Female sex is an independent risk factor for the potentially fatal drug-induced arrhythmia torsades de pointes (TdP), which is associated with prolongation of the corrected QT (QTc) interval. Mechanisms for this increased risk in women have not been completely elucidated. QTc interval duration has been shown to fluctuate throughout the phases of the menstrual cycle. Evidence indicates that the QTc interval response to repolarization-prolonging drugs is greater during the menses and ovulation phases, during which serum progesterone concentrations are lowest, and lesser during the luteal phase, during which serum progesterone concentrations are highest. Additional evidence from our laboratory suggests that progesterone may be protective against TdP. Specific Aim 1: Establish the influence of oral progesterone administration as a preventive method by which to diminish the degree of drug-induced QT interval prolongation in women. Working hypothesis: Oral progesterone administration effectively attenuates enhanced drug-induced QT interval response in women. To test this hypothesis, progesterone or placebo will be administered in a crossover fashion to women during the menses phase of the menstrual cycle. QTc interval response to low- dose (20% of therapeutic dose) ibutiilide will be assessed. The primary endpoint will be individually-corrected QT interval (QTcI) reponse to ibutilide, in the presence and absence of progesterone, which will be assessed by: 1) Effect on maximum change in QTcI, and 2) Area under the QTcI interval-time curves (AUEC). Specific Aim 2: Establish the influence of exogenous progesterone as a preventive method by which to reduce the risk of TdP. Working hypothesis: Exogenous progesterone reduces the risk of TdP via activation of the slow component of the delayed rectifier potassium current (IKs). To test this hypothesis, the effects of IKs inhibition on progesterone-associated reduction in the incidence of TdP will be assessed in an isolated perfused heart model of dofetilide-induced TdP. At the conclusion of thsi study, we will have etablished that oral progesterone administration is a safe and effective method of attenuating drug-induced QT interval prolongation. In addition, we will have established that exogenous progesterone administration reduces the risk of drug-induced TdP, and that this protective effect is due in part to IKs activation.
|Effective start/end date||07/01/2012 → 06/30/2014|