Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Issue: 2016: 116/1 (July) pp. 1-203
Pages: 181-190
Ahead of Print: 2016-04-14

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Online Supplementary Material

L. Luong (1, 2), H. Duckles (1, 2), T. Schenkel (3), M. Mahmoud (1, 2), J. L. Tremoleda (4), M. Wylezinska-Arridge (5), M. Ali (6), N. P. Bowden (1, 2), M.-C. Villa-Uriol (2), K. van der Heiden (7), R. Xing (7), F. J. Gijsen (7), J. Wentzel (7), A. Lawrie (1, 2), S. Feng (1, 2), N. Arnold (1), W. Gsell (8), A. Lungu (1, 2), R. Hose (1, 2), T. Spencer (9), I. Halliday (9), V. Ridger (1, 2), P. C. Evans (1, 2)

(1) Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; (2) INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK; (3) Department of Engineering & Mathematics, Sheffield Hallam University, UK; (4) Trauma Sciences, Queen Mary University of London, UK; (5) MRC Clinical Sciences Centre, Imperial College London, UK; (6) Division of Cardiovascular and Diabetes Research, University of Leeds, UK; (7) Erasmus MC, Rotterdam, the Netherlands; (8) Maccine Pte Ltd, Department of Imaging, Singapore; (9) Materials and Engineering Research Institute, Sheffield Hallam University, UK


Atherosclerosis, haemodynamics, inflammation


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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