Cardiovascular Research Advance Access first published online on May 28, 2009
This version [Corrected Proof] published online on June 11, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp158
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Heart rate reduction with ivabradine improves energy metabolism and mechanical function of isolated ischaemic rabbit heart
1 Department of Cardiology, University of Ferrara, Corso Giovecca, 203, 44100 Ferrara, Italy
2 Cardiovascular Research Center, Fondazione ‘Salvatore Maugeri’, IRCCS, Ferrara, Italy
3 Centro di Ricerca E Menni, Fondazione Poliambulanza, Istituto Ospedaliero, Via Bissolati 57 25124, Brescia, Italy
4 Cardiovascular Research Center, Fondazione ‘Salvatore Maugeri’, IRCCS, Lumezzane, Italy
5 Medical Statistics, University of Brescia, 25121 Brescia, Italy
* Corresponding author. Tel: +39 0532 202143; fax: +39 0532 241885. E-mail address: fri{at}dns.unife.it
Aims: The anti-anginal agent ivabradine slows heart rate (HR) by selectively inhibiting the If current in the sinus node. We report an ex vivo study to evaluate the anti-ischaemic effect of ivabradine in terms of modulation of cardiac energy metabolism.
Methods and results: A Langendorff-perfused rabbit heart model was subjected to low-flow ischaemia and reperfusion. Cardiac metabolism was studied by measuring cardiac high-energy phosphate contents via HPLC, mitochondrial respiration was analysed polarographically, and cardiac redox potentials by HPLC. Cardiac function was determined in terms of the recovery of developed pressure during reperfusion and release of creatine kinase (CK) (spectrophotometrically) and noradrenaline (HPLC) after reperfusion. Four concentrations of ivabradine (0.3, 1, 3, and 6 µM) were tested on aerobically perfused hearts to select the most effective without causing changes in mechanical parameters. This proved to be 3 µM, which was therefore the concentration selected for the ischaemia-reperfusion experiments. Ivabradine concentration-dependently reduced HR with a maximal effect of 41 ± 4% at 3 µM (P < 0.001 vs. vehicle), without a negative inotropic effect. This concentration protected the heart against ischaemia-reperfusion damage by reducing the rise in diastolic pressure (from 66 ± 3 with vehicle to 39 ± 4 mmHg, P < 0.01) and improving developed pressure after 30 min reperfusion (39 ± 3 vs. 18 ± 3 mmHg with vehicle, P < 0.01). Ivabradine reduced both CK and noradrenaline release by 47% (both P < 0.05 vs. vehicle) and improved mitochondrial respiratory control index (from 6.9 ± 0.3 to 11.9 ± 1.3, P < 0.001). It preserved cardiac energy metabolism (ATP, from 3.7 ± 0.3 to 11.0 ± 0.6 µM/g dry weight, P < 0.001) and redox state (NADPH/NADP+, from 2.5 ± 0.5 to 4.2 ± 0.5, P < 0.001). There was a significant correlation between HR reduction in the ivabradine-treated hearts and cardiac creatine phosphate (r = 0.574, P = 0.02) and ATP levels (ATP, r = 0.674, P = 0.0042) at the end of ischaemia. These benefits were no longer detectable during pacing.
Conclusion: HR reduction by ivabradine confers a marked anti-ischaemic benefit. It significantly reduces cardiac energy consumption, preserves redox potentials during ischaemia, and enhances recovery at reperfusion.
KEYWORDS Ivabradine; Heart rate reduction; Anti-ischaemic action; Cardiac metabolism
Time for primary review: 19 days
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Cardiovasc Res 2009 84: 9-10.
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