Influence of ivabradine on reverse remodelling during mechanical unloading.
OBJECTIVE
Ivabradine (Iva) has shown beneficial structural and functional effects in clinical and experimental heart failure (HF), but its action in combination with mechanical unloading (MU), such as during treatment with left ventricular assist devices (LVAD), is unknown. The aim of this study was to investigate the effects of Iva during MU, in a rodent model of HF.


RESULTS
We studied the chronic effects (4 weeks) of Iva (10 mg/kg/day) alone and in combination with MU [induced by heterotopic abdominal heart transplantation (HATx)] on whole-heart and cellular structure, function, and excitation-contraction (E-C) coupling in a rodent (rat) model of HF, 12 weeks post-left coronary artery (LCA) ligation. Effects of Iva were compared with those of β-blockade using metoprolol [(Met), 250 mg/kg/day]. Iva, but not Met, reversed myocardial fibrosis, alone and in combination with MU. MU-induced restoration of deranged E-C coupling was enhanced by Iva to a greater extent than Met: both Iva and Met enhanced the recovery of the Ca(2+) transient amplitude and the sarcoplasmic reticulum (SR) Ca(2+) content, but Iva alone maintained MU-induced normalization of L-type Ca(2+) current and t-tubule abnormalities. Met prevented MU-induced reduction in the myocardial size (myocardial atrophy); Iva had no effect on this parameter.


CONCLUSIONS
Iva shows beneficial structural and E-C coupling effects during MU: Iva reverses myocardial fibrosis and enhances the restoration of deranged E-C coupling, displaying more beneficial effects than that of Met. These results suggest that Iva may prove effective in enhancing functional recovery in heart failure patients receiving LVAD therapy.
Harefield Heart Science Centre,  Imperial College London, National Heart and Lung Institute, Laboratory of Cellular Electrophysiology, Harefield Hospital, Middlesex, Harefield UB9 6JH,  UK.
Manoraj
M
Navaratnarajah
Michael
M
Ibrahim
Urszula
U
Siedlecka
Carin
C
van Doorn
Adarsh
A
Shah
Ajay
A
Gandhi
Priyanthi
P
Dias
Padmini
P
Sarathchandra
Magdi H
MH
Yacoub
Cesare M
CM
Terracciano
D000818:Animals; D001284:Atrophy; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology; D056966:Excitation Contraction Coupling / Q000187:drug effects; D005355:Fibrosis; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D000077550:Ivabradine; D008790:Metoprolol / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D020257:Ventricular Remodeling / Q000187:drug effects*
D001552:Benzazepines; D020746:Calcium Channels, L-Type; D000077550:Ivabradine; D008790:Metoprolol; D002118:Calcium