BACKGROUND OF THE INVENTION

Atrial fibrillation (AF) affects more than three million people a year in the United States, a prevalence that is projected to reach 5.6-12.1 million by 2050 (Go A S et al., 2001, J Am Med Assoc, 285:2370-2375; Naccarelli G V et al., 2009, Am J Cardiol, 104:1534-1539). Despite such prevalence, the underlying mechanisms of AF are not fully understood. Current treatments consist of pharmacological therapies that have been combined with localized atrial catheter-based or surgical ablation (Chen P S et al., 2014, Circ Res, 114:1500-1515; Shen M J et al., 2014, Circ Res, 114:1004-1021). Ablation procedures are associated with complications such as the left atrial stiffness syndrome (Gibson D N et al., 2011, Heart Rhythm, 8:1364-1371), microembolic episodes (Schwarz N et al., 2010, Heart Rhythm, 7:1761-1767), and a risk of symptomatic or silent cerebral ischemia (Gaita F et al., 2010, Circulation, 122:1667-1673). Such drawbacks have increased the research focus on defining specific neural and cardiac substrate interactions underlying AF and with such information evolving novel nonpharmacological therapeutic options for its management (Zipes D P., 2015, Nat Rev Cardiol, 12:68-69). Bioelectric neuromodulation therapies for A F represent a novel approach to such management. Among these, vagus nerve stimulation (VNS) (Lin Y et al., 2013, Sci World J, 2013:781084; Shen M J et al., 2011, Circulation, 123:2204-2212; Sheng X et al., 2011, J Am Coll Cardiol, 57:563-571) and spinal cord stimulation (Gibbons D D et al., 2012, Am J Physiol Regul Integr Comp Physiol, 302:R357-R364; Southerland E M et al., 2012, Auton Neurosci, 169:34-42; Wang S et al., 2015, Heart Rhythm, 12:1628-1635) target various aspects of the cardiac neuronal hierarchy to reduce the arrhythmia potential.

The cardiac nervous system includes reflex networks located in the insular cortex, brain stem, spinal cord, intrathoracic sympathetic ganglia, and the intrinsic cardiac nervous system (ICNS) (Ardell J L et al., 2016, J Physiol, 594:3877-3909; Armour J A., 2008, Exp Physiol, 93:165-176; Zucker I H et al., 2012, Heart Fail Clin, 8:87-99). It has been proposed that its ICNS component acts as the final coordinator of regional cardiac indexes, doing so under the influence of intrathoracic, spinal cord, and brain stem reflexes (Armour J A., 2008, Exp Physiol, 93:165-176). Neural activity within the ICNS is influenced by afferent (mechanosensitive, chemosensitive, and ischemia-sensitive) and efferent neuronal inputs (Armour J A., 2008, Exp Physiol, 93:165-176; Armour J A et al., 2004, Cardiac sensory neurons. In: Basic and Clinical Neurocardiology, edited by Armour J A Ardell J L. New York, N.Y.: Oxford Univ Press, 2004, p. 79-117; Zucker I H et al., 1991, Reflex Control of the Circulation. Boca Raton, Fla.: CRC). These afferent and efferent inputs are processed by local circuit neurons (LCNs) in peripheral ganglia to modulate sympathetic and parasympathetic efferent postganglionic projections to all regions of the heart (Ardell J L et al., 2016, J Physiol, 594:3877-3909; Fukuda K et al., 2015, Circ Res, 116:2005-2019; Herring N et al., 2009, Exp Physiol, 94:46-53; McAllen R M et al., 2011, J Physiol, 589:5801-5818). Neuronal imbalances within the ICNS can exert deleterious effects on cardiac function, including arrhythmia induction (Armour J A et al., 1972, Am J Physiol, 223:1068-1075; Armour J A et al., 2005, Auton Neurosci, 118:68-78; Scherlag B J et al., 2011, J Cardiovasc Transl Res, 4:35-41; Shen M J et al., 2012, Nat Rev Cardiol, 9:30-39). To date, which populations of neurons within the ICNS are so involved remains unresolved.

Therefore, there is a need in the art for an improved understanding of the role that specific neurons have in mediating AF, and there is also a need in the art for improved bioelectric cardiac therapies. The present invention addresses these needs.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a method of modulating cardiac function in a subject, comprising measuring the electrical activity of at least one intrinsic cardiac neuron; and modulating the activity of a nerve or ganglion of the parasympathetic autonomic nervous system. In one embodiment, the method comprises contacting an electrode to the nerve or ganglion of the parasympathetic autonomic nervous system; and applying at least one electrical signal to the nerve or ganglion of the parasympathetic autonomic nervous system.

In one embodiment, the nerve or ganglion of the cardiac nervous system is selected from the group consisting of the vagus nerve, spinal cord, and mediastinal nerve.

In one embodiment, the electrode is contacted to at least one of the group consisting of: cervical vagosympathetic nerve trunk, intrathoracic vagosympathetic nerve trunk, and auricular branch of vagus nerve. In one embodiment, the electrical activity of the nerve or ganglion increased by application of electrical stimulation. In one embodiment, the electrical activity of the nerve or ganglion is decreased by application of kilohertz frequency alternating current (KHFAC) or charge balanced direct current (CBDC).

In one embodiment, the method comprises contacting an electrode to the spinal cord, and applying at least one electrical signal to the spinal cord. In one embodiment, the electrical activity of the spinal cord is increased by application of electrical stimulation. In one embodiment, the electrical activity of the spinal cord is decreased by application of kilohertz frequency alternating current (KHFAC) or charge balanced direct current (CBDC).

In one embodiment, measuring of electrical activity of at least one intrinsic cardiac neuron comprises contacting a recording electrode to at least one selected from the group consisting of: atrial intrinsic cardiac ganglia and ventricular intrinsic cardiac ganglia.

In one embodiment, the method further comprises measuring of electrical activity of at least one neuron of a nodose ganglia.

In one embodiment, the method further comprises measuring cardiac electrical activity by contacting a recording electrode at least one selected from the group consisting of the atrial epicardial surface, atrial endocardial surface, ventricular epicardium, ventricular epicardium, and myocardium of the atrial or ventricular tissue.

In one embodiment, modulating the activity the activity of a nerve or ganglion of the parasympathetic autonomic nervous system is controlled by detection of a signal measured from the at least one intrinsic cardiac neuron.

In one aspect, the present invention provides a closed-loop system for modulating cardiac function comprising one or more recording electrodes for measuring the activity of at least one intrinsic cardiac neuron; and one or more stimulating electrodes for applying an electrical stimulus to a nerve or ganglion of the parasympathetic autonomic nervous system.

In one embodiment, the present invention provides a method for treating or preventing a cardiac disorder in a subject, comprising modulating the activity of at least one local circuit neuron (LCN) of the cardiac nervous system. In one embodiment, the method comprises electrical stimulation of the vagus nerve of the subject

In one embodiment, the method further comprises measuring the electrical activity of at least one intrinsic cardiac neuron.

In one aspect, the present invention provides a method of monitoring multi-pole cardioneural function, comprising measuring the electrical activity of at least one intrinsic cardiac neuron; and measuring the cardiac electrical activity of the heart.

In one embodiment, the method comprises contacting at least one electrode to a location selected from the group consisting of: atrial intrinsic cardiac ganglia and ventricular intrinsic cardiac ganglia. In one embodiment, the method comprises contacting at least one electrode to the atrial epicardial surface or the atrial endocardial surface.

