A pronounced gender-based difference in response to drugs is the far greater risk for women to develop the life threatening arrhythmia torsades de pointes. Drugs that have the tendency to cause torsades in women commonly block potassium channels and thereby prolong cardiac repolarization. The Principal Investigator has performed a clinical study comparing the QT interval response to quinidine and confirmed the greater response of the QT in women compared to men. This application proposes studies to test the hypothesis that gender based differences in cardiac ion current densities are responsible for the observed differences in QT interval length and the greater sensitivity of females to drugs that cause QT lengthening. The PI has done initial studies in isolated rabbit hearts to investigate gender differences in repolarization and the development of torsades and found greater baseline and drug induced (quinidine and sotalol) changes of QT intervals in female hearts, and reduced densities of delayed rectifier and inward rectifier potassium currents, and an increased tendency to develop torsades in female hearts. This application proposes to use the rabbit model to identify gender-related differences in electrophysiology (action potential and patch clamp recordings at baseline and with quinidine and sotalol) to identify the ionic basis for the gender differences. The potential roles for sex steroid hormones in the regulation of specific ion channels will also be investigated. The application proposes that these results will provide valuable information regarding gender differences in electrophysiology and the greater risk of drug-induced arrhythmias in women, and might lead to methods of screening individuals at risk of drug-induced arrhythmias or the development of drugs with reduced risk of inducing arrhythmia.
