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54 | Chapter 4 Table 4.4 | Association between the presence of CAC and AoVC for FH patients and controls. CAC present CAC absent p-value He-FH (N = 145) • AoVC present 56 (39%) 3 (2%) < 0.001 • AoVC absent 61 (42%) 25 (17%) • AoVC-score 55 (13 - 125) 3 (0 - 3) 0.019 Control (N = 131) • AoVC present 22 (17%) 5 (4%) 0.002 • AoVC absent 51 (39%) 53 (40%) • AoVC-score * 15 (2 - 44) 24 (10 - 98) 0.257 ∗ Median AoVC-score of patients with AoVC present in Agatston units. Continuous data are expressed as median (interquartile range), AoVC = aortic valve calcification, CAC = coronary artery calcification (Agatston units), FH = familial hypercholesterolemia. He- FH = heterozygous familial hypercholesterolemia, control = patient with non-anginal chest pain. Discussion The main findings of this study can be summarized as: 1) the prevalence and extent of AoVC was higher in he-FH patients than in the non-familial hypercholesterolemia; 2) age, untreated maxLDL, LDLR-negative mutational he-FH and diastolic blood pressure were positively associated with AoVC; 3) the level of treated LDL-C was not predictive of the prevalence and extent of AoVC; and 4) the absence of CAC was associated with a low prevalence of AoVC. In a recent study by Smith et al., using Mendelian randomization, it has been shown that a genetic predisposition to elevated LDL-C was associated with the presence of AoVC and the incidence of functional aortic stenosis in large community based cohorts (24). The authors concluded that their results provided evidence supportive of a causal association between LDL-C and aortic valve disease. We also performed a Mendelian randomization approach, which is a combination of 1): An association of the genetic background (the LDL-receptormutation), with the intermediate trait (untreatedmaxLDL) and the outcome parameter (AoVC); and 2): An association between the intermediate trait (untreated maxLDL) and outcome parameter (AoVC), corrected for confounding by multiple regression analysis. This Mendelian randomization approach mimics a RCT on a genetic level, and suggests a causal role of LDL-C in beginning aortic-valve pathology. In our study, he-FH patients were exposed to extremely high levels of LDL prior to statin treatment, especially those with LDLR-negativemutational he-FH. This could have