Sven Bos

Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia

Lipoprotein(a) [Lp(a)] is an independent risk factor for aortic valve stenosis and aortic valve calcification (AVC) in the general population. In this study, we determined the association between AVC and both plasma Lp(a) levels and apolipoprotein(a) [apo(a)] kringle IV repeat polymorphisms in asymptomatic statin‐treated patients with heterozygous familial hypercholesterolaemia (FH).

Latest developments in the treatment of lipoprotein (a).

Purpose of review Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. The aim of this review is to provide an overview of treatment options for Lp(a) lowering. Recent findings Recent studies confirmed that lifestyle intervention and statins do not affect Lp(a) levels, whereas Lp(a) is lowered by oestrogens, niacin, and lipoprotein apheresis. Cholesterol ester transfer protein inhibitors and proprotein convertase subtilisin/kexin type 9 antibodies, currently studied in phase 3 trials, also lower Lp(a) concentrations by 30–50%. However, all of these compounds have modifying effects on multiple lipoprotein classes. An antisense oligonucleotide directed to apolipoprotein (a) has recently been developed to specifically lower circulating Lp(a) levels. This compound lowers Lp(a) mRNA up to 90%, and Lp(a) levels up to 82% in human volunteers independent of Lp(a) levels at baseline. Summary Multiple agents, including the next generation RNA-based antisense therapeutics have Lp(a) lowering properties. However, it remains to be established whether lowering Lp(a) reduces cardiovascular disease events with specific Lp(a) lowering therapies.

Increased Aortic Valve Calcification in Familial Hypercholesterolemia Prevalence, Extent, and Associated Risk Factors

BACKGROUND Familial hypercholesterolemia is typically caused by LDL receptor (LDLR) mutations that result in elevated levels of LDL cholesterol (LDL-C). In homozygous FH, the prevalence of aortic valve calcification (AoVC) reaches 100% and is often symptomatic. OBJECTIVES The objective of this study was to investigate the prevalence, extent, and risk-modifiers of AoVC in heterozygous FH (he-FH) that are presently unknown. METHODS Asymptomatic patients with he-FH and 131 non-familial hypercholesterolemia controls underwent CT computed tomography calcium scoring. AoVC was defined as the presence of calcium at the aortic valve leaflets. The extent of AoVC was expressed in Agatston units, as the AoVC-score. We compared the prevalence and extent of AoVC between cases and controls. In addition, we investigated risk modifiers of AoVC, including the presence of LDLR mutations without residual function (LDLR-negative mutations), maximum untreated LDL-cholesterol (maxLDL), LDL-C, blood pressure, and coronary artery calcification (CAC). RESULTS We included 145 asymptomatic patients with he-FH (93 men; mean age 52 ± 8 years) and 131 non-familial hypercholesterolemia controls. The prevalence (%) and AoVC-score (median, IQR) were higher in he-FH patients than in controls: 41%, 51 (9-117); and 21%, 21 (3-49) (p < 0.001 and p = 0.007). Age, untreated maxLDL, CAC, and diastolic blood pressure were independently associated with AoVC. LDLR-negative mutational he-FH was the strongest predictor of the AoVC-score (OR: 4.81; 95% CI: 2.22 to 10.40; p = <0.001). CONCLUSIONS Compared to controls, he-FH is associated with a high prevalence and a large extent of subclinical AoVC, especially in patients with LDLR-negative mutations, highlighting the critical role of LDL-C metabolism in AoVC etiology.

Lipoprotein (a) levels are not associated with carotid plaques and carotid intima media thickness in statin-treated patients with familial hypercholesterolemia.

BACKGROUND Lipoprotein (a), also called Lp(a), is a cardiovascular disease (CVD) risk factor. Statins do not lower Lp(a), this may at least partly explain residual CVD risk in statin-treated patients with familial hypercholesterolemia (FH). We investigated the association of Lp(a) levels with atherosclerosis in these patients. METHODS AND RESULTS We performed ultrasonography in 191 statin-treated FH patients (50% men; 48 ± 15 years) to detect carotid plaques and determine carotid intima-media thickness (C-IMT). Patients with high versus low Lp(a) levels (≤0.3 g/L) had similar plaque prevalence (36 and 31%, p = 0.4) and C-IMT (0.59 ± 0.12 and 0.59 ± 0.13 mm, p = 0.8). Patients with and without plaques had similar Lp(a) levels (median 0.35 (IQR: 0.57) and 0.24 (0.64) g/L, respectively, p = 0.4). CONCLUSIONS The Lp(a) levels were not associated with atherosclerosis in the carotid arteries of statin-treated FH patients. This suggests that adequate statin treatment delays carotid atherosclerosis in FH independently of Lp(a) levels.

Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia

Background and aims Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. Methods FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. Results 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7–0.79) vs. 0.66 mm (0.61–0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4–41.8) vs. 2.65 (0.94–7.44), p = 0.0004]. Conclusions In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.