Low Energy Defibrillation with Nanosecond Pulsed Electric Field

纳秒脉冲电场低能量除颤

• 批准号: 8941895
• 负责人: Andrei G Pakhomov
• 金额: $ 37.83万
• 依托单位: OLD DOMINION UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-12 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8941895
• 关键词: Action Potentials; Adult; Adverse effects; Animal Model; Anodes; Anti-Arrhythmia Agents; Anxiety; Apoptotic; Arrhythmia; Automated External Defibrillator; Bulla; Caliber; Cardiac; Cardiac Myocytes; Cardiac Volume; Cathodes; Cause of Death; Cell Death; Cells; Cessation of life; Charge; Cicatrix; Dose; Dyes; Electric Countershock; Electrodes; Electroporation; Endoplasmic Reticulum; Engineering; Exhibits; Frequencies; Heart; Heart Arrest; Hospitals; Human; Image; Implantable Defibrillators; Infarction; Intervention; Life; Membrane; Membrane Potentials; Modality; Modeling; Mono-S; Movement; Muscle; Muscle Cells; Myocardial; Myocardial dysfunction; Myocardium; Necrosis; Nerve; Oryctolagus cuniculus; Pain; Pathway interactions; Patients; Pattern; Physiologic pulse; Probability; Procedures; Protocols documentation; Reporting; Research; Rest; Resuscitation; Risk; Safety; Shock; Signal Transduction; Swelling; Tachycardia; Techniques; Testing; Time; Tissues; Translating; United States; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Water; base; cell injury; electric field; experience; improved; in vivo; millisecond; mortality; nanosecond; public health relevance; ratiometric; research study; solute; success; uptake; voltage; voltage gated channel

 DESCRIPTION (provided by applicant): Delivering intense electric shocks is the principal life-saving intervention to terminate ventricular fibrillation. During the past decades, a significant effort was made to improve the safety and efficiency of this procedure. Today's most common defibrillation waveform is biphasic (8-12 ms total duration) and delivers 20-40% less energy compared to earlier used monophasic shocks. The ongoing refinement of this technique is aimed at achieving the defibrillation by the first shock while minimizing the chance of complications (such as cell damage, arrhythmia, asystole, re-fibrillation, and myocardial dysfunction). We postulate that a recently introduced stimulation modality, the nanosecond pulsed electric field (nsPEF), possesses a unique combination of features that make it superior for defibrillation: (1) membranes are charged to the excitation threshold by displacement currents, so the shock energy can be markedly reduced, (2) the electric field penetrates deeper and is distributed more uniformly within tissue, (3) the excitation occurs simultaneously under the anode and the cathode and in the volume between them, thereby minimizing the chance of reentry arrhythmias and re-fibrillation, (4) the latter holds true even for myocardium with electri inhomogeneities, such as post-infarction scars, (5) simultaneous excitation of the myocardium is most effective to stop any excitation wavefronts of fibrillation, (6) in case of electroporation, nsPEF-opened membrane pores are limited to 1-1.5 nm diameter ("nanoelectropores"), so the undesired transmembrane "leaks" are reduced, (7) being less damaging, nanoporation will still have the anti-arrhythmic effect by reducing myocyte excitability, (8) transient inhibition of voltage-gated Na+ and Ca2+ channels by nsPEF will assist the anti-arrhythmic effect, and (9) the exponential increase of lethal dose values for nsPEF translates into a higher safety factor. These unique features warrant research into nsPEF as a potentially more efficient but less disruptive defibrillation modality. In our trials with Langendorff-perfused rabbit hearts, nsPEF effectively stopped fibrillation at doses about 20-fold less than reported for a biphasic waveform in a comparable setup and electrode configuration. This project will analyze and compare the effects of 10-, 60-, and 300-ns PEF with conventional mono- and biphasic waveforms (MW, 4 ms, and BW, 4+4 ms) at the single cardiomyocyte level and in hearts: (1) We will compare the success of defibrillation, assess the electroporative dye uptake and tissue damage, and the ratio of the effective and damaging E-field and energy values in Langendorff-perfused rabbit heart model, (2) We will identify nsPEF effects on the resting membrane potential, action potential, voltage-gated currents, and excitability. (3) We will quantify nsPEF effects on the viability of cardiomyocytes, identify mechanisms and pathways of cell damage and death, and compare the lethal effects of nsPEF, BW, and MW. The project is expected to establish the feasibility and benefits of nsPEF defibrillation, and provide the basis for in vivo trials.

 描述（由申请人提供）：强烈电击是终止心室颤动的主要救生干预措施。在过去的几十年中，人们为提高该手术的安全性和效率做出了巨大的努力。当今最常见的除颤波形是双相波形（总持续时间为 8-12 毫秒），与早期使用的单相电击相比，能量减少 20-40%。该技术的不断完善旨在通过第一次电击实现除颤，同时最大限度地减少并发症（如细胞损伤、心律失常、心搏停止、再颤动和心肌功能障碍）的可能性。我们假设最近引入的一种刺激方式，即纳秒脉冲电场（nsPEF），具有独特的特征组合，使其在除颤方面具有优越性：（1）膜通过位移电流充电至激励阈值，因此电击能量可以显着降低，（2）电场穿透更深，并且在组织内分布更均匀，（3）激励同时发生在 阳极和阴极以及它们之间的体积，从而最大限度地减少折返性心律失常和再颤动的机会，（4）后者即使对于具有电不均匀性的心肌（例如梗死后疤痕）也适用，（5）心肌的同时激励对于阻止颤动的任何激励波前是最有效的，（6）在电穿孔的情况下， nsPEF 开放的膜孔直径仅限于 1-1.5 nm（“纳米电孔”），因此减少了不需要的跨膜“泄漏”，(7) 破坏性较小，纳米孔化仍可通过降低心肌细胞兴奋性而具有抗心律失常作用，(8) nsPEF 对电压门控 Na+ 和 Ca2+ 通道的瞬时抑制将有助于 (9) nsPEF 致死剂量值的指数增加转化为更高的安全系数。这些独特的功能值得将 nsPEF 作为一种可能更有效但破坏性更小的除颤方式进行研究。在我们对 Langendorff 灌注兔心脏进行的试验中，nsPEF 有效地阻止了颤动，其剂量比在可比较的设置和电极配置中报道的双相波形低约 20 倍。该项目将分析和比较 10、60 和 300 ns PEF 与传统单相和双相波形（MW、4 ms 和 BW、4+4 ms）在单个心肌细胞水平和心脏中的效果：（1）我们将比较除颤的成功率，评估电穿孔染料摄取和组织损伤，以及有效和破坏性电场和能量值的比率。 Langendorff 灌注兔心脏模型，(2) 我们将确定 nsPEF 对静息膜电位、动作电位、电压门控电流和兴奋性的影响。 (3)我们将量化nsPEF对心肌细胞活力的影响，确定细胞损伤和死亡的机制和途径，并比较nsPEF、BW和MW的致死作用。该项目预计将确立 nsPEF 除颤的可行性和益处，并为体内试验提供基础。