Long term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression.

Background and purpose.  Recent clinical data suggest beneficial effects of ivabradine, a specific heart rate lowering drug, in heart failure patients. However, the mechanisms responsible for ivabradine benefit need to be fully clarified. Thus, we aimed to investigate functional/molecular changes in I(f) , i.e., the specific target of ivabradine, in the failing atrial and ventricular myocytes where this current is upregulated as a consequence of maladaptive remodelling. Experimental approach.  We investigated the effects of ivabradine on electrophysiological remodeling in atrial (LA) and ventricular (LV, RV) myocytes from post-MI rats, receiving ivabradine 10 mg.kg(-1) .day(-1) (MI + IVA) or vehicle (MI) for 90 days, with sham-operated (sham or sham + IVA) rats as controls. I(f) current was measured by patch-clamp; HCN channel isoforms and microRNA (miRNA-1 and miR-133) expression were evaluated by RT PCR. Key results.  Maximal specific conductance of I(f) was increased in MI versus sham in LV (62.6 ± 8.5 vs. 23.5 ± 7.2 pS/pF, P < 0.01) and LA myocytes (67.2 ± 11.4 vs. 21.1 ± 5.8 pS/pF, P < 0.05). Treatment with ivabradine resulted in a significant reduction of HR in both MI and sham rats (P < 0.05). In MI+IVA, I(f) overexpression was attenuated and HCN4 transcription reduced by 66\% and 54\% in LV and RV tissue versus MI rats (all P < 0.05). miR-1 and miR-133, which modulate post-transcriptional expression of HCN2 and HCN4 genes, were significantly increased in myocytes from MI + IVA. Conclusion and implication.  The beneficial effects of ivabradine may be due to the reversal of electrophysiological cardiac remodelling in post-MI rats by reduction of functional overexpression of HCN channels. This is attributable to transcriptional and post-transcriptional mechanisms.