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150 | Chapter 9 receptor negative mutation or those who started with statin therapy in adulthood. Additionally, more research is needed to evaluate whether novel therapeutic agents like PSCK-9 inhibitors can inhibit the progression towards aortic valve stenosis. Novel biomarkers In chapter5 I showthatplasmaLp(a) levelswere independentlyassociatedwithAoVCbut not with coronary atherosclerosis in asymptomatic heterozygous FH patients. A possible explanation for the lack of association of Lp(a) levels with coronary atherosclerosis is that statins reduce coronary atherosclerosis so effectively that additional risk factors like Lp(a) no longer play a role. If Lp(a) is important in the initiation of AoVC like LDL-C, it is likely that the effect of high Lp(a) levels on AoVC also remains detectable. Currently, elevated Lp(a) levels cannot be specifically treated (as discussed in Chapter 7 ) and risk reduction in patients with high L(a) levels (>0,5 g/l) should be achieved by optimizing other risk factors such as blood pressure, BMI and LDL-C. PCSK-9 inhibitors, do not only lower LDL-C, but also lower Lp(a) levels by 30% (3). The mechanism of Lp(a) lowering of these agents is currently unknown and it unclear whether this effect ads to CVD risk reduction on top of the LDL-C lowering properties. Whether specific Lp(a) lowering can reduce CVD events and stop progression of aortic valve stenosis should be evaluated in future studies, that will be made possible by the specific antisense Lp(a) agents that are currently being developed (21). In chapter 8 I chose another approach in risk prediction in FH patients by using the iTRAQ proteomic technique to identify possible proteins that are associated with subclinical atherosclerosis or atherosclerotic cardiac events. I found six novel proteins whose levels were negatively associated with atherosclerotic disease progression and subsequent coronary events in patients. These six proteins; leucine-rich alpha-2- glycoprotein (LRG1), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), complement C4-B (C4B), complement C1q subcomponent subunit B (C1QB), monocyte differentiation antigen (CD14) and histidine-rich glycoprotein (HRG) appear to mainly have functions in the coagulation pathway, arterial compliance, and inflammation. These pathways are historically involved in the development of CVD risk and therefore these results seem promising. This study was conducted in FH patients and therefore it is possible that there are additional underlying factors, unique to FH and its associated mutations, which manifest differently to a patient with CAD not associated with FH. However, it seems worth investigating whether the levels of these novel discovered proteins differ