Project Summary/Abstract Cardiovascular disease, such as heart failure, atrial and ventricular arrhythmias, hypertensive and valvular heart disease is the leading cause of morbidity and mortality in the USA and the world. Importantly, 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. Cardiovascular specialists are required to monitor the heart routinely during interventions and almost exclusively rely on surface ECG and pressure measurements from the heart and vascular compartments and in selected cases electrical mapping of the heart. Current state-of-art technologies for cardiac electrophysiological and surgical therapies for management of complex atrial and ventricular arrhythmias provide limited and time-disparate data to guide interventions and monitor patients, primarily relying on hemodynamic parameters, gross and time-consuming point-by-point electrophysiological mapping techniques, and intermittent evaluation of blood chemistries. At present these data, in addition to being limited, often have substantial time delays from sampling to usable readouts leading to increase intraoperative and post-operative recovery time. This proposal outlines development of a conceptually new approach to cardiac monitoring that can impact diagnostics, therapeutics, and ultimately lead to closed-loop bioelectronics control of the heart. For Quantum Phase 1, three aims are proposed: Aim 1: Development of bioelectronic interfaces, platforms/modules, and analytical tools for real-time assessments of the cardiac interstitial and vascular parameters (catecholamine levels, acid-base and metabolic indices), along with high-density thin-film microarrays for mapping of cardiac electrical function and recording of peripheral cardiac autonomic neural activity. Aim 2: Integration of monitoring platforms, technologies, and analytics for cardiac electrophysiological mapping, multi-point cardiac pacing, hemodynamics, autonomic function, and real-time assessments of interstitial (and plasma) neurotransmitters and neuropeptide levels, acid-base levels, and metabolic factors. Aim 3: Discovery and validation of critical autonomic, metabolic, and electrophysiological parameters that precede and predict adverse cardiac events in infarcted porcine hearts and initial proof-of-concept human studies. Developing and optimizing new mapping arrays and systems for real-time measurement and evaluation of multiple electrophysiological parameters simultaneously with instantaneous “read-outs” of regional autonomic function (neural and cardiac interstitial neurotransmitters) has the potential to revolutionize the practice of medicine and patient care.