Abstract 258: A Pharmacological Approach to Promote Shear Stress-Dependent Anti-inflammatory Mechanisms in Arteries

Atherosclerosis is influenced by blood flow whichS exert wall shear stress (WSS) on endothelial cells (EC). Low oscillatory WSS promotes atherosclerosis by inducing inflammatory molecules (e.g. VCAM-1), whereas high uniform WSS induces anti-inflammatory genes (e.g. eNOS). Ivabradine decreases heart rate by inhibiting the If current in the sinus node, without affecting blood pressure or cardiac contractility. Besides cardio-protection, ivabradine protects arteries from atherosclerosis via unknown mechanisms. We hypothesised that ivabradine reduces arterial inflammation by increasing blood flow-induced WSS. Mice (C57BL/6, male, aged 10 weeks) were treated with ivabradine for 1 week (162 mg/L in drinking water) or remained untreated. WSS was mapped at atherosusceptible (inner curvature) and protected (outer curvature) sites of the aorta by defining the geometry (CT angiography; Siemens) and flow characteristics (ultrasound; Visualsonics). Segmentation and smoothing were performed to reconstruct the volume of interest (Amira, VMTK) and a tetrahedral mesh with prismatic boundary layer was generated (IcemCFD). Fluid behavior was modeled over the cardiac cycle using Fluent 14.5 (ANSYS). Computational fluid dynamics revealed that WSS at the inner curvature of the aorta had lower magnitude and higher oscillatory index compared to the outer curvature. Ivabradine treatment reduced heart rate by 20% (p We conclude that ivabradine treatment altered hemodynamics in the murine aorta by increasing the magnitude and uniformity of shear stress. These changes were accompanied by induction of a mechanosensitive protective gene (eNOS) and suppression of inflammatory VCAM-1. Thus ivabradine may protect arteries by altering local mechanical conditions to trigger an anti-inflammatory response.