MECHANISMS OF INCREASED RISK OF TORSADES DE POINTES ASSOCIATED WITH POTASSIUM

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在美国，有超过50种可能导致危及生命的心律失常尖端扭转型室性心动过速（TdP）的药物可用。由于机制不明，左心室（LV）功能障碍导致心力衰竭（HF）的患者发生药物诱导TdP的风险增加。 我们假设HF患者中药物诱导的TdP风险增加是由于1）心肌对钾通道阻滞的反应性增加，表现为QT间期药效学改变，和/或2）肝代谢钾通道阻滞剂的药代动力学改变。 将入组接受直流电复律的HF和房颤（AF）患者，以及年龄、性别和B受体阻滞剂或胺碘酮使用情况匹配的无HF AF患者对照组。 患者将在10分钟内接受伊布利特1.0 mg静脉给药。 将在伊布利特给药前和输注结束后48小时的特定时间采集ECG和静脉血样。 将使用几种方法测量和校正QT间期，并测定血清伊布利特浓度。 预期成果：1）HF患者将具有：较低的QT间期Ec 50;较高的AUQCT;较高的QT间期Emax，2）LV功能障碍患者将具有：较高的伊布利特Cmax;降低的CL;较小的Vd;较大的AUC;较长的半衰期。 这项研究将表明，HF患者心肌对钾通道抑制的反应性增加，消除肝代谢钾通道阻滞药物的能力受损，并将对钾通道阻滞剂的使用和药物开发产生重要影响。

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.