Ventricular arrhythmias and mechanisms of parasympathetic dysfunction following myocardial infarction

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ABSTRACT Ventricular arrhythmias (VT/VF) due to cardiac disease and myocardial infarction (MI) lead to sudden cardiac death. To prevent sudden cardiac death, implantable cardiac defibrillators (ICD) are used. Although defibrillators save lives by aborting dangerous arrhythmias, they neither prevent recurrence of VT/VF nor progression of the underly disease. Recurrent ICD shocks are associated with increased mortality and hospitalizations, and decreased quality of life. Despite our current therapies, including catheter ablation, 60- 75% of patients have recurrence of their VT/ICD shocks at 2 years. Additional therapies are desperately needed. Chronic sympathetic activation and reduced parasympathetic function increase risk of VT/VF and recurrent ICD shocks. MI leads to amplification of sympathetic afferent signaling, which increases sympathetic outflow to the heart and causes release of not only, norepinephrine, but several co-transmitters, including neuropeptide Y and galanin. These neuropeptides have much longer half-lives than norepinephrine, and elevated sympathetic neuropeptide levels in MI and heart failure are associated with increased mortality. It has also been known for decades that MI reduces parasympathetic function, the body's own anti-arrhythmic drug, increasing risk of VT/VF. However, clinical trials that attempted to increase vagal outflow by stimulating mixed nerves (vagal nerve stimulation, spinal cord stimulation) have had disappointing results, likely because the reasons behind chronic parasympathetic “withdrawal” remain unknown. In order develop new targeted therapies, it is critical to understand mechanisms underlying parasympathetic dysfunction and sympathetic and parasympathetic interactions that occur in the setting of cardiac disease. In this proposal, we aim to test the novel hypotheses that (1) persistent efferent sympathetic activation due to MI inhibits parasympathetic function at the nerve-myocyte interface (the neuro-effector junction) due to release of sympathetic co- transmitters and (2) sympathetic afferent activation reduces central vagal tone. In specific aim 1, we will test whether inhibition of sympathetic neuropeptides, neuropeptide Y and galanin, improves vagal tone and prove anti-arrhythmic. In aim 2, we will test whether sympathetic afferent blockade improves parasympathetic function and decreases ventricular arrhythmias. For aims 1 and 2, we will utilize hemodynamic and multi- electrode array neural recordings simultaneously with high-density electrophysiological mapping and direct interstitial norepinephrine measurements in a large animal model. Aim 3 will evaluate whether disruptions of sympathetic signaling via cardiac sympathetic denervation, the only current therapy that interrupts sympathetic afferent fibers and potentially reduces co-transmitters levels, will improve parasympathetic function in patients with scar-mediated VT. Understanding these fundamental autonomic pathways has the potential to accelerate development of disease-modifying targeted therapies for ventricular arrhythmias in the U.S. and worldwide.