Increased arrhythmia susceptibility in type 2 diabetic mice related to dysregulation of ventricular sympathetic innervation.

Autor:	Jungen C; Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany., Scherschel K; Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany., Flenner F; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.; Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Centre, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany., Jee H; University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California., Rajendran P; University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California., De Jong KA; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, University of Hamburg, Germany., Nikolaev V; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, University of Hamburg, Germany., Meyer C; Department of Cardiology-Electrophysiology, cNEP, cardiac Neuro- and Electrophysiology research group, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany., Ardell JL; University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California., Tompkins JD; University of California, Los Angeles Cardiac Arrhythmia Center, Neurocardiology Research Program of Excellence, Department of Medicine-Cardiology, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2019 Dec 01; Vol. 317 (6), pp. H1328-H1341. Date of Electronic Publication: 2019 Oct 18.
DOI:	10.1152/ajpheart.00249.2019
Abstrakt:	Patients with type 2 diabetes mellitus (T2DM) have a greater risk of developing life-threatening cardiac arrhythmias. Because the underlying mechanisms and potential influence of diabetic autonomic neuropathy are not well understood, we aimed to assess the relevance of a dysregulation in cardiac autonomic tone. Ventricular arrhythmia susceptibility was increased in Langendorff-perfused hearts isolated from mice with T2DM ( db/db ). Membrane properties and synaptic transmission were similar at cardiac postganglionic parasympathetic neurons from diabetic and control mice; however, a greater asynchronous neurotransmitter release was present at sympathetic postganglionic neurons from the stellate ganglia of db/db mice. Western blot analysis showed a reduction of tyrosine hydroxylase (TH) from the ventricles of db/db mice, which was confirmed with confocal imaging as a heterogeneous loss of TH-immunoreactivity from the left ventricular wall but not the apex. In vivo stimulation of cardiac parasympathetic (vagus) or cardiac sympathetic (stellate ganglion) nerves induced similar changes in heart rate in control and db/db mice, and the kinetics of pacing-induced Ca 2+ transients (recorded from isolated cardiomyocytes) were similar in control and db/db cells. Antagonism of cardiac muscarinic receptors did not affect the frequency or severity of arrhythmias in db/db mice, but sympathetic blockade with propranolol completely inhibited arrhythmogenicity. Collectively, these findings suggest that the increased ventricular arrhythmia susceptibility of type 2 diabetic mouse hearts is due to dysregulation of the sympathetic ventricular control. NEW & NOTEWORTHY Patients with type 2 diabetes mellitus have greater risk of suffering from sudden cardiac death. We found that the increased ventricular arrhythmia susceptibility in type 2 diabetic mouse hearts is due to cardiac sympathetic dysfunction. Sympathetic dysregulation is indicated by an increased asynchronous release at stellate ganglia, a heterogeneous loss of tyrosine hydroxylase from the ventricular wall but not apex, and inhibition of ventricular arrhythmias in db/db mice after β-sympathetic blockade.
Databáze:	MEDLINE
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