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Cardiac pacemaker channel (HCN4) inhibition and atrial arrhythmogenesis after releasing cardiac sympathetic activation

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Item Type:Article
Title:Cardiac pacemaker channel (HCN4) inhibition and atrial arrhythmogenesis after releasing cardiac sympathetic activation
Creators Name:Chobanyan-Jürgens, K. and Heusser, K. and Duncker, D. and Veltmann, C. and May, M. and Mehling, H. and Luft, F.C. and Schröder, C. and Jordan, J. and Tank, J.
Abstract:Clinical trials and studies with ivabradine implicate cardiac pacemaker channels (HCN4) in the pathogenesis of atrial arrhythmias. Because acute changes in cardiac autonomic tone predispose to atrial arrhythmias, we studied humans in whom profound cardiac sympathetic activation was rapidly relieved to test influences of HCN4 inhibition with ivabradine on atrial arrhythmias. We tested 19 healthy participants with ivabradine, metoprolol, or placebo in a double blind, randomized, cross-over fashion on top of selective norepinephrine reuptake inhibition with reboxetine. Subjects underwent combined head up tilt plus lower body negative pressure testing followed by rapid return to the supine position. In the current secondary analysis with predefined endpoints before data unblinding, continuous finger blood pressure and ECG recordings were analyzed by two experienced cardiac electrophysiologists and a physician, blinded for treatment assignment. The total atrial premature activity (referred to as atrial events) at baseline did not differ between treatments. After backwards tilting, atrial events were significantly higher with ivabradine compared with metoprolol or with placebo. Unlike beta-adrenoreceptor blockade, HCN4 inhibition while lowering heart rate does not protect from atrial arrhythmias under conditions of experimental cardiac sympathetic activation. The model in addition to providing insight in the role of HCN4 in human atrial arrhythmogenesis may have utility in gauging potential atrial pro-arrhythmic drug properties.
Keywords:Artificial Pacemaker, Autonomic Nervous System, Blood Pressure, Cardiac Arrhythmias, Cardiovascular Agents, Cross-Over Studies, Double-Blind Method, Heart Rate, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Ivabradine, Muscle Proteins, Potassium Channels, Prospective Studies
Source:Scientific Reports
Publisher:Nature Publishing Group
Page Range:7748
Date:17 May 2018
Official Publication:https://doi.org/10.1038/s41598-018-26099-9
PubMed:View item in PubMed

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