Mechanisms of Parasympathetic Dysfunction Following Myocardial Infarction
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Mechanisms of Parasympathetic Dysfunction Following Myocardial Infarction


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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