Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA.
Department of Pharmacology, Vanderbilt University Medical Center, 2215B Garland Avenue, Room 1285B, Nashville, TN, USA.
Cardiovasc Res. 2019 Apr 15;115(5):895-903. doi: 10.1093/cvr/cvz013.
The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia 'torsades de pointes', which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.
QT 间期是心室复极的整体指标，在个体之间存在差异，并受到多种生理和病理刺激的影响，如性别、年龄、心率、电解质浓度、并存的心脏疾病以及糖尿病等其他疾病。许多药物对 QT 间期产生微小但可重复的影响，但在极少数情况下，这种影响被夸大，明显的 QT 延长可引发多形性室性心动过速“尖端扭转型室性心动过速”，可导致晕厥或心源性猝死。药物延长 QT 间期的一般公认的共同机制是阻断心脏关键复极钾电流 IKr，该电流由 KCNH2（也称为 HERG）表达产生。因此，评估新药物实体是否可能引起尖端扭转型室性心动过速的潜在风险，依赖于正常志愿者或患者在通常和高浓度下暴露于药物，并在体外评估 IKr 阻断。最近的研究集中在具有 QT 延长作用的抗癌药物上，正在确定药物可以延长 QT 的新途径。值得注意的是，一些酪氨酸激酶抑制剂在体外延长心脏动作电位（QT 的细胞相关性）的作用可以通过细胞内磷脂酰肌醇 3,4,5-三磷酸（PI3K 的下游效应物）挽救。这一发现支持通过正在研究的机制，通过直接抑制该酶或通过抑制上游激酶来抑制该酶，以延长 QT，这些机制包括在动作电位平台期间增强内向“晚期”钠电流。确定非 IKr 依赖性 QT 延长途径对于评估风险非常重要，不仅与抗癌治疗有关，而且与其他延长 QT 的药物有关，并深入了解细胞内信号转导系统的可变活性如何调节 QT 和相关的心律失常风险。
