Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction

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Abstract
Effects of the bradycardic agent ivabradine on regional blood flow, contractile function, and infarct size were studied in a pig model of myocardial ischaemia/reperfusion. Heart rate reduction by β-blockade is associated with negative inotropism and unmasked α-adrenergic coronary vasoconstriction. Ivabradine is the only available bradycardic agent for clinical use. Anaesthetized pigs were subjected to 90 min controlled left anterior descending coronary artery hypoperfusion and 120 min reperfusion. Regional blood flow was measured with microspheres, regional function with sonomicrometry, and infarct size with triphenyl tetrazolium chloride staining. Pigs received placebo or ivabradine (0.6 mg/kg i.v.) before or during ischaemia or before reperfusion, respectively. Pre-treatment with ivabradine reduced infarct size from 35 ± 4 (SEM) to 19 ± 4% of area at risk (AAR). Ivabradine 15–20 min after the onset of ischaemia increased regional myocardial blood flow from 2.12 ± 0.31 to 3.55 ± 0.56 µL/beat/g and systolic wall thickening from 6.7 ± 1.0 to 16.3 ± 3.0%; infarct size was reduced from 12 ± 4 to 2 ± 1% of AAR. Ivabradine 5 min before reperfusion still reduced infarct size from 36 ± 4 to 21 ± 5% of AAR. The benefit of ivabradine on flow and function was eliminated by atrial pacing, but part of the reduction of infarct size by ivabradine was not. Ivabradine's protection goes beyond heart rate reduction.