Effetto dell’ivabradina nelle fasi iniziali e nella progressione dell’aterosclerosi

Effect of ivabradine in the initial steps and in the progression of the atherosclerosis Purpose: Ivabradine reduces heart rate (HR) by selectively inhibiting the If current in the sinus node. A sub-group of the BEAUTifUL study showed that ivabradine reduces the incidence of myocardial infarction in coronary artery disease (CAD) patients with HR ≥ 70bpm, suggesting a protective effect on the arterial wall. The SIGNifY study is currently testing this hypothesis in more than 19000 CAD patients. In dyslipidaemic mice, ivabradine improves vascular function and reduces aortic plaques area. It has been suggested that ivabradine may exert a protective activity by decreasing low/oscillatory shear stress, which is proinflammatory in the endothelium. This study aims to determine if HR reduction with ivabradine induces an atheroprotective gene expression profile in the endothelium of dyslipidaemic mice before plaque formation. Methods: 6 week-old ApoE deficient mice (n=6), fed a chow diet, were treated with ivabradine (30 mg/Kg/day, in drinking water) for 2 or 4 weeks. Two control groups (n=6) received no ivabradine. Ivabradine reduced HR by 17.4% and 22.9% in mice treated for 2 weeks and 4 weeks respectively. At the end of treatment, endothelium-enriched RNA was isolated from the aortic arch. Gene expression was analyzed by Agilent Whole Mouse Gene Expression Microarray (60k probes). Pathway analysis was performed using DAVID tools. Principal components analysis showed that most of the variability in gene expression can be attributed to ivabradine treatment and was independent of treatment duration. Differentially expressed genes were selected as having a ≥ 1.5-fold expression difference between treated and untreated groups with a p-value ≤ 0.01 at unpaired t-test. Results: Treatment induced changes in the expression of 930 transcripts. Shear stress-modulated pathways such as MAPK signalling and steroid biosynthesis process (both inhibited by treatment) were among the most significantly affected pathways (p-value = 0.0065 and 0.0009, respectively). We found up-regulation of anti-inflammatory genes and down-regulation of pro-apoptotic and pro-inflammatory genes, the majority of which were NF-kappa B and/or Ang II-regulated genes. Among them, the receptor for oxidized lipoprotein (Olr1) was strongly downregulated (3.2 fold). Conclusions: In dyslipidaemic mice, short term treatment with ivabradine induces an atheroprotective gene expression profile in the endothelium. Since many of the affected genes are shear stress regulated, our data suggest that shear stress frequency modulation could be part of the molecular mechanisms by which ivabradine protects the endothelium.