A Mechanistic Understanding of Vagus Nerve Stimulation Therapy: Investigating the Effects of Parasympathetic Modulation on Cardiac Dynamics

Abstract

Vagus nerve stimulation (VNS) is a neuromodulatory approach that involves delivering electrical impulses to the vagus nerve to modulate the autonomic nervous system. In addition to being FDA-approved for use in epilepsy and depression, a plethora of both experimental and clinical studies also supports the potential of VNS to treat cardiovascular diseases. While promising, the precise mechanism by which this therapy exerts its cardioprotective effects are not well-established. The central dogma states that vagus nerves primarily innervate the atria with very minimal to no innervation into the ventricles. Based on this concept, parasympathetic system activation by VNS should not significantly affect ventricular properties. This is not the case, however, as VNS has been extensively shown to exert marked anti-arrhythmic effects in the ventricles. Furthermore, this supposition that there is minimal vagal innervation into the ventricular myocardium has been challenged by a series of immunohistochemical, histological, and western blot experiments. The first aim of my dissertation was to investigate the potential for a direct effect of long-term VNS on ventricular electrophysiology and test the hypothesis that VNS induces electrical remodeling of the ventricles to render the therapy’s reported anti-arrhythmic effects. Secondly, I then examined the direct contributions of the M2 muscarinic receptor activated potassium channel (M2R-IKACh) in mediating the chronotropic effects of VNS. For this second aim, I applied VNS on several transgenic mice that lack the IKACh channel constitutively, and selectively in the atria or the ventricles. Thirdly, there still does not exist a universally accepted published prospective VNS paradigm, which further highlights the complexity of parameter optimization. This work introduced an innovative concept of incorporating stochasticity when stimulating the vagus nerve (stochastic VNS, S-VNS) and I evaluated the effects of S-VNS on acute heart rate (HR) dynamics in comparison to traditional, periodic VNS. Collectively, the work performed in this thesis contribute to the mechanistic understanding of VNS therapy, in particular to the fundamental role of the parasympathetic nervous system in ventricular electrophysiology, and facilitate the optimization and improvement of VNS efficacy.