Low Energy Defibrillation with Nanosecond Pulsed Electric Field

纳秒脉冲电场低能量除颤

• 批准号: 9278268
• 负责人: Andrei G Pakhomov
• 金额: $ 37.7万
• 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/9278268
• 关键词: Action Potentials; Adult; Adverse effects; Animal Model; Anodes; 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; Closure by clamp; Dose; Dyes; Electric Countershock; Electrodes; Electroporation; Endoplasmic Reticulum; Engineering; Exhibits; Frequencies; Heart; Heart Arrest; Histologic; Hospitals; Human; Image; Implantable Defibrillators; Infarction; Intervention; Life; Membrane; Membrane Potentials; Modality; Modeling; Modernization; 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; Savings; Shock; Signal Transduction; Tachycardia; Techniques; Testing; Time; Tissues; Translating; United States; Ventricular; Ventricular Fibrillation; Ventricular Tachycardia; Water; cell injury; electric field; experience; experimental study; improved; in vivo; millisecond; mortality; nanosecond; public health relevance; ratiometric; risk minimization; 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.