Basic/Translational Science -> Cell Physiology, Pharmacology, and Signaling D-PO02 - Poster Session II (ID 47) Poster

D-PO02-023 - Long-term Therapy With Ivabradine Does Not Improve Mitochondrial Function In Left Ventricular Myocardium Of Dogs With Chronic Heart Failure (ID 165)

  H.N. Sabbah: Research (Contracted Grants for PIs and Named Investigators only) - Servier.


Background: Ivabradine (IVA), a heart rate (HR) lowering drug, acts by selective inhibition of the cardiac pacemaker current If and has been shown to improve LV systolic and diastolic function in dogs with chronic heart failure (HF).
Objective: We tested the hypothesis that long-term therapy with IVA in dogs with HF improves mitochondrial (MITO) function of constituent LV cardiomyocytes as a result of reduced HR.
Methods: Studies were performed in 24 dogs with coronary microembolizations-induced HF (LV ejection fraction, EF~35%) and 7 normal dogs (NL). HF dogs were randomized to 3 months therapy with low dose IVA (15 mg bid, n=8); high dose IVA (30 mg bid, n=8) or placebo (CON, n=8). Freshly isolated LV cardiomyocytes were used to measure MITO ADP-dependent respiration (RESPadp) and respiratory control ratio (RCR). Activities of complex-I (COX-1) of the electron transport chain was measured in MITO membrane fractions using a commercial assay kit. Enzyme activity of MITO complex-IV was determined using Strathkelvin respirometer.
Results: Compared to NL dogs, CON dogs showed a significant reduction of RESPadp, RCR, COX-I and COX-IV activities. Treatment with either low dose or high dose IVA did not significantly improve any of the MITO functional measures.
Conclusion: In HF dogs, the observed improvement in LV function with IVA therapy is not associated with improvement of MITO function and, therefore, is not a direct result of improved energy supply. The improved LV function with IVA is most likely the result of reduced cardiac workload and energy demands brought on by reduced HR, the latter a major determinant of myocardial oxygen consumption.
Mitochondria Functional Measures

NLCONIVA (15 mg bid)IVA (30 mg bid)
RESPadp (ng atoms oxygen consumed/ 106 cardiomyocytes)99 ± 645 ± 9*43 ± 7*70 ± 10*
RCR4.9 ± 0.32.8 ± 0.5*2.8 ± 0.6*3.9 ± 0.7*
COX-I Activity (µmol/min/mg protein)140 ± 1284 ± 10*81 ± 19*83 ± 17*
COX-IV Activity (µmol/min/mg protein)7.9 ± 0.54.4 ± 0.4*4.2 ± 0.3*4.3 ± 0.3*
*=p<0.05 vs. NL