Ivabradine-induced heart-rate reduction improved hindlimb perfusion in ApoE(-/-) mice from 40.5% to 60.2% and stimulated adaptive collateral artery growth.
Does heart-rate reduction with ivabradine improve collateral artery growth and perfusion in hypercholesterolemic atherosclerosis models?
Ivabradine-induced heart rate reduction stimulates adaptive collateral artery growth and improves perfusion in hypercholesterolemic mice through enhanced endothelial function and eNOS activity.
Absolute Event Rate: 60.2% vs 40.5%
AIMS: Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth. METHODS AND RESULTS: The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 ± 15.8-60.2 ± 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L-arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti-arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments. CONCLUSION: Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression.
Schirmer et al. (Sat,) conducted a other in Hypercholesterolemic atherosclerosis. Ivabradine vs. Metoprolol / Untreated was evaluated on Hindlimb perfusion (ligated/unligated hindlimb). Ivabradine-induced heart-rate reduction improved hindlimb perfusion in ApoE(-/-) mice from 40.5% to 60.2% and stimulated adaptive collateral artery growth.
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