Bioelectric monitoring and neuromodulation of the heart

文摘:

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.