Abstract
Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.
Highlights
In the rat model of acute non-reperfused myocardial infarction (MI) we showed that ivabradine prevented dispersion of electrical and biochemical properties between the infarct borderzone and the remote ventricular myocardium, essentially preventing early ischemiarelated shortening of AP and late (24 h) prolongation of AP related to downregulation of potassium channels (ERG and KVLQTI) in the infarct borderzone [25]
Other experimental studies support this conclusion: we showed that ivabradine and metoprolol provided similar protection against VA induced by acute non-reperfused MI when given at doses that ensured identical HR reduction [57]
This study suggests that upregulation of If in chronic heart failure (CHF) may be proarrhythmic in the mechanism of increased automaticity, but this trigger alone is not sufficient to induce life threatening, clinical malignant arrhythmias [65]
Summary
Hyperpolarization-activated, cyclic-nucleotide-gated channels form a family of nonselective cation channels conducting mainly sodium and potassium ions through the plasma membrane and generating a current termed If (for “funny“). They have a unique biophysical behavior, i.e., they open upon hyperpolarization and result in an inward, depolarizing, predominantly sodium current and the name of the current, “funny” [4]; they are deactivated by depolarization. They are activated by cyclic nucleotides, cAMP and cGMP [5] and they are called “hyperpolarization-activated, cyclic-nucleotide-gated” (HCN) channels. Sensitivity to cAMP is highest in HCN2 and 4, weak in HCN1, while HCN3 exhibits no cAMP sensitivity [10]
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