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.
Highlights
Sympathetic and parasympathetic nervous system mechanisms are implicated in atrial arrhythmias
Combination of norepinephrine transporter inhibition and severe orthostatic stress resulted in substantial tachycardia that was attenuated by, both, metoprolol, and ivabradine
Return to the supine position led to rapid heart rate and blood pressure recovery regardless of treatment
Summary
Sympathetic and parasympathetic nervous system mechanisms are implicated in atrial arrhythmias. While parasympathetic activation promotes atrial arrhythmias in younger healthy individuals, adrenergic mechanisms may prevail in older individuals with cardiovascular disease[1]. Rapid fluctuations in cardiac autonomic tone potently promote atrial arrhythmias. Patients with focal ectopy originating from pulmonary veins exhibited transition from cardiac sympathetic to parasympathetic predominance just before paroxysmal atrial fibrillation onset[2]. Rapid tilting back to the supine position acutely augments cardiac vagal activity while attenuating sympathetic drive. We applied the model in a placebo controlled, double blind, crossover study to test the hypothesis that hyperpolarization-activated and cyclic nucleotide-gated 4 (HCN4) channel inhibition with ivabradine promotes atrial arrhythmogenesis in healthy individuals. Beta-adrenoreceptor blockade, which in addition to lowering heart rate attenuates adrenergic influences on atrial and ventricular myocardial cells, served as control intervention
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