Simvastatin inhibits aortic valve calcification in hypercholesterolemic rabbits

Your article concerning the effect of statins in aortic tissue valve calcification [1] is an important issue of cardiac surgery which still generates debates. Especially, aortic valve stenosis is characterized by atherosclerosislike lesions, consisting of activated inflammatory cells, including T lymphocytes, macrophages, and of lipid deposits, calcific nodules, and bone tissue. Active mediators of calcification and cells with osteoblast-like activity are present in diseased valves. Moreover, extracellular matrix remodeling, including collagen synthesis and elastin degradation by matrix metalloproteinases and cathepsins, contributes to leaflet stiffening [2]. Notably, several experimental studies have proved the inhibition of hypercholesterolemia-induced calcification of aortic valve in animal models. Rajamannan et al. [3] demonstrated that atorvastatin inhibits aortic valve calcification reducing bone-formation and cellular proliferation via Lrp5 receptor pathway as well as enhancing nitric oxide synthase production. Thus, Monzack et al. [4] applied multiple in vitro disease stimuli to valvular interstitial cell (VIC) cultures and examined the impact of simvastatin treatment on VIC function. Simvastatin inhibited calcific nodule formation in a dose-dependent manner on all materials (although the level of statin efficacy was highly substrate-dependent), while decreases in nodule formation were not achieved via the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase pathway, but were correlated with decreases in Rho kinase (ROCK) activity. Moreover, unpublished data from our experimental protocols are in accordance with the above evidence. Particularly, New Zealand rabbits (n=10) fed with 4% cholesterol diet and treated with simvastatin (5 mg/kg) for eight weeks revealed a statistical significant inhibition of aortic valve atherosclerosis (P<0.001) compared to cholesterol fed rabbits (n=10). Thus, similar statistical significant inhibition of atherogenesis demonstrated the histopathological examination of ascending and descending aortas of simvastatin-treated hypercholesterolemic rabbits compared to hypercholesterolemic animals. Indeed, ascending/descending aortas of simvastatin-treated rabbits presented type I–II lesions according to AHA classification of atherosclerosis, while cholesterol fed animals revealed lesions of type IV–V compatible with atheroma. A key point that should be discussed is the high-dose of simvastatin (5 mg/kg) in a plethora of experimental protocols in the literature. In our opinion, the above dose – being safe and non-toxic in rabbits (according to FDAs recommendations) – may be responsible for simvastatins anti-inflammatory and anti-oxidative effects contributing to inhibition of atherogenesis. In addition, Lorusso et al. [5]demonstrated that atorvastatin significantly attenuates post-implant structural degeneration of artificial valve bovine pericardial tissue that was subcutaneously implanted in mice. In conclusion, based on personal data concerning the aortic valve and ascending/descending aorta in hypercholesterolemic rabbits, we support the beneficial impact of simvastatin in inhibition of hypercholesterolemiainduced atherosclerosis in rabbits.