Bioelectric monitoring and neuromodulation of the heart

摘要： 美国心脏骤停的发病率每年超过30万，平均存活率为 的~ 11%。超过50万例心脏手术和程序，需要详细的心脏诊断， 在美国，每年都要进行高强度的监测来治疗心律失常和结构性心脏病， 取决于患者的合并症，它们一起携带1- 30%的发病率和死亡率风险。的 这一建议的基本假设是：胚胎发生的进展反映了异质性 在心脏电基质中，这些基质被自主控制中的异质性放大。因此，在本发明中， 减轻自主神经异质性的干预措施应该是（并且确实是）抗抑郁的。一个主要的未满足 神经心脏病学领域的需要是提供心脏的实时预测评估的技术， 和自主神经状态，然后允许快速和有针对性的闭环神经调节治疗， 干预乳腺增生的进展。该提案的主要目标是开发生物电子 用于心脏自主神经的高分辨率、实时并发测量的技术， 电生理参数，并使用该信息来调节反馈中的自主功能 控制方式。心肌内多极电极数据分析的进展， 随着薄膜2-D微阵列部署到心外膜，将定义跨膜的电异质性。 缺血心脏的边缘区域。自主神经评估将包括实时测量 局部心脏神经递质释放曲线，利用电化学循环伏安法 （儿茶酚胺）和电容免疫探针（神经肽测量），每一个新的心脏 设置.当结合使用时，能够提供血管和心脏神经化学物质的实时读数 随着我们在心脏电基质的直接心外膜和心内膜标测方面的进展， 我们的团队能够1）识别心脏性猝死的高风险受试者; 2）定义特定的贡献 异常的电生理基质，被自主神经递质的异质性放大; 和3）使闭环神经调节治疗干预适应潜在的病理。为此，委员会建议， 提出了三个目标。目标1：开发生物电子接口、平台/模块和分析工具 用于多种心脏间质和血管神经递质水平的实时体内评估。目标二： 目的：明确局灶性心脏神经递质释放与局部神经递质调节之间的动态相互作用， 心脏电功能对心脏应激的反射反应。目标3：实现多输入多输出 （MIMO）心脏发射器的闭环控制。这种闭环的平移势 神经调节系统将在术中、术后和重症监护环境中得到应用。

ABSTRACT: The incidence of cardiac arrest in the United States exceeds 300,000 per year with an average survival rate of ~11%. Over 500,000 cardiac surgeries and procedures, which require detailed cardiac diagnostics and intense monitoring, are performed to treat arrhythmias and structural heart disease in the US each year, which together carry a morbidity and mortality risk of 1-30%, depending on a patient’s comorbidities. The fundamental hypothesis underlying this proposal is: Progression of arrhythmogenesis reflects heterogeneities in cardiac electrical substrate that are amplified by heterogeneities in autonomic control. As such, interventions that mitigate autonomic heterogeneities should be (and are) anti-arrhythmic. A major unmet need in the field of Neurocardiology is technologies that provide real-time predictive assessments of cardiac and autonomic status that would then allow for rapid and targeted closed-loop neuromodulation therapies to intervene in the progression of arrhythmogenesis. The primary goal of this proposal is to develop bioelectronic technologies for high-resolution, real-time concurrent measurements of cardiac autonomic and electrophysiological parameters and to use that information to modulate autonomic function in a feedback control manner. Advances in analytics for data derived from intra-myocardial multi-pole electrodes, coupled with the deployment of thin-film 2-D microarrays to the epicardium, will define electrical heterogeneities across the border zone areas of the ischemic heart. Autonomic assessment will include real-time measurement of regional cardiac neurotransmitter release profiles, leveraging electrochemical cyclic voltammetry (catecholamine) and capacitive immunoprobe (neuropeptide measurements), each novel to the cardiac setting. The ability to provide real-time readouts of vascular and cardiac neurochemicals, when combined with our advances in direct epicardial and endocardial mapping of the cardiac electrical substrate, provides our team the ability to 1) identify subjects at high risk for sudden cardiac death; 2) define specific contribution of abnormal electrophysiological substrate as amplified by heterogeneities in autonomic neurotransmitters; and 3) tailor closed-loop neuromodulation therapeutic interventions to the underlying pathology. To this end, three aims are proposed. Aim 1: To develop bioelectronic interfaces, platforms/modules, and analytical tools for real-time in vivo assessments of multiple cardiac interstitial and vascular neurotransmitter levels. Aim 2: To define dynamic interactions between focal cardiac neurotransmitter release and modulation of regional cardiac electrical function in reflex response to cardiac stress. Aim 3: To implement a Multi Input, Multi Output (MIMO) closed-loop control of cardiac transmitters. The translational potential of such a closed-loop neuromodulation system will find application in intraoperative, post-operative and critical care settings.