Dataset Information

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death.

ABSTRACT: Neural remodeling in the autonomic nervous system contributes to sudden cardiac death. The fabric of cardiac excitability and propagation is controlled by autonomic innervation. Heart disease predisposes to malignant ventricular arrhythmias by causing neural remodeling at the level of the myocardium, the intrinsic cardiac ganglia, extracardiac intrathoracic sympathetic ganglia, extrathoracic ganglia, spinal cord, and the brainstem, as well as the higher centers and the cortex. Therapeutic strategies at each of these levels aim to restore the balance between the sympathetic and parasympathetic branches. Understanding this complex neural network will provide important therapeutic insights into the treatment of sudden cardiac death.

SUBMITTER: Huang WA

PROVIDER: S-EPMC5777242 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Publications

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death.

Huang William A WA Boyle Noel G NG Vaseghi Marmar M

Cardiac electrophysiology clinics 20171201 4

Neural remodeling in the autonomic nervous system contributes to sudden cardiac death. The fabric of cardiac excitability and propagation is controlled by autonomic innervation. Heart disease predisposes to malignant ventricular arrhythmias by causing neural remodeling at the level of the myocardium, the intrinsic cardiac ganglia, extracardiac intrathoracic sympathetic ganglia, extrathoracic ganglia, spinal cord, and the brainstem, as well as the higher centers and the cortex. Therapeutic strate ...[more]

PMID: 29173409

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Project description:OBJECTIVES:Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice. METHODS:The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1rCM-/-). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo. RESULTS:Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1rCM-/- mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1rCM-/- mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart. CONCLUSIONS:GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.

Dataset Information

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death.

Publications

Cardiac Innervation and the Autonomic Nervous System in Sudden Cardiac Death.

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