Bioelectric monitoring and neuromodulation of the heart

摘要： 美国每年心脏骤停发生率超过30万人平均存活率 ~11%。超过500,000例心脏手术和程序，需要详细的心脏诊断和 在美国，每年都会进行密集的监测，以治疗心律失常和结构性心脏病，这 根据患者的合并症，两者合计的发病率和死亡率风险为1-30%。这个 这一建议的基本假设是：心律失常的进展反映了异质性。 在心脏电基质中，它被自主神经控制中的异质性放大。因此， 缓解自主神经异质性的干预措施应该(也是)抗心律失常。一个重大的未满足的问题 神经心脏病学领域的需要是提供对心脏疾病的实时预测评估的技术 和自主神经状态，从而允许快速和有针对性的闭环神经调节疗法 干预心律失常的进展。这项提议的主要目标是发展生物电子学 心脏自主神经和心脏功能的高分辨率、实时并行测量技术 电生理参数并使用该信息来调节反馈中的自主神经功能 控制方式。心肌内多极电极耦合数据分析的研究进展 随着薄膜2-D微阵列的部署到心外膜，将定义整个心外膜的电异质性 缺血心脏的交界区。自主评估将包括实时测量 利用电化学循环伏安法的局部心脏神经递质释放谱 (儿茶酚胺)和电容式免疫探针(神经肽测量)，每个新的心脏 布景。当组合使用时，能够提供血管和心脏神经化学物质的实时读数 随着我们在心外膜和心内膜直接标测心脏电基质方面的进展，提供了 我们的团队有能力1)识别心源性猝死的高危人群；2)确定具体的贡献 由于自主神经递质的异质性而放大的异常电生理底物； 3)为基础病理量身定做闭环式神经调节治疗干预。为此， 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 用于实时体内评估多种心脏间质和血管神经递质水平。目标2： 明确局部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 心脏应激反应中的心脏电功能。目标3：实现多输入、多输出 (MIMO)心脏传输器的闭环控制。这样一个闭合回路的平移潜力 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.