly recognized that certain cardiovascular andnon-cardiovascular medicines may induce a potentially lifethreatening form of ventricular tachyarrhythmia known astorsades de pointes (TdP; [1, 2]). This realization led to thewithdrawal of a number of drugs from the market, and proar-rhythmic testing of a drug candidate is routinely performedtodayusingabatteryofpre-clinicaltests.Yet,asdevelopmentof TdP is multifactorial with female gender, bradycardia,hypokalemia and structural heart disease as the major riskfactors, it is not surprising that the incidence of arrhythmiain healthy pre-clinical animal models isnegligible. SinceTdPis frequently not a direct read-out from the screening models,thedeterminationofproarrhythmicrisksisbasedonsurrogatemarkers.ManysuchbiomarkersforTdP havebeenproposed,including QTand APD prolongation, reverse-usedependenceofdrugs,andtemporalandspatialdispersionofrepolarizationduration [3–9]. Undoubtedly, evaluation of biomarkers forproarrhythmia advanced our knowledge of TdP mechanisms;however, utility of these biomarkers in drug development isstill limited as both their specificity and sensitivity is far fromoptimal. Moreover, regulatory authorities approving noveldrugs for use in humans are not recognizing proarrhythmicanimal models as informative of human risk. Instead, humansafety is determined based on perhaps the most imperfectbiomarker, the QTinterval, recordedfromhealthy volunteers.The potential consequences are two-fold: approval of a drugthat turns out to be proarrhythmic and discontinuation of thedevelopment of a promising therapy for an unmet medicalneed.In the present issue of Cardiovascular Drugs and Ther-apy, the proarrhythmic mechanism of dofetilide is investi-gated and various biomarkers in isolated, perfused guinea-pig heart preparations are reported [10]. Dofetilide is apotent I