Hypercholesterolemic Patients Research Articles

Familial Hypercholesterolaemia Patients with LDLR Mutation Among Asian Population in Southeast Asian Countries: Systematic Review

Familial hypercholesterolaemia (FH) is a genetic disorder associated with premature cardiovascular diseases; however, the majority of patients remain undertreated. This systematic review aimed to determine the prevalence of FH patients with low-density lipoprotein receptor (LDLR) gene pathogenic variants (PV) among the Asian population in Southeast Asian countries. Our search yielded 1,120 citations, with 28 deemed possibly suitable based on title and abstract screening. However, only six studies that utilised the Dutch Lipid Clinic Network (DLCN) or Simon Broome (SB) criteria were eligible to be included. These studies provided prevalence figures for clinically diagnosed FH patients, with a total of 17.1% (n=1,005/5,874); this rate was represented by three Malaysian studies, which estimated that 36–76% of clinically diagnosed FH patients had LDLR PV. Most patients reported having pre-existing cardiovascular disease, a family history of premature coronary artery disease and tendon xanthomata. This study found that the prevalence of LDLR PV among genetically confirmed FH patients in Southeast Asia is 20.5% (n=286/5,874). Genetically confirmed FH patients are at a higher risk of developing premature coronary artery disease, requiring more aggressive lipid-lowering treatment. Therefore, identifying LDLR PV among the population is essential for early FH diagnosis and treatment. KEYWORDS Arterial disease, autosomal dominant, LDL receptor, LDLR prevalence, pathogenic variants, premature CAD, Undertreated

Statins, but not proprotein convertase subtilisin-kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low-density lipoprotein receptor upregulation.

Hypercholesterolemia is characterized by elevated low-density lipoprotein (LDL)-cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol-lowering with statins or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) affects chemerin. Both statins and PCKS9i lowered plasma LDL-cholesterol, triglycerides and total cholesterol in hypercholesterolemic patients, and increased high-density lipoprotein (HDL)-cholesterol. Yet, only statins additionally reduced chemerin and high-sensitivity C-reactive protein (hsCRP). Applying PCSK9i on top of statins did not further reduce chemerin. Around 20% of chemerin occurred in the HDL2/HDL3 fractions, while>75% was free. Statins lowered both HDL-bound and free chemerin. Pull-down assays revealed that chemerin binds to the HDL-component Apolipoprotein A-I (ApoA-I). The statins, but not PCSK9i, diminished chemerin secretion from HepG2 cells by upregulating LDL receptor mRNA. Furthermore, chemerin inhibited HDL-mediated cholesterol efflux via its chemerin chemokine-like receptor 1 in differentiated macrophages. In conclusion, statins, but not PCSK9i, lower circulating chemerin by directly affecting its release from hepatocytes. Chemerin binds to ApoA-I and inhibits HDL-mediated cholesterol efflux. Statins prevent this by lowering HDL-bound chemerin. Combined with their anti-inflammatory effect evidenced by hsCRP suppression, this represents a novel cardiovascular protective function of statins that distinguishes them from PCSK9i.

Use of Bempedoic acid to treat hypercholesterolemia in patients affected by neuromuscular diseases

Use of Bempedoic acid to treat hypercholesterolemia in patients affected by neuromuscular diseases

The protective effects of PCSK9 inhibitors on DNA damage in peripheral blood mononuclear cells in familial hypercholesterolemic patients

The protective effects of PCSK9 inhibitors on DNA damage in peripheral blood mononuclear cells in familial hypercholesterolemic patients

Impact of LDL-cholesterol increment on the cardio-ankle vascular index (CAVI) in Lithuanian familial hypercholesterolemia patients

Impact of LDL-cholesterol increment on the cardio-ankle vascular index (CAVI) in Lithuanian familial hypercholesterolemia patients

Impact of LDL-cholesterol increment on carotid intima-media thickness in Lithuanian familial hypercholesterolemia patients

Impact of LDL-cholesterol increment on carotid intima-media thickness in Lithuanian familial hypercholesterolemia patients

The influence of LDL cholesterol increment for peripheral pulse wave velocity (PWV carotid-radial) in Lithuanian familial hypercholesterolemia patients

The influence of LDL cholesterol increment for peripheral pulse wave velocity (PWV carotid-radial) in Lithuanian familial hypercholesterolemia patients

Impact of LDL-cholesterol increment on the endothelium function, assessed by flow-mediated dilation, in Lithuanian familial hypercholesterolemia patients

Impact of LDL-cholesterol increment on the endothelium function, assessed by flow-mediated dilation, in Lithuanian familial hypercholesterolemia patients

Impact of age on carotid intima-media thickness in Lithuanian familial hypercholesterolemia patients

Impact of age on carotid intima-media thickness in Lithuanian familial hypercholesterolemia patients

Impact of LDL-cholesterol increment on the ankle-brachial index (ABI) in Lithuanian familial hypercholesterolemia patients

Impact of LDL-cholesterol increment on the ankle-brachial index (ABI) in Lithuanian familial hypercholesterolemia patients

The role of LDL-cholesterol increment in carotid artery plaques formation among familial hypercholesterolemia patients population

The role of LDL-cholesterol increment in carotid artery plaques formation among familial hypercholesterolemia patients population

The effect of convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9AB) on platelet aggregation and blood coagulation in familial hypercholesterolemia patients

The effect of convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9AB) on platelet aggregation and blood coagulation in familial hypercholesterolemia patients

The influence of LDL cholesterol increment on aortic pulse wave velocity (PWV carotid-femoralis) in Lithuanian familial hypercholesterolemia patients

The influence of LDL cholesterol increment on aortic pulse wave velocity (PWV carotid-femoralis) in Lithuanian familial hypercholesterolemia patients

LDL-cholesterol goal achievement in familial hypercholesterolemia patients followed at a secondary hospital

LDL-cholesterol goal achievement in familial hypercholesterolemia patients followed at a secondary hospital

Exploring Plasma Coenzyme Q10 Status in Paediatric Dyslipidaemia.

Coenzyme Q10 (CoQ) is a ubiquitous lipid with different biological functions. In blood, there is a close relationship between CoQ status and cholesterol, which strongly supports the study of both molecules simultaneously. The objective of this study was to evaluate plasma CoQ, lipoprotein concentrations and CoQ/Chol ratio in a cohort of paediatric patients with different types of dyslipidaemias. A total of 60 paediatric patients were recruited (age range: 7 months-18 years), including 52 with different types of hypercholesterolemia, 2 with isolated hypertriglyceridemia and 6 with hypobetalipoproteinemia. Plasma CoQ was analysed by HPLC with electrochemical detection, and lipoprotein and cholesterol concentrations by standard automated methods. The lowest CoQ values were detected in patients with hypobetalipoproteinemia and in two cases of liver cirrhosis. Mean CoQ values were significantly higher in hypercholesterolemic patients compared to controls (average values 1.07 µmol/L and 0.63 µmol/L) while the CoQ/cholesterol ratio did not show differences (170 vs. 163, respectively). Mean CoQ values were significantly lower in the group of patients with hypobetalipoproteinemia compared to controls (mean CoQ values of 0.22 µmol/L vs. 0.63 µmol/L, respectively), while those of CoQ/cholesterol did not show differences. Pearson's correlation test showed a positive correlation between the CoQ and cholesterol values (r = 0.565, p < 0.001) and between the CoQ and the LDL cholesterol values (r = 0.610, p < 0.001). Our results suggest that it is advisable to analyse plasma CoQ and cholesterol concentrations in patients with hypobetalipoproteinemia and hypercholesterolemia associated with liver damage.

Ebronucimab in Chinese patients with hypercholesterolemia---A randomized double-blind placebo-controlled phase 3 trial to evaluate the efficacy and safety of ebronucimab

Randomized clinical trials (RCTs) of PCSK9 monoclonal antibody(mAb) specifically for Chinese patients have been limited. This multi-center RCT is to clarify the efficacy and safety of a novel mAb, Ebronucimab, in Chinese patients. Patients diagnosed with primary hypercholesterolemia, including Heterozygous Familial Hypercholesterolemia, or mixed dyslipidemia, were categorized by ASCVD risk and randomly assigned at a ratio of 2:1:2:1 to receive Ebronucimab 450 mg or matching placebo every 4 weeks (Q4W), or Ebronucimab 150 mg or matching placebo every 2 weeks (Q2W). The primary outcome was the percentage change of LDL-C from baseline to week 12 for all groups. The least squares mean reduction difference (95 %CI) in LDL-C from baseline to week 12 of Ebronucimab 450 mg Q4W and Ebronucimab 150 mg Q2W groups versus the placebo group was −59.13 (-64.103, −54.153) (Adjusted p<0.0001) and −60.43 (-65.450, −55.416) (Adjusted p<0.0001), respectively. Meanwhile, the Ebronucimab group exhibited notably high rates in reaching LDL-C goals of each cardiovascular risk stratification. In addition, Ebronucimab effectively improved other lipid panel. During the double-blind treatment period, relatively frequently reported adverse events (AEs) were injection site reactions (ISR), urinary tract infection, and hyperuricemia (Incidence rate are 6.9 %, 4.8 % and 3.5 %). Among treatment-associated AEs, only injection site reactions (ISR) occurred more in the dose groups. In conclusion, Ebronucimab, with either 450 mg Q4W or 150 mg Q2W doses, demonstrated significant efficacy in lowering serum LDL-C level with a favorable safety and immunogenicity profile among hypercholesterolemic patients.

Do genetically determined very high and very low LDL levels contribute to Lp(a) plasma concentration?

Background and aimsLipoprotein(a) [Lp(a)] is a well-recognized risk factor for atherosclerotic cardiovascular disease (ASCVD). Few data are available on the distribution of Lp(a) levels among subjects at different cardiovascular risk and in subjects with monogenic and polygenic dyslipidemias (familial hypercholesterolemia, FH and familial hypobetalipoproteinemia type 1, FHBL1).The aim of this study was to investigate the distribution of Lp(a) plasma levels in subjects with high and low LDL-C levels (FH and FHBL1) and in the general population. Methods and resultsThe study cohorts included 356 hypercholesterolemic patients, 212 carrying a FH causative mutation, 144 with clinical FH (mutation negative - FHneg), 52 FHBL1 and 797 free-living subjects. Lp(a) levels were significantly higher in FH subjects (both FH and FHneg) (median 12.46 mg/dl and 14.0 mg/dl, respectively) compared with FHBL1 and free-living subjects (7.68 mg/dl and 7.18 mg/dl, respectively). More, Lp(a) levels were similar in FH subjects carrying LDLR defective and null mutations and FHneg. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels (median 10.68 mg/dl and 9.20 mg/dl, respectively) compared with low and moderate CV risk (median 5.72 mg/dl and 7.80 mg/dl, respectively) (p < 0.0008). ConclusionsFH subjects exhibit higher Lp(a) levels than FHBL1 and general population. Lp(a) slightly contribute to hypercholesterolemia in FH patients. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels compared with low and moderate CV risk. Combined evaluation of Lp(a) levels in FH subjects with other traditional risk factors could identify very high-risk individuals who may benefit from early aggressive treatments to avoid premature CV events.

Proprotein convertase subtilisin/kexin type 9 inhibitors in peripheral artery disease: A review of efficacy, safety, and outcomes.

Peripheral artery disease (PAD) is a common condition characterized by atherosclerosis in the peripheral arteries, associated with concomitant coronary and cerebrovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients. This review focuses on the efficacy, safety, and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed. Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events, offering a potential treatment option for PAD patients. Safety evaluations from trials show few adverse events, most of which are injection-site reactions, indicating the overall safety profile of PCSK9 inhibitors. Clinical outcomes show a reduction in cardiovascular events, ischemic strokes, and major adverse limb events. However, despite these positive findings, PCSK9 inhibitors are still underutilized in clinical practice, possibly due to a lack of awareness among care providers and cost concerns. Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.

Cellular and functional evaluation of LDLR missense variants reported in hypercholesterolemic patients demonstrates their hypomorphic impacts on trafficking and LDL internalization.

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased LDL-cholesterol levels. About 85% of FH cases are caused by LDLR mutations encoding the low-density lipoprotein receptor (LDLR). LDLR is synthesized in the endoplasmic reticulum (ER) where it undergoes post-translational modifications and then transported through Golgi apparatus to the plasma membrane. Over 2900 LDLR variants have been reported in FH patients with limited information on the pathogenicity and functionality of many of them. This study aims to elucidate the cellular trafficking and functional implications of LDLR missense variants identified in suspected FH patients using biochemical and functional methods. We used HeLa, HEK293T, and LDLR-deficient-CHO-ldlA7 cells to evaluate the subcellular localization and LDL internalization of ten LDLR missense variants (p.C167F, p.D178N, p.C243Y, p.E277K, p.G314R, p.H327Y, p.D477N, p.D622G, p.R744Q, and p.R814Q) reported in multiethnic suspected FH patients. We also analyzed the functional impact of three variants (p.D445E, p.D482H, and p.C677F), two of which previously shown to be retained in the ER. We show that p.D622G, p.D482H, and p.C667F are largely retained in the ER whereas p.R744Q is partially retained. The other variants were predominantly localized to the plasma membrane. LDL internalization assays in CHO-ldlA7 cells indicate that p.D482H, p.C243Y, p.D622G, and p.C667F have quantitatively lost their ability to internalize Dil-LDL with the others (p.C167F, p.D178N, p.G314R, p.H327Y, p.D445E, p.D477N, p.R744Q and p.R814Q) showing significant losses except for p.E277K which retained full activity. However, the LDL internalization assay is only to able evaluate the impact of the variants on LDL internalization and not the exact functional defects such as failure to bind LDL. The data represented illustrate the hypomorphism nature of variants causing FH which may explain some of the variable expressivity of FH. Our combinatorial approach of in silico, cellular, and functional analysis is a powerful strategy to determine pathogenicity and FH disease mechanisms which may provide opportunitites for novel therapeutic strategies.

Study of the impact of the vascular systemic risk factors on peripapillary vascular density by optical coherence tomography angiography.

The focus of therapeutic tools in glaucoma has been mainly to control of intraocular pressure. Recently there has been a growing interest in investigating the relationship of vascular risk factors in the development of glaucoma. The aim of this study was to assess the association between systemic arterial hypertension, diabetes mellitus and hypercholesterolemia, and peripapillary vascularization measured by Optical Coherence Tomography Angiography (OCTA) in glaucoma and healthy subjects. In this unicenter, observational, cross-sectional study, 212 subjects, 118 glaucoma patients and 94 controls were consecutively recruited. Of these, 86 participants were excluded due to poor OCTA image quality. Therefore, 146 subjects were included in the final analysis, 74 glaucoma patients and 72 controls. Using a linear regression model, with 95% confidence and 80% statistical power, the effect of vascular risk factors on OCTA parameters in the 146 subjects included in the final analysis was studied. No significant impact of vascular risk factors on OCTA measurements was found. Diabetic patients tended to show a lower peripapillary perfusion vascular density than subjects without diabetes (β 0.016, 95%CI 0.003;0.030, p 0.016). Similarly, hypercholesterolemia patients appeared to show less peripapillary flow index than non-hypercholesterolaemic patients (β 0.029, 95%CI 0.013;0.046, p 0.001). Glaucoma patients had 0.02% lower peripapillary perfusion vascular density (β 0.020, 95% CI 0.011;0.029, p < 0.001), 0.04% lower peripapillary flow index (β 0.036, 95%CI 0.022;0.051, p < 0.001) and 9.62% thinner retinal nerve fibre layer (β 9.619, 95%CI 5.495;13.744, p < 0.001). In conclusion glaucoma has greater effect on peripapillary vascular density parameters than any of the vascular risk factors analyzed. What is known: • Vascular disfunction plays an important role in the development of glaucoma. • Optical coherence tomography angiography makes it possible to assess the retinal microvasculature and the role that its alterations could have in the development of glaucoma. • Decrease of the peripapillary microcirculation seems to be more related to the increase in intraocular pressure and the glaucoma itself than to the presence of cardiovascular risk factors. • The effect of having diabetes, systemic arterial hypertension or hypercholesterolaemia on vascular parameters or nerve fibre layer thickness was low. • There was also no relevant impact of the systemic medication used for these diseases on the peripapillary vascular parameters studied or on nerve fibre layer thickness.