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）：提供强烈电击是终止室颤的主要救生干预措施。在过去的几十年里，人们做出了巨大的努力来提高这一过程的安全性和效率。当今最常见的除颤波形是双相的（总持续时间为8-12 ms），与早期使用的双相电击相比，其能量减少了20-40%。该技术正在进行的改进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、再纤颤和心肌功能障碍）的机会。我们假设，最近引入的刺激方式，纳秒脉冲电场（nsPEF），具有独特的功能组合，使其具有上级除颤：（1）膜通过位移电流被充电到激发阈值，因此可以显著降低冲击能量，（2）电场穿透更深并且在组织内分布更均匀，（3）在阳极和阴极下以及在它们之间的体积中同时发生激励，从而使折返心律失常和再纤维性颤动的机会最小化，（4）后者甚至对于具有电不均匀性的心肌，例如梗塞后疤痕，也是如此，（5）心肌的同时激发对于停止纤维性颤动的任何激发波前是最有效的，（6）在电穿孔的情况下，nsPEF打开的膜孔限于1- 1.5nm直径（“纳米电孔”），因此减少了不希望的跨膜“泄漏”，（7）由于损伤较小，纳米孔仍将通过降低肌细胞兴奋性而具有抗心律失常作用，（8）电压门控Na+和Ca 2+通道的短暂抑制nsPEF将有助于抗心律失常作用，和（9）nsPEF的致死剂量值的指数增加转化为更高的安全系数。这些独特的功能保证了nsPEF作为一种潜在的更有效但破坏性更小的除颤方式的研究。在我们对Langendorff灌注的兔心脏进行的试验中，nsPEF在可比设置和电极配置中的双相波形的剂量约为报告的20倍时有效地停止了纤颤。该项目将分析和比较10-，60-和300-ns的PEF与传统的单相和双相波形的效果（MW，4 ms和BW，4+4 ms）在单个心肌细胞水平和心脏中：（1）我们将比较除颤的成功，评估电穿孔染料摄取和组织损伤，（2）研究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。该项目预计将确定nsPEF除颤的可行性和益处，并为体内试验提供基础。