Key result
Ivabradine reduced heart rate by 20%, enhanced aortic wall shear stress, reduced pro-inflammatory VCAM-1 expression (p<0.01), and increased anti-inflammatory eNOS expression (p<0.01).
Why the study?
Does ivabradine reduce vascular inflammation by increasing wall shear stress in hypercholesterolemic mice?
Does ivabradine reduce vascular inflammation by increasing wall shear stress in hypercholesterolemic mice?
p-value: p=<0.01
Ivabradine protects arteries from inflammation by reducing heart rate and altering local hemodynamics to increase wall shear stress, which induces anti-inflammatory eNOS and suppresses pro-inflammatory VCAM-1.
Should not yet change practice; leaves open translation of shear stress-mediated anti-inflammatory effects to human atherosclerosis.
Blood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered haemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Hypercholesterolaemic mice were treated with ivabradine for seven weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNFα-induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20 % and enhanced WSS in the aorta. In conclusion, ivabradine treatment altered haemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.
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Le et al. (2016) studied Hypercholesterolemia and vascular inflammation. Ivabradine vs. Untreated control was evaluated on Endothelial expression of VCAM-1 and eNOS (p=<0.01). Ivabradine reduced heart rate by 20%, enhanced aortic wall shear stress, reduced pro-inflammatory VCAM-1 expression (p<0.01), and increased anti-inflammatory eNOS expression (p<0.01).
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