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Heart failure (HF) is associated with significant morbidity and mortality. The disease is characterised by autonomic imbalance with increased sympathetic activity and withdrawal of parasympathetic activity. Despite the use of medical therapies that target, in part, the neurohormonal axis, rates of HF progression, morbidity and mortality remain high. Emerging therapies centred on neuromodulation of autonomic control of the heart provide an alternative device-based approach to restoring sympathovagal balance. Preclinical studies have proven favourable, while clinical trials have had mixed results. This article highlights the importance of understanding structural/functional organisation of the cardiac nervous system as mechanistic-based neuromodulation therapies evolve.

Neural control of the heart involves continuous modulation of cardiac mechanical and electrical activity to meet the organism's demand for blood flow. The closed-loop control scheme consists of interconnected neural networks with central and peripheral components working cooperatively with each other. These components have evolved to cooperate control of various aspects of cardiac function, which produce measurable "functional" outputs such as heart rate and blood pressure. In this review, we will outline fundamental studies probing the cardiac neural control hierarchy. We will discuss how computational methods can guide improved experimental design and be used to probe how information is processed while closed-loop control is operational. These experimental designs generate large cardio-neural datasets that require sophisticated strategies for signal processing and time series analysis, while presenting the usual large-scale computational challenges surrounding data sharing and reproducibility. These challenges provide unique opportunities for the development and validation of novel techniques to enhance understanding of mechanisms of cardiac pathologies required for clinical implementation. [ABSTRACT FROM AUTHOR]

Neural control of the heart involves continuous modulation of cardiac mechanical and electrical activity to meet the organism’s demand for blood flow. The closed-loop control scheme consists of interconnected neural networks with central and peripheral components working cooperatively with each other. These components have evolved to cooperate control of various aspects of cardiac function, which produce measurable “functional” outputs such as heart rate and blood pressure. In this review, we will outline fundamental studies probing the cardiac neural control hierarchy. We will discuss how computational methods can guide improved experimental design and be used to probe how information is processed while closed-loop control is operational. These experimental designs generate large cardio-neural datasets that require sophisticated strategies for signal processing and time series analysis, while presenting the usual large-scale computational challenges surrounding data sharing and reproducibility. These challenges provide unique opportunities for the development and validation of novel techniques to enhance understanding of mechanisms of cardiac pathologies required for clinical implementation.

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T1-T3, 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ~4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential. [ABSTRACT FROM AUTHOR]

Populations of intrathoracic extracardiac neurons transduce myocardial ischemia, thereby contributing to sympathetic control of regional cardiac indices during such pathology. Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) modulates such local reflex control. In 10 anesthetized canines, middle cervical ganglion neurons were identified that transduce the ventricular milieu. Their capacity to transduce a global (rapid ventricular pacing) vs. regional (transient regional ischemia) ventricular stress was tested before and during SCS (50 Hz, 0.2 ms duration at 90% MT) applied to the dorsal aspect of the TI to T4 spinal cord. Rapid ventricular pacing and transient myocardial ischemia both activated cardiac-related middle cervical ganglion neurons. SCS obtunded their capacity to reflexly respond to the regional ventricular ischemia, but not rapid ventricular pacing. In conclusion, spinal cord inputs to the intrathoracic extracardiac nervous system obtund the latter's capacity to transduce regional ventricular ischemia, but not global cardiac stress. Given the substantial body of literature indicating the adverse consequences of excessive adrenergic neuronal excitation on cardiac function, these data delineate the intrathoracic extracardiac nervous system as a potential target for neuromodulation therapy in minimizing such effects. [ABSTRACT FROM AUTHOR]