The autonomic nervous system regulates cardiac excitability and genesis of ventricular tachyarrhythmias (VT/VF). Myocardial infarction leads to sympathetic activation and parasympathetic dysfunction, which act in concert to increase risk of sudden death due to VT/VF. The mechanism behind parasympathetic dysfunction and the electrophysiological effects of vagal nerve stimulation are poorly characterized.

The vago-symapthetic trunks carries both efferent cardiomotor as well as cardiac afferent fibers that transduce mechano-chemical changes. To better delineate and compare their functional effects, in normal porcine hearts in vivo, right and left vagal nerve stimulation (VNS) was performed and hemodynamic parameters and activation recovery interval mapping (ARI) performed. ARI is a validated surrogate of local action potential duration. Subsequently, role of afferent fiber activation during VNS on efferent control of cardiac function was assessed by transection of right and/or left, and ispilateral, contralateral, and/or bilateral trunks. Finally, mechanism behind neural parasympathetic remodeling due to myocardial infarction (MI) and the anti-arrhythmic effects of VNS were assessed in a chronic porcine infarct model.

In normal porcine hearts, right and left VNS significantly decreased heart rate and dP/dt max and prolonged regional ARI. No anterior-posterior-lateral ventricular regional differences in prolongation of ARI were found. However, endocaridal ARI increased more than epicardial ARI, and apical ARI more than basal ARI, during right and left VNS. With regards to afferent fiber activation during VNS, an augmentation in hemodynamic and electrophysiological effects of right VNS after ipsilateral vagal nerve transection was observed. Similar changes were suggested by left VNS after left vagal nerve transection, however, contralateral vagal nerve transection did not modify VNS response. Finally, measurement of regional acetylcholine, the primary neurotransmitter of cardiac parasympathetic neurons, showed that this neurotransmitter is primarily preserved in infarcted hearts. However, direct neural recordings from intrinsic cardiac ganglia showed significant alterations in the basal activity of parasympathetic efferent neurons that receive input from the left vagal trunk, suggesting a decrease in central parasympathetic drive. Augmentation of parasympathetic drive with VNS reduced ventricular tachy-arrhythmia inducibility by decreasing dispersion of repolarization in border zone regions of infarcted hearts.

In conclusion, both right and left vagi provided significant innervation to the ventricular myocardium, modulating both cardiac electrical and mechanical function. VNS activated both afferent and efferent fibers in the ispilateral vagal trunk, and afferent fiber activation reduced efferent physiological effects. Myocardial infarction led to significant neural remodeling and alteration in the behavior of parasympathetic neurons in the cardiac ganglia, changes that were suggestive of decreased central parasympathetic drive. VNS restored this drive and electrically stabilized infarct border zones, reducing ventricular arrhythmias.

The sympathetic and the parasympathetic nervous systems (PNS), exert opposing control over beat-to-beat cardiac function but following myocardial infarction (MI), their balance is disrupted. Sustained sympathetic hyperactivity coupled with PNS withdrawal promotes cardiac electrical heterogeneity and predisposes to ventricular tachycardia (VT). PNS blockade is pro-arrhythmic and the restoration of PNS function is anti-arrhythmic, in part through prolonging ventricular action potential duration (APD) and reducing electrical heterogeneity. Thus, expanding our understanding on PNS dysfunction is paramount to designing better therapies. This dissertation aims to dissect the neural circuitry underlying PNS withdrawal post-MI. Chapters 1 and 2 expand the therapeutic potential and applicability of augmenting PNS activity. Chapter 2 demonstrated that vagal nerve stimulation (VNS) remains anti-arrhythmic despite sympathoexcitation post-MI. These cardioprotective effects were mediated by prolongation of ventricular APD and reductions in electrical heterogeneity in the scar and border zone, known regions of arrhythmogenesis. Chapter 3 extends these potential anti-arrhythmic effects to patients with chronic MI. Chapter 3 assesses the role of vagal afferents in mediating vagal efferent dysfunction. In health, nociceptive afferent activation increase vagal efferent outflow. However, in vivo neural recording and detailed histology revealed that post-MI, nociceptive afferents may instead decrease PNS tone through augmented release of GABA, a novel pathway of vagal inhibition. Chapter 4 examines the role of spinal afferent signaling in suppressing central PNS outflow. Thoracic epidural anesthesia (TEA), a neuromodulatory approach under investigation for its anti-arrhythmic effects, is generally regarded as a sympatho-inhibitory technique. However, we show herein that the anti-arrhythmic effects of TEA may in part be mediated by PNS augmentation. Moreover, these studies implicate an important role for spinal afferents in post-MI PNS inhibition. Lastly, Chapter 5 explores the role of the sympathetic co-transmitter, neuropeptide Y (NPY), in cardiac control. We established the frequency dependent release of NPY in healthy pigs, in vivo. We observed that high frequency sympathetic stimulation circumvents traditional therapy with beta-blockers, even at supramaximal doses. However, the NPY Y1 receptor-selective antagonist, BIBO 3304, mitigated the residual electrophysiological effects of sympathetic stimulation. These studies set the stage for further investigations into other NPY receptor subtypes, such as the Y2� receptor, which is expressed on PNS neurons. Agonism of the Y2 receptor reduces neuronal calcium influx and the release of acetylcholine, a potential mechanism for reductions in cardiac PNS tone. In conclusion, PNS augmentation is anti-arrhythmic despite sympathoexcitation, suggesting that relief of central PNS suppression may also be independently anti-arrhythmic. However, post-MI PNS withdrawal may be mediated at several levels of the cardiac neuraxis by nociceptive afferent inhibition (vagal reflexes), spinal sympathetic afferent signaling (spinal reflexes), and/or excessive sympathetic efferent tone causing release of NPY (sympathetic – parasympathetic crosstalk). Therapies targeting these novel pathways may restore central parasympathetic tone and suppress arrhythmogenesis, especially in patients who are refractory to traditional therapy.

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