Systemic mastocytosis associates with cardiovascular events despite lower plasma lipid levels.

BACKGROUND AND AIMS: Mast cells have been implicated in the development and progression of atherosclerosis in animal models and human autopsy studies. However, it is unknown whether long-term exposure to excess of mast cells is associated with cardiovascular disease (CVD) in humans. Our objective was to compare the prevalence of CVD and cardiovascular risk factors in patients with systemic mastocytosis (SM) and controls. METHODS: In 50 patients with SM and 50 age and sex matched controls, the history of CVD and presence of cardiovascular risk factors were assessed. Carotid ultrasound was performed to assess carotid intima-media thickness (C-IMT) and plaques presence. RESULTS: CVD events were more prevalent in SM patients compared to controls (20% vs. 6%, p = 0.04). The prevalence of C-IMT and carotid plaques was similar between patients with SM and controls. In multivariate analysis, CVD events were significantly associated with SM (OR 7.0 (95% CI 1.3-37.6), p = 0.02) and hypertension (OR 9.5 (95% CI 1.9-48.7), p = 0.01). The prevalence of diabetes, hypertension, obesity and smoking was similar between the two groups. Total cholesterol and LDL-C levels were significantly lower in SM patients than in the control group. (5.1 ± 1.1 vs. 5.9 ± 0.9 mmol/l, p < 0.05 and 2.9 ± 0.8 vs. 3.5 ± 0.7 mmol/l, p < 0.05, respectively). CONCLUSIONS: Despite lower plasma total cholesterol and LDL-C, the prevalence of CVD is higher in patients with SM compared to healthy controls. Beyond the setting of SM, this study can be considered as a proof of concept study, indicating the contribution of mast cells to CVD in humans.

Soluble LR11 associates with aortic root calcification in asymptomatic treated male patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Despite statin treatment, a high prevalence of severe vascular calcification is found in patients with familial hypercholesterolemia (FH). We assessed the relation between the circulating soluble form of low-density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11), a risk factor for cardiovascular disease, and vascular calcification in asymptomatic statin-treated heterozygous FH patients. METHODS: In 123 asymptomatic heterozygous FH patients (age 40-69 years), aortic root (ARC), aortic valve (AVC) and coronary artery calcification (CAC) were determined with CT-based calcium scoring expressed in Agatston units. Plasma sLR11 levels were measured by sandwich ELISA. RESULTS: Seventy-three patients displayed ARC, 48 had AVC and 96 CAC. Plasma sLR11 levels were positively correlated with the presence of ARC (r = 0.2, p = 0.03), but not with AVC or CAC. The correlation between sLR11 levels and ARC was restricted to male FH patients (r = 0.31, p = 0.006). Multivariate logistic analyses showed that the association of plasma sLR11 with the presence of ARC was independent of other determinants (Adjusted Odds Ratio, 2.01 (95% CI = 1.28-3.16) p = 0.002). CONCLUSIONS: Plasma sLR11 is associated with ARC in male FH patients and may be mechanistically involved in the differential distribution of atherosclerotic lesions in the vasculature.

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.

Novel protein biomarkers associated with coronary artery disease in statin-treated patients with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipid metabolism. The incidence of coronary artery disease (CAD) varies among both treated and untreated FH patients. OBJECTIVE: The aim of the study was to utilize proteomics to identify novel protein biomarkers that differentiate genetically confirmed heterozygous patients with FH at high CAD risk from those at low CAD risk. METHODS: Sixty genetically confirmed FH patients were recruited and stratified into (1) asymptomatic FH with low atherosclerotic burden (FH, n = 20); (2) asymptomatic FH with high atherosclerotic burden (FH + Ca, n = 20); and (3) FH with previously confirmed symptomatic CAD (FH + CAD, n = 20). RESULTS: Six new potential proteins were identified; leucine-rich alpha-2-glycoprotein (LRG1), inter-alpha-trypsin inhibitor heavy chain H3, complement C4-B (C4B), complement C1q subcomponent subunit B (C1QB), monocyte differentiation antigen (CD14), and histidine-rich glycoprotein (HRG). There were significant associations between gender and C4B (Z = 2.31, P = .021), C1QB (Z = 2.49, P = .013), CD14 (Z = 2.17, P = .03), and HRG (Z = 2.14, P = .033). There were significant associations between smoking and LRG1 (χ22 = 6.59, P = .037), CB4 (χ22 = 7.85, P = .02), and HRG (χ22 = 6.11, P = .047). All the peptides were significantly associated with advanced CAD stages, independently of age and smoking. However, the absence of the proteins was the strongest marker. The most accurate association with CAD was HRG (area under the receiver operating characteristic curve = 0.922), whereas LRG1, C4B, and C1QB were also associated with CAD (area under the receiver operating characteristic curve >0.9). For either coronary atherosclerosis or CAD, LRG1, C4B, C1QB, and HRG were relatively well associated. CONCLUSIONS: The present study has identified 6 novel protein biomarkers that are associated with more advanced stages of atherosclerotic disease and subsequent coronary events in patients with heterozygous FH.

Carotid artery plaques and intima medial thickness in familial hypercholesteraemic patients on long-term statin therapy: A case control study.

BACKGROUND AND AIMS: Statins reduce subclinical atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). However, some FH patients still develop ASCVD despite statin therapy. We compared subclinical atherosclerosis assessed by carotid plaque presence and intima media thickness (C-IMT), in long-term statin-treated FH patients and healthy controls. Furthermore, we analysed whether carotid ultrasonography findings associated with subclinical coronary atherosclerosis. METHODS: We assessed the presence of carotid plaques and C-IMT in 221 asymptomatic heterozygous FH patients (48% men; 46 ± 15 years) on long-term (10.0 ± 7.8 years) statin treatment and 103 controls (32% men, 47 ± 16 years). RESULTS: The frequency of carotid plaques and C-IMT did not differ significantly between the FH patients and controls (69 (31%) versus 24 (23%), p = 0.1 and 0.58 ± 0.13 versus 0.58 ± 0.12 mm, p = 0.9, respectively). In a subgroup of 49 FH patients who underwent cardiac computed tomography, coronary artery calcification correlated with carotid plaque presence (R = 0.47; p = 0.001), but not with C-IMT (R = 0.20; p = 0.2). CONCLUSIONS: Carotid plaques and C-IMT did not differ between long-term statin-treated heterozygous FH patients and healthy controls. This shows that long-term statin treatment in these FH patients reduces carotid atherosclerosis to a degree of a healthy population. These findings strongly suggests that sonography of the carotid arteries during follow-up of statin-treated FH patients has limited value.

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.

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.