Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization- activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the If current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of If inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.
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