Abstract 13721: Heart Rate Reduction by If-Channel Blockade With Ivabradine Stimulates Collateral Artery Growth in Hypercholesterolemic Atherosclerosis
Background: Collateral artery growth protects from ischemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effects of heart rate reduction (HRR) by the If-channel inhibitor ivabradine on collateral artery growth in the peripheral circulation.
Methods and Results: Ivabradine reduced heart rate by 11% in wildtype and 15% in cholesterol-fed ApoE-/- mice and restored endothelium-dependent relaxation in aortic rings of ApoE-/- mice. Six weeks after initiation of treatment, the right femoral artery was ligated. Microsphere perfusion under conditions of maximal vasodilation demonstrated that ivabradine did not change hindlimb perfusion in wildtype mice but improved perfusion recovery in ApoE-/- mice from 40.5±4.4 to 60.2±4.0% ligated/unligated hindlimb. Angiographies showed increased collateralization following HRR, while capillary density was unaffected. Heart rate reduction (13%) with beta-blockade (metoprolol) failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS as well as eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE-/- mice. Co-treatment with NO-inhibitor L-NAME 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 CXCL10 and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE /- hindlimb tissue. eNOS and inflammatory cytokine expression were unchanged in wildtype 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 heart rate reduction stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity and modulation of inflammatory cytokine gene expression.
- Heart rate/Heart rate variability
- Nitric oxide synthase
- Endothelial function
- © 2011 by American Heart Association, Inc.