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Abstract 501: Selective i
 n vivo
 Modulation of Vagal-Muscarinic Signaling Prevents Sudden Cardiac Death in a Pressure Overload Model of Heart Failure


 Introduction:
 Sudden cardiac death (SCD) from ventricular tachyarrhythmias (VT/VF) claims a quarter millions lives/year in USA. Patients with heart failure (HF) have high SCD risk. We previously demonstrated that differential remodeling of cardiac muscarinic receptors plays a critical role in pathogenesis and for effective therapy of HF and SCD risk [PMID: 25733594]. Ongoing clinical trials of chronic vagus nerve stimulation (cVNS) aimed at improving left ventricular (LV) function in HF patients have had mixed preliminary results. However, the effect of cVNS on SCD risk is unexplored. While
 acute
 VNS terminates VT/VF, cVNS likely alters the arrhythmogenic substrate. A better understanding of the underlying mechanisms is necessary for the design of new, more effective therapies.
 
 
 Hypothesis:
 cVNS prevents SCD by reducing calcium, autonomic and redox derangements in LV myocytes and improving repolarization reserve in pressure overloaded hearts.
 
 
 Methods:
 Guinea pigs are randomized to Sham or aortic constriction (AC) with daily brief (30-min) low-dose β-adrenergic stress (Shami; ACi), with and without
 in vivo
 cVNS therapy via an implanted device, with and without
 in vivo
 end-organ muscarinic receptor blockade (MRB) using glycopyrrolate. Echocardiography and continuous 24-hour ECG analyses are performed. Animals are sacrificed at 4 weeks for biochemical, excised perfused heart (pressure-volume, electrophysiology, optical mapping) and isolated LV myocyte studies at 37°C.
 PRELIMINARY RESULTS:
 Compared to Sham, the M2 subtype of muscarinic receptors are upregulated in AC and ACi, along with reduced calcium cycling, sarcomere shortening and β-adrenergic responsiveness. Whereas ACi+MRB markedly increased SCD incidence, ACi+cVNS prevented SCD. Interestingly, cVNS prolonged but also stabilized the ECG QT interval by reducing dispersion of repolarization in ACi model. Echocardiographic fractional shortening was also higher in ACi+cVNS (52±1%; 4 weeks) compared to ACi (27±2%; 4 weeks) and ACi+MRB (23±5%; 2 weeks).
 
 
 Conclusions:
 Chronic
 in vivo
 perturbation of cholinergic signaling may be an effective strategy for SCD therapy. Ongoing experiments are aimed at dissecting underlying mechanisms and identifying potential targets for SCD therapy.
