Jeffrey L. Ardell - US grants

DESCRIPTION (adapted from the applicant's abstract): The applicant proposes to investigate the physiologic importance of the intrinsic cardiac nervous system. The applicant's principal objective is to identify the specific deficits within the intrinsic cardiac ganglia and at the myocyte receptor-effector synaptic junctions that occur subsequent to decentralization of the heart and/or adrenalectomy. For this purpose five specific aims have been defined. Specific Aim 1. To determine if prolonged loss of extrinsic nerve inputs to the heart and/or loss of adrenal medullary support modifies basal nerve activity and synaptic interactions within the in vivo intrinsic cardiac ganglia in response to application of specific cholinergic and non-cholinergic agonists and antagonists. Specific Aim 2. To determine if prolonged loss of extrinsic nerve inputs to the heart and/or loss of adrenal medullary support alters the membrane properties and synaptic efficacy of cardiac neurons. Using intracellular microelectrode techniques applied to in vitro whole mount intracardiac ganglia, somatic responses to specific cholinergic and non-cholinergic agonists and antagonists will be evaluated prior to and during electrical stimulation of interganglionic nerves. Specific Aim 3. Using receptor autoradiography, to determine if prolonged loss of extrinsic nerve inputs to the heart and/or prolonged loss of adrenal medullary support modifies specific cholinergic, adrenergic and angiotensin II receptor densities and distributions within the intrinsic cardiac ganglia or within the electrical and contractile tissues of the canine heart. Specific Aim 4. To determine if prolonged loss of extrinsic nerve inputs to the heart and/or prolonged loss of adrenal medullary support modifies signal transduction within cardiac myocytes. Specific Aim 5. To determine if restoration of circulating catecholamines alleviates the cardiodepression associated with chronic adrenalectomy with and without concurrent prolonged loss of extrinsic nerve inputs to the heart.

DESCRIPTION (provided by applicant): Imbalances in neurohumoral control, especially those leading to excessive sympathetic efferent neuronal activation, are associated with adverse short- and long-term alterations in cardiac function - including cardiac arrhythmias and pump failure. As a corollary, stabilization of such imbalances within select components of the cardiac neuronal hierarchy can reduce the arrhythmic substrate, maintain myocyte viability and prolong survival. Thus, the primary objective for this competitive renewal is to first determine the role of interdependent interactions within and between central and peripheral components of the cardiac neuronal hierarchy and secondly how such linkages remodel in response to acute and chronic cardiac stress (e.g. myocardial ischemia/infarction). As the intrinsic cardiac nervous system represents the final common integrator of cardiac control, this organ component of the cardiac neuronal hierarchy represents a primary focus for targeted neuromodulation therapy. We hypothesize that chronic myocardial infarction/ischemia remodels the peripheral (intrinsic cardiac and extra cardiac intrathoracic) nervous system, thereby contributing to both the genesis of cardiac arrhythmias and deterioration of contractile function. We further hypothesize that targeted neuromodulation mitigates ischemia-induced remodeling of the intrinsic cardiac and extra cardiac intrathoracic nervous systems, thereby reducing the substrate for cardiac arrhythmia formation while sustaining contractile function. This grant exploits the opportunities afforded by electrical neuromodulation via spinal cord stimulation (SCS), a clinical therapy with recognized anti-antiginal properties - a therapeutic approach that has potential for management of both i) arrhythmias and ii) congestive heart failure. Central nexus points within the cardiac neuronal hierarchy will be stimulated electrically (dorsal T1-T3 SCS) to modulate the intrinsic cardiac nervous system to impact regional cardiac electrical stability and support contractile function. Specific aim 1 will determine a) how regional atrial electrical events are coordinated by the intrinsic cardiac neuronal activity such that excessive activation of its select nerve inputs lead to atrial arrhythmias and b) if chronic SCS modifies cholinergic and noncholinergic synaptic interactions within the intrinsic cardiac nervous system to reduce this arrhythmogenic potential. Specific aim 2 will determine a) if chronic myocardial infarction/ischemia remodels the intrinsic cardiac nervous system such that this atrial arrhythmogenic neuronal substrate becomes enhanced and then to test the capacity of b) chronic SCS to modify synaptic interactions within the intrinsic cardiac nervous system in the suppression of atrial arrhythmias. Specific Aim 3 will determine if chronic myocardial infarction/ischemia adversely remodels intrinsic cardiac and extra cardiac intrathoracic autonomic neural function, thereby contributing to deterioration of cardiac mechanical function and, if so, whether chronic SCS mitigates such changes. PUBLIC HEALTH RELEVANCE: Interactions between central and peripheral aspects of the cardiac nervous system play a major role in control of the normal and stressed heart. Imbalances within this system are associated with deleterious effects including abnormal heart beats, sudden cardiac death and heart failure. The fundamental concept underpinning this proposal is to: 1) understand the interdependent interactions occurring within and between central and peripheral components of the cardiac neuronal hierarchy;2) to determine how such linkages remodel in response to chronic cardiac stress (e.g. myocardial ischemia/infarction);and 3) to determine what are the optimum therapeutic strategies to target select elements of the cardiac nervous system to mitigate the progression of congestive heart failure and the potential for sudden cardiac death.

? DESCRIPTION (provided by applicant): The cardiac neuronal hierarchy is made up of interdependent feedback loops comprising somata located in i) intrinsic cardiac ganglia, ii) intrathoracic extracardiac (stellate, middle cervical) as well as iii) the spinal cord, iv) brainstm and v) higher centers (up to the insular cortex). Each of these processing center contains afferent, efferent and interactive (local circuit ones in peripheral ganglia) neurons which interac locally and in an interdependent fashion with other levels to coordinate regional cardiac indices on a beat-to-beat basis. It is now recognized that autonomic dysregulation is central to the evolution of heart failure and arrhythmias. With respect to heart disease and the cardiac nervous system, there is an upregulation of the sympathetic nervous system and a corresponding decrease in parasympathetic activity. Many of these changes are driven by alterations in afferent transduction and processing of that information at multiple levels of the cardiac nervous system. There is little understanding of how such neural systems adapt during disease progression. There are two critical unmet needs in the field of cardio-neural mapping: 1) Development and optimization of 2D and 3D electrode arrays for chronic, high-fidelity neural recording from peripheral ganglia and 2) Integration of neural recordings with chronic high-fidelity recording of cardiac electrophysiological function. To address this need three aims are proposed. Specific aim 1: To develop 2D and 3D microelectrode arrays and systems for chronic, high-fidelity neural recording from intrinsic cardiac ganglia. Proposed methods include development of thin-film based flexible microelectrode arrays with up to 256 electrode contacts. Once proof of concept is established in the acute setting, chronic packages and fixation techniques will be developed to enable chronic recordings from large animal models. Specific aim 2: To develop 3D electrode arrays and systems for chronic, high-fidelity neural recording in peripheral encapsulated sympathetic (stellate) and sensory (nodose) ganglia. Proposed methods include development of thin-film based 3D penetrating microelectrode arrays (up to 256 electrode contacts). Once proof of concept is established in the acute setting, chronic packages and fixation techniques will be developed to enable chronic recordings from encapsulated peripheral ganglia from large animal models. Specific aim 3: To develop conformal high-definition grid electrodes for chronic, high-resolution electrophysiological mapping from atrial and ventricular epicardial surfaces. These `HD grid electrodes' will have up to 512 sites. Similar to and in conjunction with Aims 1 and 2, chronic packages and fixation techniques will be developed to enable chronic high-fidelity cardiac-neural mapping for up to 28 days. New Knowledge and Innovation: Creation of a distributed electrode system for chronic and continuous high fidelity cardio-neural mapping in normal and pathological states.

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.

Project Summary/Abstract Sudden cardiac death (SCD) due to ventricular tachyarrhythmias (VT) is the leading cause of death in the United States. Dysregulation of the autonomic nervous system, specifically sympathoexcitation, plays a major role in the pathophysiology of cardiac arrhythmias secondary to ischemic heart disease. The spinal cord serves as a major nexus point for control of sympathetic reflexes to the heart. However, there are major gaps in the understanding of regulation of cardiac excitability at the level of the spinal cord. Spinal neuromodulation therapies- spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation, show promise towards reducing VTs, but the mechanisms underlying the therapeutic benefits of these innovative approaches remain largely unknown. The goal of this proposal is to determine how the spinal cord processes cardiac afferent impulses during myocardial ischemia and to explain how neuromodulation therapies reduce ventricular arrhythmias, leading to their more effective and expansive use. In this proposal, it is hypothesized that unique cardiospinal neural networks integrate the cardiac afferent signals during myocardial ischemia (MI) and control sympathoexcitation, thereby modulating arrhythmogenesis. Further, MI triggers pathologic remodeling of cardiospinal neural circuits, which increase myocardial sympathoexcitation. SCS and DRG stimulation, reduce sympathetic output through induction of GABA signaling pathways in the spinal cord, reducing ventricular excitability and arrhythmias after chronic MI. Importantly, preliminary functional data shows anti-arrhythmic effects of SCS during acute I/R were abolished in the presence of GABA receptor antagonists, supporting the hypothesis. Real Time PCR also shows expression of GABAA and GABAB receptors is increased by SCS therapy in spinal cord during MI. Thus, modulation of cardiac afferent neural inputs to the spinal cord presents a novel target for suppression of excessive sympathetic reflex activation and cardiac arrhythmias. To mechanistically understand the therapeutic potential of such approaches, proposed experiments will evaluate the effects of neuromodulation on cardiospinal neural network and ventricular excitability. The proposed studies will evaluate novel mechanisms of regulation of cardiac excitability at the spinal level. Specific aims 1 is designed to provide a mechanistic understanding of the role of spinal cord processing of afferent cardiac neural inputs. Electrophysiological and neurochemical alterations in cardiospinal neural network in chronic MI will be compared with healthy hearts when subjected to additional cardiac stress (acute ischemia/reperfusion). Molecular mechanisms through which chronic MI induces pathologic remodeling of the cardiospinal neural network will be characterized. In specific aim 2 and 3, mechanisms by which SCS and DRG stimulation reduce cardiospinal neural network remodeling and decrease myocardial sympathoexcitation in chronic MI will be identified. The proposed studies will provide the framework to maximize the therapeutic potential of neuromodulation in mitigation of cardiac and neural remodeling in chronic MI.

Project Summary/Abstract Sudden cardiac death (SCD) due to ventricular tachyarrhythmias (VT) is the leading cause of death in the United States. Dysregulation of the autonomic nervous system, specifically sympathoexcitation, plays a major role in the pathophysiology of cardiac arrhythmias secondary to ischemic heart disease. The spinal cord serves as a major nexus point for control of sympathetic reflexes to the heart. However, there are major gaps in the understanding of regulation of cardiac excitability at the level of the spinal cord. Spinal neuromodulation therapies- spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation, show promise towards reducing VTs, but the mechanisms underlying the therapeutic benefits of these innovative approaches remain largely unknown. The goal of this proposal is to determine how the spinal cord processes cardiac afferent impulses during myocardial ischemia and to explain how neuromodulation therapies reduce ventricular arrhythmias, leading to their more effective and expansive use. In this proposal, it is hypothesized that unique cardiospinal neural networks integrate the cardiac afferent signals during myocardial ischemia (MI) and control sympathoexcitation, thereby modulating arrhythmogenesis. Further, MI triggers pathologic remodeling of cardiospinal neural circuits, which increase myocardial sympathoexcitation. SCS and DRG stimulation, reduce sympathetic output through induction of GABA signaling pathways in the spinal cord, reducing ventricular excitability and arrhythmias after chronic MI. Importantly, preliminary functional data shows anti-arrhythmic effects of SCS during acute I/R were abolished in the presence of GABA receptor antagonists, supporting the hypothesis. Real Time PCR also shows expression of GABAA and GABAB receptors is increased by SCS therapy in spinal cord during MI. Thus, modulation of cardiac afferent neural inputs to the spinal cord presents a novel target for suppression of excessive sympathetic reflex activation and cardiac arrhythmias. To mechanistically understand the therapeutic potential of such approaches, proposed experiments will evaluate the effects of neuromodulation on cardiospinal neural network and ventricular excitability. The proposed studies will evaluate novel mechanisms of regulation of cardiac excitability at the spinal level. Specific aims 1 is designed to provide a mechanistic understanding of the role of spinal cord processing of afferent cardiac neural inputs. Electrophysiological and neurochemical alterations in cardiospinal neural network in chronic MI will be compared with healthy hearts when subjected to additional cardiac stress (acute ischemia/reperfusion). Molecular mechanisms through which chronic MI induces pathologic remodeling of the cardiospinal neural network will be characterized. In specific aim 2 and 3, mechanisms by which SCS and DRG stimulation reduce cardiospinal neural network remodeling and decrease myocardial sympathoexcitation in chronic MI will be identified. The proposed studies will provide the framework to maximize the therapeutic potential of neuromodulation in mitigation of cardiac and neural remodeling in chronic MI.