ELECTROPHYSIOLOGICAL EFFECTS OF NEURAL REMODELING OF THE VENTRICLES

描述（由申请人提供）：室性心律失常引起的心源性猝死（SCD）是美国死亡的主要原因，每年导致25万人死亡。自主神经系统在导致SCD的心律失常的病理生理中起着重要作用，神经轴调节为治疗干预提供了重要的场所。我们研究的主要目的是研究心脏交感神经支配在心律失常发生中的作用，以及神经轴向调节在预防人类心律失常中的作用。正常和患病人类心脏中交感神经控制心肌兴奋性的机制，特别是区域差异（心尖与基底、心外膜与心内膜、右与左星状神经节神经支配）仍然未知，需要进一步研究。此外，缺血性和非缺血性心肌病的心肌疤痕显示，由于神经重塑，疤痕边缘区出现神经芽肿，这与室性心律失常的病理生理有关。在这种情况下，神经刺激的功能影响以及神经轴阻断如何在这些疾病的人类中起作用仍然未知，这些知识可以帮助指导治疗。在这个提议中，直接区域心脏神经刺激和胸交感神经节的轴向调节的电生理效应将被研究。在接受介入性电生理手术和心脏移植的患者中，将描绘由左右星状神经节调节的心脏区域。了解神经轴向调节有可能在短期内进一步开发针对这些通路的治疗方法。诸如右、左或双侧颈胸交感神经切除术等疗法已经被“重新引入”临床实践（由我们的团队和其他人），已经显示出很大的希望，并可能成为一种新颖/优雅的治疗方法，对预防SCD也具有成本效益。因此，鉴于植入式除颤器的高昂成本和发病率阻碍了其扩大使用，神经轴向调制是一种有可能产生全球影响的方法。

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) due to ventricular arrhythmias is the leading cause of mortality in the United States, resulting in 250,000 deaths/year. The autonomic nervous system plays a major role in the pathophysiology of arrhythmias leading to SCD and neuraxial modulation provides an important venue for therapeutic intervention. The major goal of our research is to investigate the role of cardiac sympathetic innervations in the genesis of arrhythmias, and that of neuraxial modulation in prevention of these arrhythmias in humans. The mechanisms underlying sympathetic control of myocardial excitability in normal and diseased human hearts, and specifically, regional differences (apex versus base, epicardium versus endocardium, right versus left stellate ganglion innervation) remain unknown and need to be studied. Further, myocardial scars seen in ischemic and non-ischemic cardiomyopathy show nerve sprouting at the border zone of scars due to neural remodeling, which has been implicated in the pathophysiology of ventricular arrhythmias. The functional effects of nerve stimulation in this setting and how neuraxial blockade works in humans in these diseases are still unknown and this knowledge can help guide therapy. In this proposal, electrophysiological effects of direct regional cardiac nerve stimulation and neuraxial modulation of the thoracic sympathetic ganglia will be investigated. Areas of the heart regulated by the right and left stellate ganglia will be delineated in patients undergoing interventional electrophysiology procedures and cardiac transplantation. Understanding neuraxial modulation has the potential to further develop therapies that target these pathways in the very near term. Therapies such as right, left, or bilateral cerviocothoracic sympathectomy which has been 're-introduced' into clinical practice (by our group and others) already show a lot of promise and could emerge as novel/elegant therapies that are also cost-effective for the prevention of SCD. Therefore, neuraxial modulation is an approach that has the potential to have a global impact given the prohibitive high cost and morbidity associated with implantable defibrillators which prevent their expanded use.