Olujimi A. Ajijola, Ph.D. - US grants

? DESCRIPTION (provided by applicant): This proposal describes the five-year mentored training program devised to facilitate the career development of Olujimi A. Ajijola MD PhD, into an independent physician scientist, capable of high-level scientific investigation. The important role of the intrinsic cardiac nervous system (ICNS) in the beat-to-beat regulation of cardiac contractile and electrophysiologic function is increasingly recognized, yet, it remains poorly understood. In the long term, the candidate seeks to develop a scientific and clinical niche in the field of intrinsic- neurocardiology, initially in the basic aspects, and in the future, bedside application of fundamental findings from studying ICNS physiology in normal and diseased states. The end objective of this career track is to develop therapeutic strategies modulating the ICNS (and higher cardiac neuro-regulatory centers) for patient care. The short- to intermediate-term goals of the candidate are to develop an expertise in neuroscience, and to expand his skill sets to include neuroscientific research methods and techniques, building on his expertise in cardiac structural biology and electrophysiology, and foundations in neuroscience. The career development plan for Dr. Ajijola have the following key elements: 1) mentorship by two well-recognized and invested experts in the fields of neuroscience (including ICNS physiology) and cardiac electrophysiology; 2) didactic and hands on training in developing an expanded knowledge base, scientific research tools, and techniques in neuroscience; 3) continued expansion of cardiac electrophysiologic expertise; and 4) a pathway for tracking the candidate's overall development, and the gradual assumption of independence, expected to be fully realized by the conclusion of the grant period. The proposed track has already been initiated, with preliminary data reinforcing the scientific aims of the proposal. The research objectives of the present proposal are to identify the mechanisms by which a clinically successful neuromodulatory therapy, bilateral cardiac sympathetic decentralization (BCSD), imparts antiarrhythmic benefits. Imbalances in neuro-hormonal activation resulting from neuronal remodeling within the cardiac neural-axis occur following significant cardiac injury. These imbalances lead to excessive and destabilizing efferent cardiac sympathetic neurotransmission. BCSD, the resection of the lower pole of the stellate ganglion and the sympathetic ganglia at the 2nd through 4th thoracic levels, likely eliminates these efferent cardiac sympathetic inputs from reaching the heart, however, the mechanistic translation of this effect to cardiac neuro- regulation, especially in infarcted myocardium, is unknown. We hypothesize that the intrinsic cardiac nervous system (ICNS), as the final integrator of cardiac afferent and efferent neurotransmission, is the end-target for BCSD. Specifically, BCSD mitigates the abnormal integration and processing of neurotransmission, to and from the heart, and remodeling of structural and functional elements within the ICNS, induced by enhanced sympathetic inputs originating from higher neural centers. By so doing, BCSD, via the ICNS, attenuates cardiac action potential duration heterogeneity, and enhanced myocyte automaticity, two known mechanisms of arrhythmogenesis under states of enhanced sympathetic tone. We plan to exploit this clinically beneficial antiarrhythmic therapy to understand how cardiac information is processed within the ICNS, and the cardiac electrophysiologic consequences of stochastic ICNS signaling patterns before and after BCSD. Combining high resolution cardiac electrophysiologic mapping with in vivo recordings of neuronal signals within the ICNS, this proposal will identify novel interactions within the cardiac nervous system and their electrophysiologic consequences. In specific aim 1a, we will determine how information is processed within the ICNS in normal and infarcted hearts, before and after BCSD performed immediately after infarction, or delayed till remodeling changes have set in. In aim 1b, we will examine how ICNS structural and neurochemical (i.e. neuropeptide) properties are altered by infarction, and impact of stabilizing efferent input by BCSD. In aim 2, we will assess how post-infarct ICNS signaling impacts cardiac electrophysiological properties by performing high resolution focal and global electrophysiologic mapping in infarcted hearts with an without BCSD; and further the differences between immediate post-infraction BCSD, and delayed BCSD. Cardiac and neuronal electrophysiologic mapping of this nature has not been previously performed. Impactful findings derived from these animal studies will form the basis for future bench to bedside studies aimed at developing novel or improving current neuromodulation therapies for treating ventricular arrhythmias.

PROJECT SUMMARY/ABSTRACT Sudden cardiac death (SCD) from ventricular arrhythmias remains the leading cause of death in developed nations, and is rapidly increasing in the rest of the world. The link between efferent sympathetic signaling and SCD has been recognized for a century; however, neuro-modulatory strategies to mitigate SCD have largely been limited. Diversity of neurotransmitters released in the heart, structural and functional remodeling of neurons within the cardiac neuraxis, and alterations in neural information processing are typically not factored in, and remain controversial. Following cardiac injury, widespread structural and neurochemical alterations occur in peripheral ganglia mediating cardiac afferent and efferent neurotransmission, yet, the functional consequences of such changes on intra- and inter-ganglionic signal processing are not understood. In addition, the dynamic nature of the cardiac electrophysiologic substrate is not considered, as changes in efferent sympathetic tone can dramatically alter the cardiac electrophysiologic properties even in scarred hearts. Utilizing multimodal approaches, we will test the hypothesis that the peripheral neural circuitry of SCD can be resolved, and related to cardiac electrophysiological behavior. This idea will be tackled in humans and animal models of ischemic cardiomyopathy and SCD. We will determine molecular, structural, and neurochemical alterations occurring in stellate ganglia, and how they occur. Intra- and inter-ganglionic neural processing by remodeled neurons will be assessed by neuronal recordings using high-throughput, high-density novel arrays, with simultaneous high-density cardiac electrophysiologic mapping. Efferent responses to afferent loads will be examined by detailed mapping of cardiac electrophysiologic and contractile function, and from bioelectric sensors in the myocardial interstitium to determine patterns of classical and non-classical neurotransmitter release. Finally, the arrhythmogenicity of altered processing will be examined in 2D and 3D models of cardiac tissue. If successful, this study will elucidate the neural signature of arrhythmic risk/SCD. The ability to monitor neural signatures and resolve the temporal risk of SCD answers a longstanding question in arrhythmia biology, with significant implications for discovering key therapies that are low cost and be utilized globally.