MECHANISMS OF INCREASED RISK OF TORSADES DE POINTES ASSOCIATED WITH POTASSIUM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. More than 50 drugs with the potential to cause the life threatening arrhythmia torsades de pointes (TdP) are available in the U.S. Patients with heart failure (HF) due to left ventricular (LV) dysfunction are at increased risk for drug-induced TdP, due to undetermined mechanisms. We hypothesize that the increased risk of drug-induced TdP in patients with HF is due to 1) Increased myocardial responsiveness to potassium channel blockade, manifested by altered QT interval pharmacodynamics, and/or 2) Alterations in pharmacokinetics of hepatically metabolized potassium channel blocking agents. Patients with HF and atrial fibrillation (AF) undergoing DC cardioversion will be enrolled, as will a control group of AF patients without HF matched for age, sex, and B-Blocker or amiodarone use. Patients will receive ibutilide 1.0 mg intravenously over 10 minutes. ECGs and venous blood samples will be taken before ibutilide administration and at specific times for 48 hours following the end of infusion. QT intervals will be measured and corrected using several methods and serum ibutilide concentrations will be determined. Expected outcomes: 1) Patients with HF will have: Lower QT interval Ec50; Higher AUQCT; Greater QT interval Emax, 2) Patients with LV dysfunction will have: Higher ibutilide Cmax; Reduced CL; Smaller Vd; Greater AUC; Longer half-life. This research will show that patients with HF have increased myocardial responsiveness to potassium channel inhibition and impaired ability to eliminate a heptically metabolized potassium channel blocking drug, and will have important implications regarding use of potassium channel blocking agents and for drug development.