15289-s-bos

146 | Chapter 9 Patients with homozygous FH patients have a high prevalence of aortic valve disease (AoVC) and this is, in addition to coronary artery disease (CAD), the major cause of premature death in this group. On the other hand, whether AoVC is more common in heterozygous FH patients (heFH) compared to non-FH individuals is unknown. In chapter 4 I show that AoVC is more prevalent in asymptomatic FH patients than in non-FH controls. Among heFH patients, the prevalence of AoVC was highest in FH patients with a LDL-receptor negative mutation with the highest untreated LDL-C levels compared to FH patients with a LDL-receptor defective mutation. This suggests a causal role of LDL-C in the early onset of aortic valve pathology. Therefore, I established that the health of heFH patients is threatened beyond “classical” atherosclerotic CVD through the accelerated development of AoVC. While statin therapy can significantly diminish the risk of CVD, statins do not affect the course of AoVC and stenosis once this is established. This study implies: 1) to start with statin therapy at a young age not only to prevent CVD but also to prevent AVC; 2) that regularly screening heFH patients for AoVC might be needed. Part 2: Non-traditional risk factors and residual cardiovascular risk in FH patients. Lp(a) is a genetically determined atherogenic lipoprotein which is currently not part of the traditional lipid panel. Lp(a) is not only an independent risk factor for CVD, but has also been associated with aortic valve stenosis with SNPs in the LPA gene as well as plasma Lp(a) levels (2). In Chapter 5 I show that Lp(a) levels are associated with AoVC determined by CTCA in asymptomatic FH patients. In Chapter 6 I investigated whether Lp(a) levels were associated with atherosclerosis depicted as C-IMT and carotid plaques measured by carotid ultrasonography in statin-treated HeFH patients. I found no association between Lp(a) levels and carotid ultrasonography outcomes. In Chapter 7 I discuss the latest developments in the treatment of Lp(a). Both statins, the most widely used lipid lowering agents, and lifestyle intervention have no effect on Lp(a) levels. The new protein subtilisin/kexin type 9 inhibitors lower Lp(a) by 30-50%, but also lower LDL-C. It is unknown whether specifically lowering of Lp(a) can reduce CVD risk. However, recently an antisense oligonucleotide directed to apolipoprotein (a) has been developed which can specifically lower Lp(a) levels up to 90%. Trials with this new drug shall reveal whether reduction of Lp(a) levels can decrease CVD risk. In Chapter 8 I identified six novel proteins associated with atherosclerosis and CVD events in heFH patients. For this purpose I used the isobaric tag for relative and absolute quantification