Mechanically-Induced Cardiac Excitation: Mechanisms and Modifiers

机电耦合是心脏自动调节的一个组成部分，允许心脏对循环需求的变化做出反应。这种内在的调节过程甚至存在于移植的（即去神经支配的）心脏中。机电耦合可用于外部触发有效的心脏收缩（例如，通过心前区重击[PT]），这比被动胸外按压显著更有效（心输出量为机械诱导兴奋基线的77%，而即使采用最佳胸外按压，心输出量也为38%）。几十年来，PT被认为是终止快速性心律失常的潜在有用手段，但最近的研究表明，基于病例报告和非前瞻性研究设计的阳性发表偏倚，这是一种没有根据的预期。尽管如此，根据最新的心肺复苏科学国际共识声明，“没有足够的证据建议或反对使用心前区重击来证明房室传导障碍引起的心搏停止发作”。因此，在严重心动过缓中使用PT进行机械起搏是一个国际公认的研究需求领域，如本文所提出的。由于缺乏可持续性，心脏在1：1夺获丧失之前对有限数量的刺激做出反应，机械起搏的临床适用性也不确定。当开始机械起搏时，心脏会对每一个刺激做出反应，进行有效的收缩。然而，在多次心跳后，心脏将停止反应，即使它仍然是电兴奋的。这不是机械夺获的永久停止：在没有机械干预的一段时间后，1：1夺获恢复，心脏恢复到与以前相同的可持续性水平（无组织损伤）。机械诱导收缩的潜在机制以及暂时丧失夺获的原因尚不清楚。我的项目的总体目标是：（一）了解机械诱导兴奋的机制，（二）解释夺获的丧失和恢复，（三）识别这些现象的机械，电气和药理学调节剂，以潜在地实现心脏的可持续机械起搏。为了实现这些目标，我将对膜电压和局部缩短进行兔全心脏光学标测。我将检查急性心搏停止心脏的最大机械起搏频率，并评估可持续性的潜在调节剂，为评估连续PT在原发性心搏停止紧急情况下的效用提供全面的科学基础。这些实验将与计算模型的开发相结合，以整合数据，引导湿实验室研究，并预测潜在的临床相关性。

Mechanoelectric coupling is an integral part of cardiac autoregulation, allowing the heart to respond to changes in circulatory demand. This intrinsic regulatory process is present even in the transplanted (i.e. denervated) heart. Mechanoelectric coupling can be utilised to externally trigger competent cardiac contractions (for example by a precordial thump [PT]) which are significantly more productive than passive chest compressions (cardiac output is 77 % of baseline for mechanically-induced excitation, compared to 38 % even with optimally performed chest compressions). For many decades, PT was thought to be a potentially useful means of terminating tachy-arrhythmias, but more recent studies have shown this to be an ill-founded expectation, based on the positive publication bias of case reports and non-prospective study designs. Still, according to the latest International Consensus Statement on cardio-pulmonary resuscitation science, “There is insufficient evidence to recommend for or against the use of the precordial thump for witnessed onset of asystole caused by atrioventricular conduction disturbance”. So the use of PT for mechanical pacing in severe bradycardia is an area with an internationally acknowledged need for research, such as proposed here.The clinical applicability of mechanical pacing is also uncertain due to a lack of sustainability, where hearts respond to a limited number of stimuli before loss of 1:1 capture. When mechanical pacing is initiated, the heart undergoes a competent contraction in response to every stimulus. However, after a number of beats the heart will stop responding, even though it remains electrically excitable. This is not a permanent cessation of mechanical capture: After a period of time without mechanical interventions, recovery of 1:1 capture occurs, with hearts returning to the same level of sustainability as before (no tissue injury). The underlying mechanisms of mechanical induction of contractions, and the reasons for the temporary loss of capture, are not known. Both preclude assessment of the clinical utility of mechanical pacing.The overall goals of my project are (i) to understand mechanisms of mechanically-induced excitation, (ii) to explain loss and recovery of capture, and (iii) to identify mechanical, electrical, and pharmacological modulators of these phenomena, to potentially enable sustainable mechanical pacing of the heart. To address these goals I will perform rabbit whole-heart optical mapping of both membrane voltage and local shortening. I will examine maximal mechanical pacing rates in the acutely asystolic heart and assess potential modulators of sustainability, to provide a thorough scientific foundation for the assessment of the utility of serial PT in the emergency setting of primary asystole. These experiments will be done in conjunction with the development of computational models to integrate data, steer wet-lab research, and project towards potential clinical relevance.