CARDIAC NEUROMODULATION IN HUMANS: MECHANISMS & THERAPIES

心血管疾病病因和临床特征的认识现状 心血管疾病：心血管疾病是美国发病率和死亡率的主要原因， 世界自主神经系统（ANS）在神经系统疾病的发病机制中起着重要作用。 几种心血管疾病，如房颤、高血压、心肌梗死 (MI)、室性快速性心律失常/颤动（VT/VF）和心力衰竭进展中 （HF）.心力衰竭也给美国卫生系统带来了重大的财政负担， 到2030年估计将增长到800万人。交感迷走神经平衡， 在正常的健康状况下，在心脏病的存在下感到不安，导致“净” 交感神经兴奋，这是由于交感神经输出的增加和伴随的 副交感神经输出减少。神经调节疗法旨在恢复 交感迷走神经平衡，从而试图逆转/预防心血管疾病的进展 疾病神经调节治疗，如星状神经节切除术/心交感神经 去神经支配（CSD）现在正在临床上使用，其他神经轴向方法显示出 包括迷走神经刺激（VNS）在内的许多承诺。然而，临床试验 显示出混合的结果，阻碍了治疗的广泛应用。这突出了主要 关于其作用机制和确定 在临床环境中的最佳生物电参数和生理读数。作为 例如，耳屏迷走神经刺激（TVNS），已证明在减少 炎症和防止进行性心肌病理性重构。然而， 知道如何给药治疗，以最大限度地发挥TVNS在预防或 逆转已经患有心脏病的患者的自主神经功能障碍 如MI。在一系列转化/机制研究中，神经调节将被应用于 健康受试者和患有心脏病（MI或VT）的受试者以定义最佳参数， 读出，并确定神经调节如何影响神经元的电生理参数。 心

Current state of knowledge on the etiology and clinical characteristics of cardiovascular disease: Cardiovascular disease is the leading cause of morbidity and mortality in the US and the world. The autonomic nervous system (ANS) plays a central role in the pathogenesis of several cardiovascular diseases such as atrial fibrillation, hypertension, myocardial infarction (MI), ventricular tachyarrhythmias/fibrillation (VT/VF) and in the progression of heart failure (HF). Heart failure also places a major financial burden on the US health system, affecting five million people, and it is estimated to grow to eight million by 2030. Sympathovagal balance, seen in normal health, is perturbed in the presence of cardiac disease leading to ‘net’ sympathoexcitation, which is due to an increase in sympathetic output and a concomitant decrease in parasympathetic output. Neuromodulation therapies are directed toward restoring sympathovagal balance and thereby attempt to reverse/prevent progression of cardiovascular disease. Neuromodulation therapies such as stellate ganglionectomy/cardiac sympathetic denervation (CSD) are now being clinically utilized and other neuraxial approaches show a lot of promise including vagus nerve stimulation (VNS). However, clinical trials have shown mixed results preventing broad application of therapy. This highlights the major knowledge gap that exists regarding their mechanisms of action and the determination of optimal bioelectric parameters and physiological readouts in the clinical setting. As an example, tragal vagus nerve stimulation (TVNS), has demonstrated potential benefit in reducing inflammation and preventing progressive myocardial pathological remodeling. However, little is known about how to dose the therapy to maximize the effects of TVNS in preventing or reversing autonomic dysfunction in patients who have already suffered from cardiac disease such as MI. In a series of translational/mechanistic studies, neuromodulation will be applied to healthy subjects and to those with heart disease (MI or VT) to define optimal parameters and readouts and to determine how neuromodulation impacts electrophysiological parameters of the heart.