Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark.
Department of Health Science and Technology, University of Aalborg, Fredrik Bajers Vej 7E, 9220, Aalborg, Denmark.
Exp Physiol. 2019 Apr;104(4):490-504. doi: 10.1113/EP087531. Epub 2019 Feb 28.
What is the central question of this study? Are modifications in the restitution of ventricular action potential duration induced by antiarrhythmic drugs the same when assessed with premature extrastimulus application at variable coupling intervals (the standard stimulation protocol) and with steady state pacing at variable rates (the dynamic stimulation protocol)? What is the main finding and its importance? With class I and class III antiarrhythmics, the effects on electrical restitution determined with the standard stimulation protocol dissociate from those obtained during dynamic pacing. These findings indicate a limited value of the electrical restitution assessments based on extrasystolic stimulations alone, as performed in the clinical studies, in estimating the outcomes of antiarrhythmic drug therapies.
A steep slope of the ventricular action potential duration (APD) to diastolic interval (DI) relationships (the electrical restitution) can precipitate tachyarrhythmia, whereas a flattened slope is antiarrhythmic. The derangements in APD restitution responsible for transition of tachycardia to ventricular fibrillation can be assessed with cardiac pacing at progressively increasing rates (the dynamic stimulation protocol). Nevertheless, this method is not used clinically owing to the risk of inducing myocardial ischaemia. Instead, the restitution kinetics is determined with a premature extrastimulus application at variable coupling intervals (the standard stimulation protocol). Whether the two protocols are equivalent in estimating antiarrhythmic drug effects is uncertain. In this study, dofetilide and quinidine, the agents blocking repolarizing K currents, increased epicardial APD in perfused guinea-pig hearts, with effects being greater at long vs. short DIs. These changes were more pronounced during dynamic pacing compared to premature extrastimulations. Accordingly, although both agents markedly steepened the dynamic restitution, there was only a marginal increase in the standard restitution slope with dofetilide, and no effect with quinidine. Lidocaine and mexiletine, selective Na channel blockers, prolonged the effective refractory period without changing APD, and increased the minimum DI that enabled ventricular capture during extrastimulations. No change in the minimum DI was noted during dynamic pacing. Consequently, although lidocaine and mexiletine reduced the standard restitution slope, they failed to flatten the dynamic restitution. Overall, these findings imply a limited value of the electrical restitution assessments with premature extrastimulations alone in discriminating arrhythmic vs. antiarrhythmic changes during drug therapies.
这项研究的核心问题是什么？抗心律失常药物引起的心室动作电位时程复极的改变，在用不同时程的早搏刺激（标准刺激方案）和不同频率的稳定起搏（动态刺激方案）评估时是否相同？主要发现及其重要性是什么？对于 I 类和 III 类抗心律失常药物，用标准刺激方案确定的电复极效应与动态起搏时获得的效应不同。这些发现表明，仅基于早搏刺激进行的电复极评估在估计抗心律失常药物治疗的结果方面价值有限，如临床研究中所进行的那样。
心室动作电位时程（APD）与舒张期（DI）关系的陡峭斜率（电复极）可引发心动过速性心律失常，而平坦斜率则具有抗心律失常作用。APD 复极的紊乱导致心动过速向室性颤动的转变，可以通过逐渐增加频率的心脏起搏（动态刺激方案）来评估。然而，由于存在诱发心肌缺血的风险，该方法并未在临床上使用。相反，通过在不同时程的早搏刺激（标准刺激方案）来确定复极动力学。在估计抗心律失常药物的效果方面，这两种方案是否等效尚不确定。在这项研究中，多非利特和奎尼丁这两种阻断复极化 K 电流的药物增加了豚鼠心脏灌流的心外膜 APD，长 DI 时的效果大于短 DI。与早搏刺激相比，在动态起搏时这些变化更为明显。因此，尽管两种药物都明显使动态复极变陡，但多非利特仅使标准复极斜率略有增加，而奎尼丁则没有影响。利多卡因和美西律，选择性钠通道阻滞剂，延长有效不应期而不改变 APD，并增加了早搏时心室捕获的最小 DI。在动态起搏时未观察到最小 DI 的变化。因此，尽管利多卡因和美西律降低了标准复极斜率，但未能使动态复极变平。总的来说，这些发现表明，仅通过早搏刺激进行的电复极评估在区分药物治疗期间的心律失常与抗心律失常变化方面的价值有限。
