Investigating the Impact of Selective Vagal Neuromodulation on Heart Failure Indices

Project Summary/Abstract With a five-year mortality rate of over 50% and an estimated 70 billion dollar annual cost burden projected for the United States by 2030, improved treatment modalities are needed to advance treatments for heart failure. Because the heart is heavily regulated by autonomic nervous system inputs and neuronal circuitry within the heart, the investigation of neuromodulation strategies is of great interest. Parasympathetic pathways of the vagus nerve balance hyperactivity associated with sympathetic overdrive, and infer cardioprotective effects by preventing hypertrophy of cardiomyocytes, reducing structural remodeling in the heart, and down-regulating inflammatory mediators. However, vagus nerve stimulation (VNS) in clinical trial heart failure patients has not translated to improvements in primary metrics of cardiac remodeling, functional output, and rate of death, although quality of life metrics were improved in multiple studies. Due to the lack of translation from pre-clinical data to clinical outcomes, better understanding of the neural interface is needed. The current project will study the impact of selective vagal neuromodulation in a heart failure model on left ventricle structure & function indices as well as inflammatory mediators in the myocardium. The study will employ optical neuromodulation of the vagus nerve which enables axonal recruitment profiles not feasible with electrical VNS. Selective activation of cholinergic (efferent) and glutamatergic (afferent) neuronal subsets will be targeted to isolate the impact of these vagal components. Micro-resolution, 3D-printed silicone nerve cuffs will be leveraged in rodent models of heart failure to characterize the effect of a chronic two-month period of vagal stimulation on left ventricle structure & function and inflammatory mediators in the myocardium. Results of this study will inform stimulation protocols for current VNS systems by assessing the therapeutic contribution of cholinergic and glutamatergic axonal subsets in heart failure treatment.