Termination of Cardiac Arrhythmia by High Frequency Electric Field

高频电场终止心律失常

• 批准号: 8098063
• 负责人: Ronald D Berger
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098063
• 关键词: Adverse effects; Animal Model; Arrhythmia; Axon; Boxing; Cardiac; Catheters; Cell model; Cells; Complement; Computer Simulation; Data; Defibrillators; Devices; Electric Countershock; Electrocardiogram; Electrodes; Experimental Models; Family suidae; Frequencies; Functional disorder; Goals; Heart; Heart Block; Heart failure; Human; Implantable Defibrillators; In Vitro; Incidence; Individual; Literature; Malignant - descriptor; Maps; Measurement; Modeling; Modification; Myocardial; Nerve; Nerve Block; Optics; Pain; Patients; Peripheral Nerves; Physiologic pulse; Potassium; Prevention; Procedures; Refractory; Reporting; Research; Shock; Sinus; Skeletal Muscle; Sodium Channel; System; Techniques; Testing; Tissue Model; Tissues; Translating; Trauma; Ventricular; Ventricular Fibrillation; Work; base; clinical practice; comparative efficacy; electric field; heart rhythm; high risk; implantable device; improved; in vivo; innovation; insight; meetings; monolayer; mortality; novel; novel strategies; prevent; psychologic; public health relevance; research study; response; spatiotemporal; success; sudden cardiac death; voltage

DESCRIPTION (provided by applicant): Defibrillation is now recognized as the only effective means to prevent sudden cardiac death, and implantable cardioverter-defibrillators have been shown to improve survival in high risk individuals. Nevertheless, the high voltage shocks from these devices are associated with a host of adverse effects, including increased incidence of heart failure, abnormal rhythms, cellular and tissue dysfunction, significant skeletal muscle stimulation, and pain. Modifications to the shock waveforms and novel electrode systems have met with limited success in avoiding these problems. This project will utilize a novel approach to defibrillate the heart by a completely different mechanism than what occurs with conventional defibrillation. Our central hypothesis, borne out by preliminary data, is that in response to an external alternating electric field in the kHz range, the transmembrane voltage of cardiac cells becomes trapped at a partially elevated potential and is held in a refractory state. This state completely blocks impulse propagation and can reliably terminate reentrant arrhythmias such as fibrillation. Our approach may represent an enormous advance because skeletal muscle and nerves may be similarly unable to activate during the HF field, reducing or eliminating the pain associated with defibrillation. Furthermore, because defibrillation is the result of propagation block, device testing will no longer require induction and termination of ventricular fibrillation, as propagation block can be assessed during normal or paced rhythm. The specific aims of this project are: (1) to optimize the waveform parameters to block impulse propagation and terminate arrhythmia by persistently depolarizing cardiac cells without evoking repetitive activity, and (2) to test the hypothesis that HF stimulation will inhibit myocardial impulse propagation and terminate fibrillation in an intact mammalian heart. These ideas will be tested using a three-prong approach consisting of (a) detailed, biophysical studies in an in vitro cell monolayer model; (b) computational tissue models of different mammalian species, including human, that will provide mechanistic insight, and (c) experiments in the intact pig to compare efficacy of HF defibrillation with conventional defibrillation and to determine whether HF stimulation provokes induction of arrhythmias and skeletal muscle activation. In summary, the proposed research will evaluate the efficacy of high frequency field stimulation as a novel form of electrical therapy that can block cardiac impulse propagation and terminate arrhythmia, with minimal adverse cardiac effects and reduced pain. The results from this basic work have the potential to translate directly into clinical practice by revolutionizing arrhythmia management. PUBLIC HEALTH RELEVANCE: Defibrillation is now recognized as the only effective means to prevent sudden cardiac death, and implantable devices have been shown to improve survival in high risk individuals. Nevertheless, high voltage shocks delivered by present-day defibrillators are associated with a host of adverse effects, including increased incidence of heart failure, abnormal cardiac rhythms, damage to the heart, and pain. The goal of this project is to determine whether a novel approach for arrhythmia termination that we have discovered translates into more effective defibrillation together with a reduction of heart damage, pain, and ensuing psychological trauma widely associated with defibrillation shocks.

描述（由申请人提供）：除颤现在被认为是预防心脏性猝死的唯一有效手段，植入式心律转复器已被证明可提高高危人群的生存率。然而，这些器械的高压电击与许多不良反应相关，包括心力衰竭、心律异常、细胞和组织功能障碍、显著骨骼肌刺激和疼痛的发生率增加。对冲击波形和新型电极系统的修改在避免这些问题方面取得了有限的成功。 该项目将利用一种新的方法，通过与传统除颤完全不同的机制来除颤心脏。我们的中心假设，证实了初步的数据，是在响应于kHz范围内的外部交变电场，心肌细胞的跨膜电压被困在一个部分升高的电位，并保持在一个不应状态。这种状态完全阻断脉冲传播，可以可靠地终止折返性心律失常，如纤维性颤动。我们的方法可能代表了一个巨大的进步，因为骨骼肌和神经可能同样无法在HF场期间激活，从而减少或消除与除颤相关的疼痛。此外，由于除颤是传播阻滞的结果，器械测试将不再需要诱导和终止室颤，因为可以在正常或起搏节律期间评估传播阻滞。 本项目的具体目标是：（1）优化波形参数，通过持续去极化心脏细胞而不引起重复活动来阻断脉冲传播并终止心律失常，以及（2）测试HF刺激将抑制完整哺乳动物心脏中的心肌脉冲传播并终止纤颤的假设。这些想法将使用三管齐下的方法进行测试，包括（a）在体外细胞单层模型中进行详细的生物物理研究;（B）不同哺乳动物物种（包括人类）的计算组织模型，其将提供机理洞察，以及（c）在完整的猪中进行实验，以比较HF除颤与常规除颤的功效，并确定HF刺激是否引起心律失常的诱导，骨骼肌激活 总之，拟议的研究将评估高频场刺激作为一种新型电疗法的疗效，这种电疗法可以阻断心脏脉冲传播并终止心律失常，同时对心脏的不良影响最小，疼痛减轻。这项基础工作的结果有可能通过彻底改变心律失常管理直接转化为临床实践。 公共卫生关系：除颤现在被认为是预防心脏性猝死的唯一有效手段，植入式设备已被证明可以提高高危人群的生存率。然而，由现今的除颤器递送的高压电击与许多不利影响相关，包括心力衰竭、心律异常、心脏损伤和疼痛的发生率增加。本项目的目标是确定我们发现的一种终止心律失常的新方法是否可以转化为更有效的除颤，同时减少心脏损伤，疼痛以及与除颤电击广泛相关的心理创伤。