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58 | Chapter 4 equally hold for LDLR-negative and LDLR-defective mutations. We have analyzed patients with a major locus effect in the cholesterol metabolism, but we cannot exclude contributions from variants of other genes, like NOTCH1 (37,38). Especially calcified bicuspid aortic valves have very high heritability. Bicuspid aortic valves have an estimated prevalence of 1-2%. The linkage peaks of aortic stenosis and the NOTCH1 gene have not been found on chromosome 19 on which the LDL receptor is located (19p13.2). Without co-segregation with the mutations in the LDL receptor, it is unlikely that our cohort was enriched with variants of these other genes. Recent studies on coronary atherosclerosis showed that the calcified plaque component increased after long-term statin therapy (39,40). In our study, patients with he-FH and particularly patients with LDLR-negative mutations, received higher dosages of statins for longer periods of time and statin use could therefore be a more complex confounder in our analyses. However, in our multivariable ordinal regression model, the time of statin treatment was not significantly associated with AoVC in he-FH patients. As compared to the general population, we did not find male gender to be a risk modifier of AoVC. This is likely caused by the relatively small size of our study as compared to the large population based Heinz Nixdorf Recall Study or the Multi-Ethnic Study of Atherosclerosis (2,5,27). Conclusion We found that: he-FH is associated with a high prevalence and a large extent of subclinical AoVC; age, diastolic blood pressure, untreated maxLDL, and LDLR-negative mutations were associated with the extent of AoVC; the difference between LDLR- negative and defective mutations provides important evidence for the critical role of LDL-Cmetabolism for the pathogenesis of AoVC and; the absence of CACwas associated with low prevalence of AoVC suggesting shared pathophysiological determinants. Worldwide, the majority of he-FH patients, who have been treated with statins for a substantial period of their life, are still too young to express valve diseases. However, due to the prolonging survival in these patients, because of statin treatment, our results suggest that aortic valve pathology will be a common problem in aging he-FH patients, especially in those with LDLR-negative mutations.