Over half of all deaths in non-ischemic heart failure (HF) are due to ventricular arrhythmias, primarily ventricular tachycardia (VT) degenerating to ventricular fibrillation (VF). In non-ischemic HF, VT can initiate by non- reentrant (focal) mechanisms likely due to delayed after depolarizations (DADs). The heterogeneous HF substate may then allow focal activity to convert to reentrant VT/VF. Thus, lethal arrhythmias in HF likely require a focal triggr for initiation and a vulnerable substrate that promotes reentry. HF electrophysiological remodeling can promote DADs and cause pro-arrhythmic changes to the substrate. ?-adrenergic receptor (?-AR) stimulation can exacerbate DADs and further perturb the abnormal ionic currents and Ca2+ transients (CaT) found in HF. Moreover, cardiac sympathetic nerve remodeling in HF may lead to localized ?-AR stimulation and spatially heterogeneous effects. Electrophysiological and sympathetic remodeling has been individually linked to arrhythmia in HF. However, the interplay between local ?-AR stimulation and altered HF electrophysiology in arrhythmogenesis has not been explored. The overall objective of this proposal is to systematically determine the role of local ?-AR stimulation in producing the trigger and substrate for ventricular arrhythmias and how electrophysiological remodeling in non-ischemic HF exacerbates these effects. Our over-arching hypothesis is that local ?-AR stimulation causes 1) spatiotemporal synchronization of DADs across many cells to provide focal triggers;and 2) local electrophysiological heterogeneity to produce the substrate for reentrant VT/VF. We further hypothesize that electrophysiological remodeling in HF exacerbates the pro-arrhythmic effects of local ?-AR stimulation, both in generating triggers and in modifying the substrate. To address these hypotheses, dual optical mapping of Vm and Ca2+ will be performed on isolated rabbit hearts while administering local norepinephrine (NE).
Aim 1 will focus on the mechanisms by which local ?-AR stimulation triggers focal arrhythmia in healthy rabbit hearts. We will then systematically test the effects of HF- associated electrophysiological remodeling on the propensity to focal activity by pharmacologically mimicking key HF phenotypes.
Aim 2 focuses on the role of local ?-AR stimulation in contributing to the substrate for reentry via dispersion o action potential and CaT properties and development of alternans. We will also test the effects of key HF-associated electrophysiological mechanisms in contributing to reentry during local ?-AR stimulation.
In Aim 3, we will determine the arrhythmogenic role of localized ?-AR stimulation in a rabbit model of non-ischemic HF by applying exogenous as well as invoking endogenous sympathetic stimulation followed by a quantitative assessment of neurochemistry in HF. We will then assess the therapeutic potential of reversing key HF phenotype(s) with newly proposed anti-arrhythmic strategies. Overall, the results of this project will define the firt mechanistic link between sympathetic dysfunction and ventricular arrhythmias in non-ischemic HF and will greatly advance our long-term goal of predicting and preventing sudden cardiac death in HF.

Public Health Relevance

Heart failure predisposes patients to deadly cardiac arhythmias (disturbances of the normal heart rhythm). Increased activity of the cardiac sympathetic nerves is known to be associated with arrhythmias. But how exactly sympathetic nerve activity leads to arrhythmias and the interaction between nerve activity and other changes that occur in the heart during heart failure are unknown. The goal of this project is to determine the role of local sympathetic nerve activity in leading to arrhythmias in heart failure. The result of this study will shed new light on proper therapeutic treatments for heart failure patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Lathrop, David A
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University of California Davis
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United States
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