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European Heart Journal Advance Access originally published online on July 10, 2008
European Heart Journal 2008 29(18):2265-2275; doi:10.1093/eurheartj/ehn337
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

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

Gerd Heusch*, Andreas Skyschally, Petra Gres, Patrick van Caster, Dustin Schilawa and Rainer Schulz

Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany

Received 15 May 2008; revised 19 June 2008; accepted 25 June 2008; online publish-ahead-of-print 10 July 2008.

* Corresponding author. Tel: +49 201 723 4480, Fax: +49 201 723 4481, Email: gerd.heusch{at}uk-essen.de

Aims: 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 {alpha}-adrenergic coronary vasoconstriction. Ivabradine is the only available bradycardic agent for clinical use.

Methods and results: 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.

Conclusion: Ivabradine's protection goes beyond heart rate reduction.

Key Words: Bradycardic agent • Myocardial ischaemia • Myocardial infarction • Reperfusion • Heart rate


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[Abstract] [Full Text] [PDF]


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