Myocardial infarction alters information processing within the intrinsic cardiac nervous system

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION (provided by applicant): Sudden cardiac death due to ventricular arrhythmias is the leading cause of mortality in the world, resulting in over 4 million deaths each year. Autonomic nervous system (ANS) dysregulation is central to the pathogenesis of ventricular arrhythmias. The ANS projects to the heart via the intrinsic cardiac nervous system (ICNS), a distributed network of ganglia and interconnecting nerves located primarily in epicardial fat that modulates cardiac function on a beat-to-beat basis. This system contains all the neuronal elements necessary for intracardiac reflex control, namely afferent neurons, sympathetic and parasympathetic efferent postganglionic neurons, and local circuit neurons (LCNs), with the latter acting as the processing elements for intracardiac reflexes. The ICNS works in concert with the intrathoracic extracardiac ganglia, spinal cord, brainstem, and higher centers to coordinate regional cardiac function. Cardiac disease, such as myocardial infarction (MI), adversely affects the myocardium and multiple components of the cardiac neural hierarchy, including intrinsic cardiac neurons. Our hypothesis is that MI causes disruption of afferent information processing within the cardiac neural hierarchy, and specifically the ICNS, ultimately leading to neuroendocrine activation and detrimental effects on the heart. This neural dysregulation underlies the electrical and mechanical disturbances responsible for the initiation of arrhythmias and progression to heart failure. The goal of this project is to systematically evaluate in a porcine model the effects of chronic MI on information processing within the ICNS, by obtaining neural and cardiac electrophysiological data concurrently. Specific Aim 1 will determine the effects of chronic MI on ICNS processing of cardiac sensory afferent inputs. The underlying concept of Aim 1 is that chronic MI induces changes in afferent inputs to the ICNS, reflecting altered transduction of the mechanical and chemical milieu by sensory neurites arising from the infarct, border, and remote zones of the heart. Specific Aim 2 will determine the effects of chronic MI on ICNS processing of central efferent inputs. The underlying concept of Aim 2 is that chronic MI induces changes in efferent inputs downstream of the ICNS at the level of the cardiomyocytes. Specific Aim 3 will determine the effects of chronic MI on integrated processing of cardiovascular reflexes by the ICNS, particularly LCNs. The underlying concept of Aim 3 is that chronic MI induces changes in information processing by LCNs, primarily due to altered afferent inputs. Collectively, these aims are designed to define the `neural signature' of the ICNS as it adapts to the stresses imposed by chronic MI. We hope to ultimately identify neuronal targets within the ICNS to mitigate this adverse remodeling, and thereby open avenues for novel neuraxial modulation therapies.