Candesartan Treatment Associates With Reduced Expression of Collagen and Matrix Metalloproteinase Genes in Severely Stenotic Human Aortic Valves: A Prospective, Placebo-controlled, Randomized, Double-blinded Clinical Trial

Abstract

Introduction: Calcific aortic valve stenosis (AS) is a progressive disease resulting from long-lasting inflammatory, fibrotic, and calcifying processes in the aortic valve leaflets. The renin-angiotensin-aldosterone system (RAAS) has been demonstrated to be active in human stenotic aortic valves. In experimental animals, administration of an angiotensin II type 1 receptor blocker has exerted both anti-inflammatory and antifibrotic effects on stenotic aortic leaflets. In human aortic smooth muscle cells, angiotensin II increases the expression of matrix metalloproteinase. The migration of vascular smooth muscle cells (VSMCs) is an early event of atherosclerosis. Indeed, angiotensin II increases matrix metalloproteinase 13 (MMP13)'s expression in aortic smooth muscle cells (SMCs) and the silencing or inhibition of MMP13 results in reduced SMCs' migration. Here were examined whether candesartan would beneficially affect the major pathogenic valvular mechanisms active in severe AS. Methods: In this placebo-controlled, randomized, double-blinded, prospective study a total of 43 AS patients were randomized to receive candesartan (target dose: 16 mg/d) or placebo for an average of about 5 months (164 ± 67 days) before undergoing aortic valve replacement surgery. In the explanted valves, the mRNA levels of markers for fibrosis were assessed using an mRNA assay panel and quantitative polymerase chain reaction (qPCR). Moreover, markers of fibrosis, inflammation, and neovascularization were analyzed immunohistologically. Results: In the candesartan group, the mRNA expression levels of Collagen Type X Alpha 1 Chain (Col10a1) (p = 0.003), Col11a1 (p = 0.002), Col12a1 (p = 0.016), and of MMP8 (p = 0.024) and MMP13 (p = 0.007) were lower than in the placebo group. During this short intervention period, immunohistological analysis did not show differences in fibrosis, calcification, neovascularization, or inflammation of the valves. Conclusion: In the present study, we found the potential mechanism for candesartan to interact with the progression of aortic valve stenosis by modeling the mRNA expressions of collagens and matrix metalloproteinases. Provided these potentially beneficial antifibrotic effects candesartan could retard the progression of AS. However, additional longer interventional studies are needed to prove possible beneficial clinical effects of candesartan in AS. Disclosure: Nothing to disclose