Abstract 11819: Long-Term Monotherapy with Ivabradine Attenuates Mitochondrial Permeability Transition Pore Opening in Cardiomyocytes of Dogs with Chronic Heart Failure
Background: Mitochondria (MITO) respiratory function is abnormal in heart failure (HF). Mitochondrial permeability transition pore (MPTP) opening can affect MITO inner membrane potential and MITO function. We previously showed that long-term monotherapy with ivabradine (IVA), a novel selective and specific inhibitor of the cardiac pacemaker current If, improves LV function and prevents progressive LV remodeling in dogs with moderate HF (LV ejection fraction ∼35%). This study examined the effects of IVA on MPTP opening and state-3 MITO respiration (ADP-dependent oxygen consumption reflecting mitochondrial function) in isolated cardiomyocytes.
Methods: Experiments were performed in isolated cardiomyocytes of 22 HF dogs randomized to 3 months oral monotherapy with high dose (HD) IVA (30 mg twice daily, n=7), low dose (LD) IVA (15 mg twice daily, n=8) or to no therapy at all (Control, n=7). MPTP opening was measured after loading cardiomyocytes with calcein AM for 20 minutes and assessing their intensity by fluorescence microscopy. MITO state-3 respiration was measured with a Clark Electrode. Historical data from 7 normal (NL) dogs were used for comparison.
Results: Data are shown in the table (mean ± SEM). 20 minutes after loading with calcein AM, MITO of control HF dogs showed 31% of maximal level of calcein fluorescence. Calcein fluorescence increased to 41% of maximum level in HF dogs treated with LD-IVA. HD-IVA significantly slowed the exit of calcein from mitochondria by 53% of maximum level compared to controls. State-3 respiration was not affected by LD-IVA but increased by 36% in HF dogs treated with HD-IVA compared to controls.
Conclusions: In dogs with moderate HF, long-term HR reduction with IVA attenuates MPTP opening and, therefore, contributes to the improvement of MITO function. These findings are consistent with the observed beneficial effects of IVA on LV function and LV chamber remodeling.
- Heart failure
- Mitochondrial energetics, heart failure, arrhythmias
- Ventricular function
- Ventricular remodeling
- © 2011 by American Heart Association, Inc.