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(申请人提供)：提供强烈的电击是终止室颤的主要救命干预措施。在过去的几十年里，人们做出了巨大的努力来提高这种手术的安全性和效率。如今最常见的除颤波形是双相的(总持续时间为8-12ms)，与早期使用的单相电击相比，提供的能量减少了20%-40%。这项技术的不断完善旨在通过首次电击实现除颤，同时将并发症(如细胞损伤、心律失常、停搏、再颤动和心肌功能障碍)的可能性降至最低。我们推测，最近引入的一种刺激方式，纳秒脉冲电场(NsPEF)，具有一种独特的特征组合，使其在除颤方面具有优势：(1)膜通过位移电流带电到激发阈值，因此冲击能量可以显著降低；(2)电场穿透更深，在组织内分布更均匀；(3)在阳极和阴极下以及它们之间的体积中同时发生激发，从而最大限度地减少折返性心律失常和再颤动的机会；(4)即使对于具有电不均匀的心肌，如梗死后瘢痕，后者也适用。(5)同时兴奋心肌是最有效地阻止任何纤颤的激发波阵面，(6)在电穿孔的情况下，nsPEF开放的膜孔被限制在1-1.5 nm直径(“纳米电孔”)，从而减少了不必要的跨膜“泄漏”，(7)较小的损害，纳米粒子仍将通过降低心肌细胞的兴奋性而具有抗心律失常的作用，(8)nsPEF瞬时抑制电压门控的Na+和Ca2+通道将有助于抗心律失常的作用，(9)nsPEF致死剂量的指数增加转化为更高的安全系数。这些独特的特征值得研究nsPEF作为一种潜在的更有效但破坏性更小的除颤方式。在我们对兰登多夫灌流的兔心进行的试验中，nsPEF在剂量上有效地阻止了纤颤，其剂量比在类似设置和电极配置下报道的双相波形低约20倍。本项目将分析和比较10 ns、60 ns和300 ns PEF与常规单相和双相波形(MW，4 ms，和BW，4+4 ms)在单细胞水平和心脏中的影响：(1)我们将比较除颤成功与否，评估电穿孔染料摄取和组织损伤，以及有效电场和受损电场与能量值的比率；(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对心肌细胞活性的影响，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。该项目有望确定nsPEF除颤的可行性和益处，并为体内试验提供基础。