Ivabradine is as effective as metoprolol in the prevention of ventricular arrhythmias in acute non-reperfused myocardial infarction in the rat

Mariusz Marciszek,Urszula Mackiewicz,Aleksandra Paterek,Michał Mączewski,Marta Oknińska

doi:10.1038/s41598-020-71706-3

Mariusz Marciszek, Urszula Mackiewicz + Show 3 more

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https://doi.org/10.1038/s41598-020-71706-3

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Journal: Scientific Reports	Publication Date: Sep 14, 2020
Citations: 5	License type: open-access

Affiliation: Postgraduate School of Molecular Medicine

Abstract

Ventricular arrhythmias are a major source of early mortality in acute myocardial infarction (MI) and remain a major therapeutic challenge. Thus we investigated effects of ivabradine, a presumably specific bradycardic agent versus metoprolol, a β-blocker, at doses offering the same heart rate (HR) reduction, on ventricular arrhythmias in the acute non-reperfused MI in the rat. Immediately after MI induction a single dose of ivabradine/ metoprolol was given. ECG was continuously recorded and ventricular arrhythmias were analyzed. After 6 h epicardial monophasic action potentials (MAPs) were recorded and cardiomyocyte Ca2+ handling was assessed. Both ivabradine and metoprolol reduced HR by 17% and arrhythmic mortality (14% and 19%, respectively, versus 33% in MI, p < 0.05) and ventricular arrhythmias in post-MI rats. Both drugs reduced QTc prolongation and decreased sensitivity of ryanodine receptors in isolated cardiomyocytes, but otherwise had no effect on Ca2+ handling, velocity of conduction or repolarization. We did not find any effects of potential IKr inhibition by ivabradine in this setting. Thus Ivabradine is an equally effective antiarrhythmic agent as metoprolol in early MI in the rat. It could be potentially tested as an alternative antiarrhythmic agent in acute MI when β-blockers are contraindicated.

Highlights

Ventricular arrhythmias are a major source of early mortality in acute myocardial infarction (MI) and remain a major therapeutic challenge
In this context we have recently shown that ivabradine, a putative selective inhibitor of cardiac pacemaker F current (IF) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and pure heart rate (HR) reducing agent that is devoid of hemodynamic effects of β-blockers[4], reduces ventricular arrhythmias and mortality in the model of acute non-reperfused MI in the r at[5]
Within 1 h of MI induction 7, 7 and 8 animals died in MI, MI + Iva and MI + Meto groups, respectively, as well as one animal in the Sham + Meto group, due to bradycardia associated with complete atrioventricular block, without preceding arrhythmia

Summary

Introduction

Ventricular arrhythmias are a major source of early mortality in acute myocardial infarction (MI) and remain a major therapeutic challenge. After 6 h epicardial monophasic action potentials (MAPs) were recorded and cardiomyocyte Ca2+ handling was assessed Both ivabradine and metoprolol reduced HR by 17% and arrhythmic mortality (14% and 19%, respectively, versus 33% in MI, p < 0.05) and ventricular arrhythmias in post-MI rats. In this context we have recently shown that ivabradine, a putative selective inhibitor of cardiac pacemaker F current (IF) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channel and pure HR reducing agent that is devoid of hemodynamic effects of β-blockers[4], reduces ventricular arrhythmias and mortality in the model of acute non-reperfused MI in the r at[5] As it was given as prophylaxis before MI induction and was found to e.g. prevent HCN4 overexpression, it is unknown if its acute administration after MI induction would be effective. metoprolol[7], and ivabradine, at doses providing equal HR reduction, given immediately after induction of a non-reperfused MI in the rat and studied potential mechanisms of these drugs

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