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（由适用提供）：提供激烈的电击是终止心室纤颤的主要挽救生命的干预措施。在过去的几十年中，为提高此程序的安全性和效率做出了巨大的努力。当今最常见的定义波形是双相（总持续时间为8-12毫秒），与早期使用的单相冲击相比，能量降低了20-40％。该技术的持续改进旨在通过第一次冲击来实现除颤的，同时最大程度地减少并发症的机会（例如细胞损伤，心律不齐，疗程，重新纤维化和心肌功能障碍）。我们假设最近引入的模拟方式，即纳秒脉冲电场（NSPEF），潜力具有独特的功能组合，使其具有优越性的除颤：（1）膜被向兴奋的兴奋性，通过位移电流的兴奋性阈值，因此在震惊的情况下可以显着降低电场，并在电场中渗透到（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）阳极与阴极以及它们之间的体积，从而最大程度地减少了重新进入心律不齐和重新纤维的机会，（4）后者即使是对心肌的电气不良性也是如此 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 exciting, (8) transient inhibition of voltage-gated Na+ and Ca2+ channels by nsPEF will assist the anti-arrhythmic效应，（9）NSPEF致命剂量值的指数增加转化为更高的安全系数。这些独特的功能保证对NSPEF的研究可能是一种可能更有效但破坏性的除颤方式。在我们与Langendorff陷入困境的兔子心脏的试验中，NSPEF在可比的设置和电极构型中有效地停止了剂量的原纤维剂量约20倍。该项目将分析并比较单个心肌细胞水平，在心脏上，在心脏中，并比较传统的单和双相波形（MW，4 ms和BW，4+4 ms）的效果以及心脏：（1）我们将比较除颤的成功，并评估降压和电动染色的损坏和造成的损坏，并与造成的损坏和施加症状相比。 Langendorff渗透的兔心脏模型，（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的影响。 （3）我们将量化NSPEF对心肌细胞生存能力的影响，确定细胞损伤和死亡的机制和途径，并比较NSPEF，BW和MW的致命作用。预计该项目将确定NSPEF定义的可行性和好处，并为体内试验提供基础。