Nanosecond megavolt pulse technology for cardiac stimulation and defibrillation

描述(申请人提供)：我们的长期目标是确定超短、高场电脉冲作为心脏刺激、增强收缩和除颤机制的可行性。心力衰竭的主要死亡方式是心源性猝死(SCD)和顽固性泵衰竭。室颤(VF)是SCD的主要病因，只能通过除颤来治疗，除颤使用高压电场，以疼痛、不适和电池消耗为代价获得成功。使用正性肌力药治疗泵衰竭可改善血流动力学，但会导致长期死亡率增加。需要新的除颤和增强收缩的策略。最近发现，超短(Ns)、高场(mV/m)、低能(MicroJ)脉冲可在非兴奋性细胞中触发多种细胞效应，包括细胞内钙释放、核膜疏松、磷脂酰丝氨酸从质膜内层移位到外层，以及诱导细胞凋亡。这些反应被认为是由产生的强大的细胞内电场引起的，电场太短而不能充电或不可逆转地破坏质膜，被认为对电场是“透明的”。对可兴奋细胞的影响还没有系统地研究，但初步数据表明，超短、高场电脉冲可以刺激心肌细胞，并潜在地产生增强的收缩，而能量消耗要低得多。该项目的第一个目标是描述纳秒、兆伏特/米的电脉冲对分离的兔心肌细胞的生理影响。我们将对不同生理条件下的脉冲疗法和反应进行系统的研究，以描绘电压和钙的反应及其机制。第二个目标是探索纳秒、高场脉冲在心脏脉冲在二维心脏基质中传播的影响。我们将首先开发用于将兆伏特纳秒脉冲传输到较大心脏组织的电极配置。然后，我们将研究这些脉冲对新生大鼠心肌细胞单层脉冲传播的影响。将评估脉冲对起搏、螺旋波和纤颤传播的影响，以确定其作为抗纤颤策略的可行性。如果成功，我们的研究将为一种新的、低能量的心脏起搏和除颤技术提供基础，这种技术可以改善数百万心力衰竭患者的生活质量和存活率。

DESCRIPTION (provided by applicant): Our long-term objective is to establish the feasibility of ultrashort, high field electrical pulses as a mechanism of cardiac stimulation, contraction enhancement, and defibrillation. The major modes of death in heart failure are sudden cardiac death (SCD) and refractory pump failure. Ventricular fibrillation (VF) is the leading cause of SCD and can only be treated by defibrillation, which uses high voltage fields and succeeds at the cost of pain, discomfort and battery demands. Pump failure treatment with positive inotropic agents leads to hemodynamic improvements but causes long-term increased mortality. New strategies to defibrillate and enhance contraction are needed. Ultrashort (ns), high-field (MV/m), low energy (microJ) pulses have recently been shown to trigger a variety of cellular effects in nonexcitable cells, including calcium release from intracellular stores, poration of the nuclear membrane, translocation of phosphatidylserine from the inner to the outer layer of the plasma membrane, and induction of apoptosis. These responses are thought to be caused by the substantial intracellular electric fields generated, which are too brief to charge or irreversibly damage the plasma membrane, deemed to be "transparent" to the fields. Effects on excitable cells have not been systematically studied, but preliminary data suggests that ultra-short, high-field electric pulses can excite cardiac cells and potentially generate enhanced contraction with much lower energy use by. The first aim of this project is to delineate the physiological effects of nanosecond, megavolt-per-meter electric pulses in isolated rabbit myocytes. Systematic studies of pulse regimens vs. responses under different physiological conditions will be performed to delineate the voltage and calcium responses and their mechanisms. The second aim is to explore the effects of nanosecond, high-field pulses in cardiac impulse propagation in 2-dimensional cardiac substrates. We will first develop electrode configurations for delivery of megavolt nanosecond pulses to larger cardiac tissues. We will then study the effects of these pulses on impulse propagation in neonatal rat myocyte monolayers. Effects of pulses on paced, spiral wave and fibrillatory propagation will be assessed to establish their feasibility as an antifibrillatory strategy. If successful, our studies would provide a basis for a new, low energy technology for cardiac pacing, and defibrillation which could improve the quality of life and survival of millions of patients with heart failure.