CARDIAC NEUROMODULATION IN HUMANS: MECHANISMS & THERAPIES

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Current state of knowledge on the etiology and clinical characteristics of cardiovascular disease: Cardiovascular disease is the leading cause of morbidity and mortality in the US and the world. The autonomic nervous system (ANS) plays a central role in the pathogenesis of several cardiovascular diseases such as atrial fibrillation, hypertension, myocardial infarction (MI), ventricular tachyarrhythmias/fibrillation (VT/VF) and in the progression of heart failure (HF). Heart failure also places a major financial burden on the US health system, affecting five million people, and it is estimated to grow to eight million by 2030. Sympathovagal balance, seen in normal health, is perturbed in the presence of cardiac disease leading to ‘net’ sympathoexcitation, which is due to an increase in sympathetic output and a concomitant decrease in parasympathetic output. Neuromodulation therapies are directed toward restoring sympathovagal balance and thereby attempt to reverse/prevent progression of cardiovascular disease. Neuromodulation therapies such as stellate ganglionectomy/cardiac sympathetic denervation (CSD) are now being clinically utilized and other neuraxial approaches show a lot of promise including vagus nerve stimulation (VNS). However, clinical trials have shown mixed results preventing broad application of therapy. This highlights the major knowledge gap that exists regarding their mechanisms of action and the determination of optimal bioelectric parameters and physiological readouts in the clinical setting. As an example, tragal vagus nerve stimulation (TVNS), has demonstrated potential benefit in reducing inflammation and preventing progressive myocardial pathological remodeling. However, little is known about how to dose the therapy to maximize the effects of TVNS in preventing or reversing autonomic dysfunction in patients who have already suffered from cardiac disease such as MI. In a series of translational/mechanistic studies, neuromodulation will be applied to healthy subjects and to those with heart disease (MI or VT) to define optimal parameters and readouts and to determine how neuromodulation impacts electrophysiological parameters of the heart.