H031 Short-term heart rate reduction induced by ivabradine administered to rats with well-established heart failure improves cardiac function, augments neo-angiogenesis and reduces myocardial hypoxia

Long-term heart rate reduction (HRR) initiated in a pathophysiological situation of moderate left ventricular (LV) dysfunction prevents the deterioration of cardiac function. This is probably related to shortterm effects of HRR, i.e. improved myocardial perfusion and reduced O2 consumption, and long-term HRR effects on LV structure, i.e. improved capillary density. However, it is currently unknown 1) whether the short-term effects of HRR are sufficient to improve LV function when HRR is initiated in a setting of well-established chronic heart failure (CHF) and/or 2) whether short-term HRR triggers/activates early mechanism(s) involved in the structural long-term effects of HRR. Thus, we assessed, in a rat model of CHF (coronary ligation), the effects of short-term HRR induced by the If current inhibitor ivabradine (Iva ; 10 mg/kg/day as food admix for 4 days starting 93 days after ligation). The table shows heart rate (HR ; beats/min), cardiac output (CO ; ml/min), LV end-systolic pressure (LVESP ; mmHg), LVESP-volume relation (LVESPVR ; mmHg/Relative Volume Unit), LV end-diastolic pressure (LVEDP ; mmHg), Tau (msec), LVEDP-volume relation (LVEDPVR ; mmHg/Relative Volume Unit) as well as myocardial hypoxia-inducible factor protein levels (HIF-a ; arbitrary unit), micro-vessel density (nb/mm 2 ) and endothelial cell proliferation (nb BrdU positive cells/mm 2 ). We found that short-term Iva preserves CO despite the HRR, improves LV filling, contraction, relaxation and compliance, while it reduces myocardial tissue hypoxia and triggers endothelial cell proliferation. In conclusion, in rats with well-established CHF, acute HRR induced by Iva improves systolic and diastolic cardiac function, probably due to the decrease in myocardial O2 consumption and to the increase in myocardial perfusion induced by HRR, causing a reduction in LV tissue hypoxia. Iva also induces endothelial cells proliferation, illustrating neo-angiogenesis by a HIF-a independent pathway. The increase in endothelial proliferation might explain, at least in part, the increase of capillary density observed after long-term HRR.