Following myocardial infarction (MI), patients have an increased risk of ventricular arrhythmias and sudden cardiac death. Remodeling of the cardiac sympathetic nervous system (SNS) occurs post-MI and recent experimental and clinical studies suggest that both sympathetic hyperinnervation and denervation are associated with ventricular arrhythmias. Adverse electrophysiological (EP) remodeling also occurs post-MI and includes changes to ion channels, gap junctions, and Ca2+ handling that can lead to both the trigger and substrate for ventricular arrhythmia. Individually, many SNS and EP factors have been linked to ventricular arrhythmias. However, the precise mechanisms by which post-MI SNS remodeling contributes to ? and interacts with ? EP remodeling have never been systematically investigated. The overall objective of this project is to determine the individual and interacting roles of SNS and EP remodeling in producing the triggers and substrate for ventricular arrhythmias post-MI, which may unveil novel anti-arrhythmic strategies. To meet this objective, an innovative set of methodologies has been developed, including novel approaches for modulation of cardiac innervation combined with dual optical mapping of Vm and intra-sarcoplasmic reticulum (SR) Ca2+ in the intact, fully innervated Langendorff-perfused rabbit heart.
Aim 1 will focus on acute effects of SNS stimulation in the normal heart and how SR and intracellular Ca2+ handling play a role in mediating arrhythmogenic changes. Experiments will address the hypothesis that SNS-dependent effects on SR Ca2+ and Ca2+i generate triggers for arrhythmia and modulate repolarization to create the substrate for reentry. The impact of non-classical neurotransmitters in mediating these effects will also be examined.
Aim 2 will determine the impact of chronic SNS remodeling (hyper- or denervation) on arrhythmogenesis, including the role of Ca2+ handling in mediating these effects. Here, hyper- or denervation will be created independent of MI, allowing for the separation of MI-induced changes from SNS remodeling. The contributions of acute SNS stimulation and circulating catecholamines to hyper- or denervation-induced arrhythmias will be examined.
Aim 3 will focus on the interplay between SNS remodeling and EP remodeling in the post-MI rabbit heart and novel anti-arrhythmic strategies aimed at preventing SNS remodeling will be tested. The results of this study will provide unprecedented mechanistic insight into the individual and synergistic contributions of SNS and EP remodeling in post-MI arrhythmogenesis and will determine whether targeting key nerve-heart interactions represents a novel therapeutic approach.

Public Health Relevance

Myocardial infarction (MI, also known as a heart attack) predisposes patients to deadly cardiac arrhythmias (disturbances of the normal heart rhythm). Following MI, the sympathetic nerves in the heart undergo changes to their structure and function and these changes are 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 after MI are unknown. The goal of this project is to determine the role of sympathetic nerve activity in leading to arrhythmias, which may lead to new anti-arrhythmic treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111600-07
Application #
9402115
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Tjurmina, Olga A
Project Start
2012-04-16
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Davis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Lindsey, Merry L; Jung, Mira; Yabluchanskiy, Andriy et al. (2018) Exogenous CXCL4 Infusion Inhibits Macrophage Phagocytosis by Limiting CD36 Signaling to Enhance Post-myocardial Infarction Cardiac Dilation and Mortality. Cardiovasc Res :
Ripplinger, Crystal M (2018) The best thing since sliced bread? Optical mapping of transverse cardiac slices in the mouse heart. J Physiol 596:3825-3826
Francis Stuart, Samantha D; Wang, Lianguo; Woodard, William R et al. (2018) Age-related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation. J Physiol 596:3977-3991
Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838
Parrish, Diana C; Francis Stuart, Samantha D; Olivas, Antoinette et al. (2018) Transient denervation of viable myocardium after myocardial infarction does not alter arrhythmia susceptibility. Am J Physiol Heart Circ Physiol 314:H415-H423
Ripplinger, Crystal M (2017) From drugs to devices and back again: chemical vagal nerve stimulation for the treatment of heart failure. Cardiovasc Res 113:1270-1272
Lang, Di; Sato, Daisuke; Jiang, Yanyan et al. (2017) Calcium-Dependent Arrhythmogenic Foci Created by Weakly Coupled Myocytes in the Failing Heart. Circ Res 121:1379-1391
De Jesus, Nicole M; Wang, Lianguo; Lai, Johnny et al. (2017) Antiarrhythmic effects of interleukin 1 inhibition after myocardial infarction. Heart Rhythm 14:727-736
Murphy, Shannon R; Wang, Lianguo; Wang, Zhen et al. (2017) ?-Adrenergic Inhibition Prevents Action Potential and Calcium Handling Changes during Regional Myocardial Ischemia. Front Physiol 8:630
Chiamvimonvat, Nipavan; Chen-Izu, Ye; Clancy, Colleen E et al. (2017) Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics. J Physiol 595:2229-2252

Showing the most recent 10 out of 34 publications