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56 | Chapter 4 can lead to tissue remodelling and promote inflammation, leading to calcification, stenosis, and ultimately valve failure (26). Messika-Zeitoun et al. investigated determinants and progression of AoVC in a population based follow-up study, using electron-beam-CT. De novo AoVC was found to be associated with elevated LDL-C levels, whereas established AoVC progressed independently of atherosclerotic risk factors and faster with increasing initial extent of AoVC (27). This led to the hypothesis that elevated levels of LDL-C have their atherogenic effect during the early phase of AoVC, before the start of statin treatment. As shown in the results section, patients with LDLR-negative mutational he-FH started using statins at younger age and used statins for a longer period of time. However, despite their more intense statin treatment, these patients showed a higher prevalence of AoVC, which more rapidly increased with age. To investigate the effect of statin treatment on AoVC in our cohort of he-FH patients of whom we knew were exposed to high levels of LDL-C early in life, we included “duration of statin use” in a multivariable ordinal regression model. Duration of statin use was however not associated with AoVC after correction for age, untreated maxLDL, LDLR-negative mutational he-FH and diastolic blood pressure. All other variables remained statistically significant (data not shown). In addition, three major prospective randomized trials could not demonstrate any impact of lipid lowering therapy on the rate of progression of AoVC (28-30). However, macrophage and osteoclast infiltration of the AoVC were reduced by atorvastatin in cholesterol fed mice (31). Apparently, other pathogenic risk mechanisms prevail once AoVC has been established. It is known that during the later stages of calcific aortic stenosis, a process of osteoblastic activity prevails over the initial atherosclerotic process, resulting in progressive calcification of the valve that seems unrelated to LDL-C levels or statin treatment and fits the observed independence of AoVC from lipid profile or statin treatment. The extensive AoVC in our young study population suggest that statins have their main effect in preventing aortic valve pathology prior to the development of aortic valve stenosis. The three prospective randomized trials were restricted to patients with beginning aortic valve pathology in whom statins could not exert a preventive effect anymore. Even though the exact role of serum lipids in the pathogenesis of aortic valve disease is unknown, it is evident that lipid depositions are found within and in proximity to aortic valve lesion which is not the case in healthy valve leaflets (25). This suggests a critical role for lipids in the early onset of aortic valve pathology. The concept of two different phases in the development of AoVC progression is not