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Background and Aims: Limited evidence exist regarding the association between ongericimab, a novel recombinant humanized anti-PCSK9 monoclonal antibody, and primary hypercholesterolemia and mixed dyslipidemia. This study aimed to evaluate the efficacy and safety of ongericimab administered by prefilled syringe (PFS) or autoinjector (AI) in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia on stable optimized lipid-lowering therapy., Methods and Results: A total of 255 patients on stable optimized lipid-lowering therapy were randomized in a 2:1:2:1 ratio to receive PFS for the subcutaneous injection of ongericimab 150 mg every 2 weeks (Q2W) or a matching placebo, or AI for the subcutaneous injection of ongericimab 150 mg Q2W or a matching placebo. The primary efficacy endpoint was the percent change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 12. Safety was also evaluated. At week 12, the least squares mean percent changes were -72.7% (3.9%) for PFS and -71.1% (3.8%) for AI (all P < 0.001) compared to respective matching placebo groups. Beneficial effects were also seen for all secondary lipid parameters, notably with robust reduction in Lp (a). Treatment-emergent adverse events (TEAEs) and serious AEs with ongericimab were reported in 46.2% and 2.4% of patients, compared to 44.2% and 3.5% with placebo., Conclusion: In Chinese patients with primary hypercholesterolemia and mixed dyslipidemia, a 12-week treatment regimen with ongericimab administered by PFS or AI significantly reduced LDL-C and other lipid parameters, proving to be safe and well tolerated. Patients experienced consistent effects from PFS or AI devices., Clinical Trial Registration: CTR20220027; January 11, 2022; http://www.chinadrugtrials.org.cn/index.html., Competing Interests: Declaration of competing interest Minghui Wang, Yi Zhao, and Xuelian Bai are employees of Shanghai Junshi Biosciences Co., Ltd. The remaining authors declare that they have not received support from any organization for the submitted work, do not have any financial relationships with organizations that might have an interest in the submitted work over the past three years, and have not engaged in any activities that may have influenced the submitted work., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Sitosterolemia is a rare inherited lipid metabolic disorder characterized by increased levels of plant sterols and accelerated atherosclerosis. Although early detection is beneficial for the prevention of disease progression, it is largely underdiagnosed by routine screening based on conventional lipid profiles., Materials and Methods: A gas chromatography-mass spectrometry (GC-MS)-based profiling has been developed and validated to measure the levels of biologically active free sterols, including five endogenous sterols and three plant sterols (sitosterol, campesterol, and stigmasterol) in dried blood spot (DBS)., Results: Within- and between-run precisions were 1.4-11.1 % and 2.2-14.1 %, respectively, while the accuracies were all 86.3 ∼ 121.9 % with the correlation coefficients (r 2 ) > 0.988 for all the sterols. In the patients (four girls and two boys, 6.5 ± 2.8 years), sitosterol levels were significantly increased, with an optimal cut-off value of 2.5 µg/mL distinguishing them from ninety-three age-matched healthy children. A cut-off value of 31.9 µg/mL differentiated the patients from six ABCG5/ABCG8 heterozygous carriers. In addition, the molecular ratios of sitosterol to cholesterol, desmosterol, and 7-dehydrocholesterol provided excellent cut-off values of 26.3, 67.6, and 21.6, respectively, to distinguish patients from both healthy controls and heterozygous carriers., Conclusions: The novel DBS-based GC-MS profiling of free sterols accurately identified patients with sitosterolemia, with a performance comparable to that of a serum assay. The DBS profiling could be more feasible method in clinical practice as well as population screening programs, and it can provide diagnostic cut-off values for individual plant sterols., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Although dyslipidemia is a major risk factor for chronic kidney disease (CKD), the relationship between dietary cholesterol and CKD remains unknown. We investigated the association between cholesterol intake and CKD risk., Methods and Results: The Korea National Health and Nutrition Examination Survey (KNHANES) 2019-2021 (n = 13,769) and the Korean Genome and Epidemiology Study (KoGES) (n = 9225) data were used for this study. Cholesterol intake was assessed using a 24-h recall food frequency questionnaire, and participants were categorized into three groups (T1, T2, and T3) based on cholesterol intake. Primary outcomes were prevalence and incidence of CKD. Higher cholesterol intake was modestly associated with increased serum levels of total, low-density lipoprotein, and high-density lipoprotein cholesterol in the KNHANES. However, we found no significant association between cholesterol intake and CKD prevalence in the KNHANES, regardless of a history of hypercholesterolemia. In the KoGES, during a median follow-up of 11.4 years, cholesterol intake was not associated with incident CKD in participants without hypercholesterolemia (hazard ratio [HR] per 10 mg increase, 1.00; 95 % confidence interval [CI], 0.99-1.01) and in those with hypercholesterolemia (HR, 1.01; 95 % CI, 0.98-1.04). Egg consumption also showed no significant association with the risk of incident CKD. Additionally, cholesterol intake had no significant interaction on the relationships between serum cholesterol levels and incident CKD., Conclusion: Although cholesterol intake was associated with increased serum cholesterol levels, it was not associated with CKD prevalence and incidence. Our findings suggest that reducing cholesterol intake alone may not be sufficient to prevent CKD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Lowering the blood concentration of low-density lipoprotein cholesterol (LDL-C), is a cornerstone in preventing atherosclerotic cardiovascular disease (ASCVD). Current European guidelines recommends LDL-C < 1.4 mmol/L for secondary prevention in high-risk patients. The aim of this study is to investigate monitoring and treatment of hypercholesterolemia one year after a ASCVD event., Methods: Danish patients with hypercholesterolemia and an incident ASCVD event from 2015 to 2020 were included in this nationwide cohort study. Patients' LDL-C measurements and lipid-lowering treatment were followed for one year after ASCVD event, or until death or migration. Imputation was used to estimate absolute LDL-values when patients were unmeasured., Results: A total of 139,043 patients were included in the study with a mean follow-up time of 10.4 months. During the one-year period, 120,020 (86%) patients had their LDL-C measured at least once, 83,723 (60%) patients were measured at least twice. During the period one to six months after ASCVD event 25,999 (19%) achieved an LDL-C < 1.4 mmol/L, 93,349 (67%) failed to achieve an LDL-C < 1.4 mmol/L, and 196,950 (14%) had died or migrated. Missing LDL-C values were estimated via imputation. At the end of month twelve, 60,583 (44%) patients were in statin monotherapy, 2926 (2%) were treated with other lipid-lowering treatment, 42,869 (31%) were in no treatment, and 32,665 (23%) had died or migrated., Conclusions: Many Danish patients are not appropriately followed-up with LDL-C measurements, and a substantial number of patients are not in lipid-lowering treatment one year after an ASCVD event., Competing Interests: Declaration of competing interest This study was supported by Novartis as a company sponsored study. No data access was granted to the sponsor or any of the sponsor's employees at any time, likewise, the sponsor or its' employees did not participate directly in management, analysis, or any other handling of data., (Copyright © 2024. Published by Elsevier B.V.)

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies., Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia., Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified., Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life., Funding: Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron., Competing Interests: Declaration of interests The competing interests of individual collaboration members are listed in the appendix (pp 11–14)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Severe hypercholesterolemia (LDL-cholesterol ≥ 5 mmol/l) is a major risk factor for coronary artery disease (CAD). The etiology incudes both genetic and nongenetic factors, but persons carrying mutations in known hypercholesterolemia-associated genes are at significantly higher CAD risk than non-carriers. Yet, a significant proportion of mutation carriers remains undetected while the assessment of genetic candidate variants in clinical practice is challenging., Methods: To address these challenges, we set out to test the utility of a practical approach to leverage data from a large reference cohort, the FinnGen Study encompassing 356,082 persons with extensive longitudinal health record information, to aid the clinical evaluation of single genetic candidate genes variants detected by exome sequence analysis in a target population of 351 persons with severe hypercholesterolemia., Results: We identified 23 rare missense mutations in known hypercholesterolemia genes, 3 of which were previously described mutations (LDLR Pro309Lysfs, LDLR Arg595Gln and APOB Arg3527Gln). Subsequent in silico and clinical assessment of the remaining 20 variants pinpointed two likely hypercholesterolemia-associated variants in LDLR (Arg574Leu and Glu626Lys) and one in LDLRAP1 (Arg151Trp). Heterozygous carriers of the novel LDLR and LDLRAP1 variants received statin treatment more often than non-carriers (OR 2.1, p = 1.8e-6 and OR 1.4, p = 0.001) and untreated carriers had higher risk for ischemic heart disease (OR 2.0, p = 0.03 and OR 1.8, p = 0.008)., Conclusions: Our data elucidate the wide spectrum of genetic variants impacting hypercholesterolemia and demonstrate the utility of a large reference population to assess the heterogeneous impact of candidate gene variants on cardiovascular disease risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Refractory hypercholesterolemia (RH), caused primarily by the loss-of-function mutation of LDL receptor (LDLR) gene seen in HoFH and HeFH patients, remains a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Statin and ezetimibe combination therapy lower circulating LDL by 30% in HoFH patients. PCSK9 mAB, being an LDLR-dependent therapy, is not effective in HoFH, but lowers LDL by 25% in HeFH patients. A maximum reduction of 50% was noted in HoFH patients treated with ANGPTL3 mAB, which was not enough to achieve therapeutic goal of LDL. Therefore, new approaches are warranted to offer hopes to individuals intolerant to higher dose statins and not able to achieve recommended LDL level., Data Synthesis: New approaches to lower LDL include gene therapy and gene editing. AAV-based gene therapy has shown encouraging results in animal models. Using CRISPR/Cas9-mediated genome/base editing, gain of function and loss of function have been successfully done in animal models. Recent progress in the refinement of genome/base editing has overcome the issues of off-target mutagenesis with ∼1% mutagenesis in case of PCSK9 and almost no off-target mutagenesis in inactivating ANGPTL3 in animal models showing 50% reduction in cholesterol. Current approaches using CRISPR-Cas9 genome/base editing targeting LDLR-dependent and LDLR-independent pathways are underway., Conclusions: The new information on gain of LDLR function and inactivation of ANGPTL3 together with developments in genome/base editing technology to overcome off-target insertion and deletion mutagenesis offer hope to refractory hypercholesterolemic individuals who are at a higher risk of developing ASCVD., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Cholesterol control and management in patients with hypercholesterolemia are significant for the primary and secondary prevention of atherosclerotic cardiovascular disease. This study analyzed the trend of serum total cholesterol (TC) control (<240 mg/dL and <200 mg/dL) in American adults with hypercholesterolemia and thereby make some effective recommendations for the public health measures., Methods and Results: Basing on the National Health and Nutrition Examination Survey (NHANES) data from 1988 to 2018 (12 cycles), we calculated the weighted and representative rate of patients with hypercholesterolemia who had controlled TC, and then described the trend. Among the adults with hypercholesterolemia, the age-adjusted rate of those whose TC was less than 240 mg/dL increased from 7.67% (95%CI: 5.94%-9.40%) in 1988-1991 to 58.52% (95%CI: 55.89%-61.15%) in 2013-2014 and then remained stable; and the age-adjusted rate of those whose TC was less than 200 mg/dL increased from 2.49% (95%CI: 1.48%-3.50%) in 1988-1991 to 44.58% (95%CI: 40.00%-49.16%) in 2017-2018., Conclusion: We concluded that the rate of controlling TC below 200 mg/dL among all patients had shown an increasing trend from 1988 to 2018 in America, while the rate of controlling TC below 240 mg/dL remained stable in recent years after an increasing., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Bempedoic acid significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia but its effects in patients with metabolic syndrome (MetS) have not been well characterized. We sought to determine the efficacy and safety of bempedoic acid in patients with hypercholesterolemia by baseline MetS status., Methods: This study used pooled data from four phase 3 studies. Using modified International Atherosclerosis Society guidelines, patients were grouped into two pools: those with and those without MetS. Patients with diabetes were excluded. Endpoints assessed change from baseline to week 12 in lipid and glycemic parameters and high-sensitivity C-reactive protein (hsCRP), and safety., Results: The study included 936 patients with MetS (bempedoic acid, 648; placebo, 288) and 1573 without MetS (bempedoic acid, 1037; placebo, 536). Significant placebo-corrected reductions in LDL-C were observed with bempedoic acid (p < 0.0001), with a slightly larger decrease in patients with vs. without MetS (-22.3% vs. -18.4%; interaction p = 0.0472). Compared with placebo, bempedoic acid significantly (p < 0.0001) lowered total cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, and hsCRP, with a similar magnitude of benefit observed between MetS categories. Triglycerides increased with bempedoic acid but only to a lesser extent than with placebo in patients without MetS (placebo-corrected difference, -4.4%; p = 0.02). Only patients with MetS experienced decreases in glycated hemoglobin (-0.07%; p < 0.0001) and fasting plasma glucose (-2.4 mg/dL; p = 0.002). Safety was comparable between MetS categories and treatment groups., Conclusions: These data suggest that bempedoic acid is a suitable therapy for patients with and without MetS who require additional lipid lowering., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MDS has received research grant(s)/support paid to his institution from Amgen, Esperion Therapeutics, Ionis Pharmaceuticals, the National Institutes of Health, NewAmsterdam Pharma, and Novartis, and honoraria for consultancy from EmendoBio, Ionis Pharmaceuticals, Novartis, and Regeneron Pharmaceuticals. He has also served on scientific advisory boards for Amgen, Novartis, and Precision BioSciences. PRT has received funding/grant support from the American Heart Association, the National Institutes of Health, and the Federal Emergency Management Agency, and honoraria for consultancy from Amgen, Bayer, Boehringer Ingelheim, Esperion Therapeutics, Medtronic, Novartis, Novo Nordisk, and Sanofi. MJL is an employee of Esperion Therapeutics, Inc. LL is a consultant for Esperion Therapeutics, Inc. CMB has received research grant(s)/support paid to his institution from Abbott Diagnostics, Akcea Therapeutics, Amarin, Amgen, Esperion Therapeutics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, Roche Diagnostics, Sanofi Synthelabo, the National Institutes of Health, the American Heart Association, and the American Diabetes Association; he has also served as a consultant for Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Intercept Pharmaceuticals, Ionis Pharmaceuticals, Matinas BioPharma Holdings, Merck, Novartis, Novo Nordisk, Regeneron Pharmaceuticals, Roche Diagnostics, and Sanofi Synthelabo., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hyperlipidemia is a common complication after liver transplantation (LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia., Methods: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria., Results: Early posttransplant hypercholesterolemia (EPHC) was independently inversely associated with the risk of recurrence [hazard ratio (HR) = 0.630; P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC (B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence (HR = 0.504; P = 0.006) and mortality (HR = 0.511; P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival (89.6% and 83.7% vs. 83.8% and 72.7% respectively; P = 0.023), and 1-year and 3-year overall survival (95.8% and 84.8% vs. 94.6% and 77.6% respectively; P = 0.039). In the subgroup analysis, B-EPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria; whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC (recurrence HR = 0.306, P = 0.011; mortality HR = 0.325, P = 0.031)., Conclusions: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria., (Copyright © 2022. Published by Elsevier B.V.)

Background and Aims: We aimed to understand the impact of physicians' perception about LDL-cholesterol (LDLc) control on the management of patients with dyslipidemia in Spain., Methods: We performed a cross-sectional and multicenter study, in which 435 healthcare professionals participated in face-to-face meetings, collecting qualitative and quantitative information related to hypercholesterolemia management. Additionally, aggregated anonymized data of the last 10 patients with hypercholesterolemia attended by each physician were collected., Results: A total of 4,010 patients (8%, 13%, 16% and 61% with low, moderate, high, and very high cardiovascular [CV] risk) were included. Physicians' perception was that 62% of their patients attained LDLc goals (66%, 63%, 61% and 56%, for low, moderate, high and very high CV risk, respectively). However, when looking into the data only 31% (vs 62% p<0.01) of patients attained the LDLc goals (47%, 36%, 22% and 25%, respectively). Overall, 33% of patients were taking high intensity statins, 32% statin/ezetimibe, 21% low/moderate intensity statins and 4% PCSK9 inhibitors. These numbers were 38%, 45%, 8% and 6% for very high risk patients and 44%, 21%, 21% and 4% for high CV risk patients. In 32% of patients, a change in lipid lowering therapy was performed after the visit, mainly combining statins/ezetimibe (55%)., Conclusions: In Spain, most patients with dyslipidemia do not achieve the recommended LDLc goals because of an insufficient intensification of lipid lowering therapy. On the one hand, this is in part due to physicians misperception on preventive LDLc control and the need for repeated advice to patient, and, on the other, to the lack of patient adherence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Juan Cosin-Sales: has received conference fees from Almirall, Amgen, Daiichi-Sankyo, Ferrer, MSD, Novartis, Organon, Rovi and Sanofi; has participated in advisory services for Almirall, Amgen, MSD and Sanofi; and has received research grants from Amgen, Ferrer, MSD and Sanofi. Raquel Campuzano: has received conference fees from Amgen, Daiichi-Sankyo, Ferrer, Mylan, MSD, Organon, Sanofi, Servier and Novartis; has participated in advisory services for Novartis, Amgen, Sanofi and Servier; and has received collaborations to scientific or research projects from Amgen, Daiichi-Sankyo, Ferrer, Organon, Servier and Novartis. José Luis Díaz: has received fees for presentations, advisory services or scientific collaborations from Amgen, Bayer, Boëringher, BMS, Lilly, MSD, Mylan, Novartis, Novo-Nordisk, Pfizer, Rovi, Rubió, Sanofi, Daiichi-Sankyo and Servier. Carlos Escobar: has received fees for conferences/advisory services from: Almirall, Amgen, Daiichi-Sankyo, Esteve, Ferrer, MSD, Novartis, Organon, Rovi, Sanofi, Servier and Viatris. María Rosa Fernández: has received fees for conferences from Amgen, Sanofi, Ferrer, Daiichi-Sankyo, Organon and Rovi; has participated in advisory services for Novartis, Amgen, Sanofi and Amarin. Juan José Gómez-Doblas: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo, Organon and MSD; has participated in advisory services for Amgen, Sanofi and Amarin; and has received collaborations to scientific or research projects from Amgen, Sanofi, Ferrer and Daiichi-Sankyo. José María Mostaza: has participated in advisory services and/or conferences, or has carried out projects for Pfizer, Amarin, Ferrer, Sanofi, Amgen, Alter, Servier, Novartis and Daiichi-Sankyo. Juan Pedro-Botet: has received fees for conferences from Amarin, Amgen, Daiichi-Sankyo, Esteve, MSD, Sanofi and Viatris; and has participated in advisory services for Amarin, Amgen, Daiichi-Sankyo, Esteve, Ferrer, Sanofi and Viatris. Núria Plana: has received fees for conferences from Amgen, Sanofi, Daiichi-Sankyo Mylan and Alexion. Pedro Valdivielso: has received fees for conferences from Amgen, Sanofi, Ferrer, Amarin, Akcea, Sobi, MSD, Novartis and Daiichi-Sankyo; has participated in advisory services for Daiichi-Sankyo, Amgen, Sanofi, Akcea and Amarin; and has received research grants from Ferrer and Akcea., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10 -4 ). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10 -6 ). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aims: Serum phytosterol profiles are essential for the diagnosis and management of sitosterolemia. However, pediatric reference interval (RI) studies are scarce and various mass spectrometry (MS) approaches for phytosterol analysis still face multiple limitations. Therefore, an optimized gas chromatography (GC)-MS assay and age-related RIs in children are both required., Materials and Methods: Cholesterol and phytosterols (sitosterol, campesterol, cholestanol, stigmasterol, and sitostanol) were simultaneously determined by optimized GC-MS and performance was verified by the lower limit of quantification (LLOQ), linearity, precision, recovery, matrix effects, and method comparison. Healthy children (247 males and 263 females) were recruited, sex and age dependence were assessed using quantile regression (2.5th percentile and 97.5th percentile), and RIs were established according to Clinical and Laboratory Standards Association guideline C28-A3. These RIs were validated in 19 patients with sitosterolemia and 23 patients with hypercholesterolemia., Results: The optimized method shortened the sample processing time by approximately 60 min. Among the five phytosterols, all precision, recoveries (ranging from 89.97% to 104.94%), and relative matrix effects (%CV: ranging from 0.08% to 13.88%) met the specifications. GC-MS showed good agreement with lower cholesterol concentrations compared to conventional enzymatic methods. No significant differences between males and females were observed for all phytosterols, but age dependency was found and age-related RIs were established accordingly. Five phytosterols were significantly higher than RIs in patients with sitosterolemia., Conclusion: We established age-related RIs for five phytosterols in children based on an optimized GC-MS assay, providing a screening tool for the diagnosis of sitosterolemia in children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In contrast to strong evidence-based clinical recommendations for lipid-lowering treatment, there is no analogous definitive diagnostic definition of hypercholesterolemia and its various subtypes. For many clinicians, guideline indications for hypolipidemic treatment can become broadly conflated with hypercholesterolemia in a non-specific sense. In this statement, we propose a unified definition and mechanism-based classification of hypercholesterolemia, which in turn should help to stratify patients and guide efficient diagnosis without interfering with the current strategies of ASCVD risk reduction., (Copyright © 2022. Published by Elsevier Inc.)

Background: In 2011, the American Academy of Pediatrics recommended universal lipid screening during childhood and adolescence. However, this approach was shown to be lacking in adherence. Only 6% of non-high-risk children received lipid screening by age 12. Our study designed a school-based universal screening for hypercholesterolemia in children. The goal was to investigate a feasible strategy for lipid screening of children., Methods: The study enrolled all the fourth-grade students of 30 elementary schools from 2020 to 2021. Non-fasting non-HDL was used as a screening tool. These students were classified into three groups: acceptable group (non-HDL < 120 mg/dL), borderline group (120-144 mg/dL), and abnormal group (≥145 mg/dL). The abnormal group was referred to our hospital for confirmatory fasting lipid studies. The complete rate and timing were calculated., Results: Six hundred students were enrolled in this study. In the abnormal group (95 children), a total of 92 students received confirmatory fasting lipid studies. These confirmatory studies were completed within three months after the family received their reports. The study had a rate of coverage of 62% and the referred percentage of the abnormal group was 97%. BMI had poor association with fasting LDL (CORR = 0.06752, p = 0.444). In the abnormal group, only 29.5% children had family history of early CVD or dyslipidemia., Conclusion: School-based universal screening for hypercholesterolemia in children is a feasible and effective way to identify patients at high-risk for early CVD. Neither BMI nor family history was a good indicator for the screening of dyslipidemia., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Lipoprotein(a) [Lp(a)] concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown. We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH., Methods: We conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR, APOB, APOE and PCSK9) and controls from de Aragon Workers' Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort., Results: Adjusted geometric means (95% confidence interval) of Lp(a) in controls (n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB-dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR-dependent FH, 21.7 mg/dL (17.9, 26.4). These differences were also observed in heFH from the SEA cohort. The number of plasminogen-like kringle IV type-2 repeats of LPA, the hypercholesterolemia polygenic score or LDLc concentration did not explain these differences. In LDLR-dependent FH, Lp(a) levels were not different depending on the affected protein domain., Conclusions: Lp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Sitosterolemia, also known as phytosterolemia, results from increased intestinal absorption of plant sterols and decreased intestinal and biliary excretion of sterols, resulting in increased levels of plant sterols in the plasma. The most common symptoms include xanthomas, premature atherosclerosis, hemolytic anemia and macrothrombocytopenia, however delayed diagnosis or misdiagnosis also occur., Patient and Methods: Clinical exome sequencing was performed on a 10-year-old boy whom we followed up with signs of pancytopenia accompanied by macrothrombocytopenia and stomatocytosis. In addition, the blood sterol levels of the patient and his family were studied., Results: A novel homozygous c.904 + 5G > C intronic variant was detected in ABCG5 gene in index case. The mother and father were identified as carriers. The blood plant sterol levels of the patient and his family were studied, and the levels in the patient confirmed Sitosterolemia. Sitosterol levels decreased dramatically with restricted diet and ezetimibe treatment., Conclusion: In children, signs of Sitosterolemia may be subtle and the only symptom may be hematological. Therefore, Sitosterolemia should be kept in mind in children with stomatocytosis and macrothrombocytopenia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background & Aims: Whether bioactive lysophospholipids (lyso-PLs) and trimethylamine-N-oxide (TMAO) serve as non-invasive biomarkers in early human hypercholesterolemia (HC) is unknown. This study aimed to assess whether serum lyso-PLs and plasma TMAO may be suitable susceptibility/risk biomarkers of HC in humans. Secondarily, we aimed to evaluate the relationships between targeted metabolites, diet composition and circulating liver transaminases, and verify these results in hamsters., Methods: A targeted metabolomics and lipidomics approach determined plasma TMAO and serum lysophosphatidylcholines (lyso-PCs) and lysophosphatidylethanolamines (lyso-PEs) in low (L-LDL-c) and moderate to high (MH-LDL-c) LDL-cholesterol subjects. Additionally, the relationships between targeted metabolites, liver transaminases and diet, particularly fatty acid intake, were tested. In parallel, plasma and liver lyso-PL profiles were studied in 16 hamsters fed a moderate high-fat (HFD) or low-fat (LFD) diet for 30 days., Results: Predictive models identified lyso-PC15:0 and lyso-PE18:2 as the most discriminant lyso-PLs among groups. In MH-LDL-c (n = 48), LDL-cholesterol and saturated FAs were positively associated with lyso-PC15:0, whereas in L-LDL-c (n = 70), LDL-cholesterol and polyunsaturated fatty acids (PUFAs) were negatively and positively related to lyso-PE18:2, respectively. Interestingly, in MH-LDL-c, the lower lyso-PE 18:2 concentrations were indicative of higher LDL-cholesterol levels. Intrahepatic accumulation of lyso-PLs-containing essential n-6 PUFAs, including lyso-PE18:2, were higher in HFD-fed hamsters than LFD-fed hamsters., Conclusions: Overall, results revealed a possible hepatic adaptive mechanism to counteract diet-induced steatosis in animal and hypercholesterolemia progression in humans. In particular, low serum lyso-PE18:2 suggests a suitable susceptibility/risk biomarker of HC in humans., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Sitosterolemia is a rare form of dyslipidemia that has diverse clinical manifestations, and insufficient knowledge of the disease frequently leads to a delay in diagnosis. We report a case of sitosterolemia in a 26-year-old Chinese woman, characterized by anemia, thrombocytopenia, persistent hypercholesterolemia, premature atherosclerosis, extensive xanthoma, and arthralgia-tenosynovitis. Successive misdiagnoses of Evans syndrome and familial hypercholesterolemia had been made, and the patient had responded minimally to steroid therapy, splenectomy, and statin treatment; therefore, she was referred to our hospital. On admission, a peripheral blood smear revealed the presence of abnormally shaped erythrocytes and giant platelets. Multiple atherosclerotic lesions, sites of tenosynovitis, and carotid sheath xanthomas were identified on ultrasonography. Compound heterozygous mutations of the ABCG5 gene, including a hot variant (c.1,336, exon10 C>T, p.(R446*)) and a novel variant (c.1,325-3(IVS9)&#95;c.1325-2(IVS9)delCA) were separately identified in her parents by pedigree analysis. Plant sterols analysis by high performance liquid chromatography method revealed remarkably elevated plasma plant sterol concentrations after drug withdrawal but reduced rapidly after restarting ezetimibe during follow-up period. After 21 months of treatment with ezetimibe and a low-plant sterol diet, her hematologic abnormalities, tenosynovitis, and hypercholesterolemia had significantly improved; and ultrasonography showed that her skin and carotid sheath xanthomas had resolved or shrunk. This case demonstrates that morphological changes in blood cells on a peripheral blood smear, ultrasonographic findings and ABCG5/ABCG8 gene screening are valuable, and plant sterol analysis in serum is crucial to confirm diagnosis and assess treatment adequacy for sitosterolemia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Low-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype., Methods: First, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data., Results: The mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10-0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk., Conclusions: This 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Hypercholesterolemia refers to dyslipidemia with an increased circulating cholesterol levels. This is the most common dyslipidemia and is associated with an increased risk of developing atheromatous cardiovascular diseases. One of the major challenges in primary prevention is to define the threshold for therapeutic intervention that allow to obtain a significant clinical benefit without unnecessarily expose the patient to potential side effects of lipid-lowering treatments. It is also important to recall to screen patient for heterozygous familial hypercholesterolemia, a common genetic disease of lipid metabolism responsible for particularly severe and early coronary disease. In this article, the issues of hypercholesterolemia screening, the definition of therapeutic targets and expected benefits as well as the modalities of therapeutic management (by also addressing the problem of statin intolerance) will be addressed., (Copyright © 2020 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Aims: The DASH diet was designed for helping control of blood pressure but, fortunately, it can also be prescribed for many other chronic conditions. The current study intended to assess the potential effects of DASH diet on metabolic risk factors in patients with chronic disease., Data Synthesis: We carried out a systematic literature search for RCTs from inception until July 2020. A total of 54 clinical trials were included in the final analysis. Compared to control groups, a significant lower effect of the DASH diet was noted for body weight (-1.59 kg; p < 0.001), BMI (-0.64 kg/m 2 ; p < 0.001), and WC (-1.93 cm; p < 0.001) as well as for SBP (-3.94 mmHg; p < 0.001) and DBP (-2.44 mmHg; P < 0.001). The DASH diet significantly decreased TC (-5.12 mg/dl; p = 0.008) and LDL-C levels (-3.53 mg/dl; p = 0.041), but not HDL-C (0.30 mg/dl; p = 0.510), TG (-4.22 mg/dl; p = 0.067), and VLDL-C (-2.16 mg/dl; p = 0.062). No significant effect of the DASH diet was noted for blood glucose (-0.38 mg/dl; p = 0.216), insulin (-0.03 μIU/mL; p = 0.817), HOMA-IR (-0.15; p = 0.132), and CRP (-0.33 mg/l; p = 0.173)., Conclusions: The DASH diet is a feasible approach to weight loss and to control blood pressure and hypercholesterolemia., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

Lipoprotein measurements are pivotal in the management of patients at risk for atherosclerotic coronary heart disease (CHD) with myocardial infarction and coronary death as the main outcomes, and for atherosclerotic cardiovascular disease (ASCVD), which includes CHD and stroke. Recent developments and changes in guidelines affect optimization of using lipid measures as cardiovascular biomarkers. This scientific statement reviews the pre-analytical, analytical, post-analytical, and clinical aspects of lipoprotein measurements. Highlights include the following: i) It is acceptable to screen with nonfasting lipids. ii) non-high-density lipoprotein HDL-cholesterol (non-HDL-C) is measured reliably in either the fasting or the nonfasting state and can effectively guide ASCVD prevention. iii) low density lipoprotein cholesterol (LDL-C) can be estimated from total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglyceride (TG) measurements. For patients with LDL-C>100 mg/dL and TG ≤150 mg/dL it is reasonable to use the Friedewald formula. However, for those with TG 150-400 mg/dL the Friedewald formula for LDL-C estimation is less accurate. The Martin/Hopkins method is recommended for LDL-C estimation throughout the range of LDL-C levels and up to TG levels of 399 mg/dL. For TG levels ≥400 mg/dL LDL-C estimating equations are currently not recommended and newer methods are being evaluated. iv) When LDL-C or TG screening results are abnormal the clinician should consider obtaining fasting lipids. v) Advanced lipoprotein tests using apolipoprotein B (apoB), LDL Particle Number (LDL-P) or remnant cholesterol may help to guide therapeutic decisions in select patients, but data are limited for patients already on lipid lowering therapy with low LDL-C levels. Better harmonization of advanced lipid measurement methods is needed. Lipid measurements are recommended 4-12 weeks after a change in lipid treatment. Lipid laboratory reports should denote desirable values and specifically identify extremely elevated LDL-C levels (≥190 mg/dL at any age or ≥160 mg/dL in children) as severe hypercholesterolemia. Potentially actionable abnormal lipid test results, including fasting triglycerides (TG) ≥500 mg/dL, should be reported as hypertriglyceridemia. Appropriate use and reporting of lipid tests should improve their utility in the management of persons at high risk for ASCVD events., (Copyright © 2021. Published by Elsevier Inc.)

Background: The most cost-effective strategy to diagnose patients with autosomal dominant hypercholesterolemia (ADH) is to perform cascade genetic screening., Objective: To present the cascade genetic screening program for ADH in Norway., Methods: A national cascade genetic screening program for ADH in Norway has been operating at Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital for twenty years. This program has been run by just one genetic counsellor. We now present the main findings of this cascade genetic screening program., Results: After genetic counselling, 8182 at-risk relatives have consented to genetic testing for the mutation that causes ADH in the family. Of these, 3076 (37.6%) relatives have tested positive. Among mutation-positive relatives 31.3% were on lipid-lowering therapy at the time of genetic testing. However, only 9.8% of these relatives had a value for low density lipoprotein (LDL) cholesterol below 2.5 mmol/l (97 mg/dl). At follow-up six months after genetic testing, reductions in the levels of total serum cholesterol and LDL cholesterol of 12% and 17%, respectively were observed. A total of 8811 ADH heterozygotes have been diagnosed in Norway. Thus, the number of patients diagnosed by this modest cascade genetic screening program constitutes 35% of all Norwegian ADH patients provided with a molecular genetic diagnosis., Conclusion: Cascade genetic screening for ADH is very effective and should be organized at a national level. Even a modest cascade genetic screening program with small resources, can result in a large number of patients being identified., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Background: Sitosterolemia is a rare lipid disorder caused by mutations in adenosine triphosphate-binding cassette genes (ABCG) 5 and 8., Objective: To evaluate the phenotypic/genotypic features of sitosterolemia in a group of Turkish patients., Methods: Seven probands with unexplained hematologic abnormalities and their 13 relatives were enrolled. Sterol levels were measured by gas chromatography and genetic studies were performed using Sanger sequencing. Individuals were diagnosed with sitosterolemia if they were found to have frankly elevated sitosterol level >15 μg/mL and/or pathogenic variants of the ABCG5/ABCG8., Results: The seven probands and their six relatives  were diagnosed with frank sitosterolemia, and all these patients had hematologic abnormalities. The remaining seven relatives were asymptomatic heterozygous carriers. Three novel variants in the ABCG5 gene (c.161G>A, c.1375C>T, IVS10-1G>T), one novel variant in the ABCG8 gene (c.1762G>C) and one known variant in the ABCG5 gene (c.1336 C>T) were identified. No variant was identified in one case. The mean sitosterol level was significantly higher and mean platelet count was significantly lower in patients with homozygous variants compared to heterozygous variants (p<0.05, for all). Diets low in plant sterols were recommended for 13 symptomatic cases. Four homozygotes received ezetimibe, and their splenomegaly, anemia, and thrombocytopenia completely resolved except one., Conclusion: The five pathogenic variants identified in this study indicate the genetic heterogeneity of sitosterolemia in Turkish population. Patients with unexplained hematologic abnormalities (specifically macrothrombocytopenia) should have their sterol level measured as initial testing. Ezetimibe can be a good choice for sitosterolemia., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aims: High-density lipoprotein cholesterol (HDL-C) concentration and variability are both important factors of cardiovascular disease (CVD) and mortality. We aimed to explore the associations of HDL-C and longitudinal change in HDL-C with risk of mortality., Methods and Results: We recruited a total of 69,163 participants aged ≥40 years and had medical examination records of HDL-C during 2010-2014 from the Yinzhou District, Ningbo, China. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. We observed a non-linear association of HDL-C with risks of non-accidental and CVD mortality. Compared with the moderate concentration group (1.4-1.6 mmol/L), HDL-C <1 mmol/L was associated with a higher risk of non-accidental mortality (HR: 1.13 (95% CI: 1.01-1.27)) and both HDL-C <1 mmol/L and ≥2 mmol/L were associated with a higher risk of CVD mortality (HRs: 1.23 (95% CI: 1.01-1.50) and 1.37 (95% CI: 1.03-1.82), respectively). Compared with the stable group ([-0.1, +0.1 mmol/L]), a large decrease ([-0.5, -0.3 mmol/L]) and very large decrease (<-0.5 mmol/L) in HDL-C were associated with a higher risk of non-accidental mortality (HRs: 1.40 (95% CI: 1.21-1.63) and 1.78 (95% CI: 1.44-2.20), respectively). Similar results were observed for CVD mortality and cancer mortality., Conclusion: Extremely low or high HDL-C and a large decrease or very large decrease in HDL-C were associated with a higher risk of cause-specific mortality. Monitoring of HDL-C may have utility in identifying individuals at higher risk of mortality., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: To systematically evaluate the evidence regarding the effects of foods on LDL cholesterol levels and to compare the findings with current guidelines., Data Synthesis: From inception through June 2019, we searched PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for guidelines, systematic reviews, and RCTs (for coffee intake only) of at least 13 days duration. Additionally, we searched Trip database for guidelines from 2009 through Oct 2019. Language was restricted to English. The strength of evidence was evaluated using The Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 37 guidelines, 108 systematic reviews, and 20 RCTs were included. With high evidence, foods high in unsaturated and low in saturated and trans fatty acids (e.g. rapeseed/canola oil), with added plant sterols/stanols, and high in soluble fiber (e.g. oats, barley, and psyllium) caused at least moderate (i.e. 0.20-0.40 mmol/L) reductions in LDL cholesterol. Unfiltered coffee caused a moderate to large increase. Soy protein, tomatoes, flaxseeds, and almonds caused small reductions. With moderate evidence, avocados and turmeric caused moderate to large reductions. Pulses, hazelnuts, walnuts, high-fiber/wholegrain foods, and green tea caused small to moderate reductions, whereas sugar caused a small increase. Other identified foods were either neutral or had low or very low evidence regarding their effects., Conclusions: Several foods distinctly modify LDL cholesterol levels. The results may aid future guidelines and dietary advice for hypercholesterolemia., Competing Interests: Declaration of competing interest There are no conflicts to report., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Apoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed., Methods and Results: The study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression. The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05-1.99) and female (OR = 2.22, 95%CI = 1.58-3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression)., Conclusion: A common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male., Competing Interests: Declaration of competing interest None of the authors have competing interests related to this work., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia (FH) is a codominant autosomal disease characterized by a high risk of cardiovascular disease when not in lipid-lowering treatment. However, there is a large variability in the clinical presentation in heterozygous subjects (HeFH). Maternal hypercholesterolemia has been proposed as a cardiometabolic risk factor later in life. Whether this phenotype variability depends on the mother or father origin of hypercholesterolemia is unknown. The objective of this study was to analyze potential differences in anthropometry, superficial lipid deposits, comorbidities, and lipid concentrations depending on the parental origin of hypercholesterolemia within a large group of HeFH., Methods: This is a cross-sectional observational, multicenter, nation-wide study in Spain. We recruited adults with HeFH to study clinical differences according to the parental origin. Data on HeFH patients were obtained from the Dyslipidemia Registry of the Spanish Atherosclerosis Society., Results: HeFH patients were grouped in 1231 HeFH-mother-offspring aged 45.7 (16.3) years and 1174 HeFH-father-offspring aged 44.8 (16.7) years. We did not find any difference in lipid parameters (total cholesterol, triglycerides, LDLc, HDLc, and Lp(a)), nor in the comorbidities studied (cardiovascular disease prevalence, age of onset of cardiovascular disease, obesity, diabetes, and hypertension) between groups. Lipid-lowering treatment did not differ between groups. The prevalence of comorbidities did not show differences when they were studied by age groups., Conclusions: Our research with a large group of subjects with HeFH shows that a potential maternal effect is not relevant in FH. However, due to the size of our sample, potential differences between genders cannot be completely ruled out. This implies that severe maternal hypercholesterolemia during pregnancy is not associated with additional risk in the FH affected offspring., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Many patients with hypercholesterolemia fail to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering despite use of guideline-recommended lipid-lowering therapies. This study evaluated LDL-C lowering with the combination of bempedoic acid, ezetimibe, and atorvastatin., Methods: This was a phase 2, randomized, double-blind, placebo-controlled study (NCT03051100). After washout of lipid-lowering drugs, patients were randomized 2:1 to triple therapy (bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg; n = 43) or placebo (n = 20) once daily for 6 weeks. The primary endpoint was percent change from baseline in LDL-C at week 6., Results: Mean age for the 63 randomized patients was 61.2 years; baseline LDL-C was 154.8 mg/dL. At week 6, mean LDL-C lowering with triple therapy (-63.6%) was significantly greater than with placebo [-3.1%; difference, -60.5% [(95% CI, -68.0% to -53.0%); p < 0.001]. Significant reductions with triple therapy vs. placebo were also observed for non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein (p < 0.001 for all). With triple-therapy, 90% of patients achieved LDL-C <70 mg/dL and 95% of patients had ≥50% lower LDL-C from baseline to week 6; no patients in the placebo group met either goal. The majority of treatment-emergent adverse events were mild to moderate in severity. No patients experienced clinically relevant elevations in aminotransferase or creatine kinase levels., Conclusions: Among patients with hypercholesterolemia, the combination of bempedoic acid, ezetimibe, and atorvastatin significantly lowered LDL-C, allowing more than 90% of patients in this study to reach guideline-recommended LDL-C goals., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia is most frequently caused by genetic variants in the LDLR gene. Most of LDLR pathogenic variants are missense, followed by splicing and deletion/insertions variants. Mosaicism is a genetic condition in which an individual shows more than one clone of cells with different genotypes. The objective of this article was the molecular characterization of a patient with hypercholesterolemia., Methods and Results: Genetic analysis of DNA from peripheral blood and saliva was performed by NGS, Sanger sequencing and pyrosequencing technologies. NGS analysis detected the pathogenic variant LDLR:c.1951G > T:p.(Asp651Tyr) in 9%-12% of reads. The presence of the variant was confirmed by pyrosequencing analysis. The variant found was functional characterized using an in vitro model (CHO-ldlA7 cells). Activity and expression of cell surface LDLR were measured by flow cytometry. Colocalization LDLR-Dil-LDL was detected by immunofluorescence. The LDLR activity showed 80% uptake, 50% binding and 53% expression of cell surface LDLR regarding wild type., Conclusions: Herein, we report the first case of a mosaic single nucleotide variant affecting the LDLR gene in a patient with familial hypercholesterolemia. As it has been described for other pathologies, mosaicism could be underestimated in FH and its detection will improve with the introduction of NGS technologies in the diagnostic routine., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: The increased risk of cardiovascular disease under hypercholesterolemia is due to associations between oxidized low-density lipoprotein (ox-LDL) and lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) and between ox-LDL and coagulant profiles. We investigated the impact of different ox-LDL levels on coagulation time and plasma metabolomes in subjects with borderline hypercholesterolemia., Methods and Results: One hundred thirty-one subjects with borderline hypercholesterolemia (serum cholesterol ≥200 mg/dL) were divided into low ox-LDL (n = 66) and high ox-LDL (n = 65) groups. After adjusting for confounding factors, the high ox-LDL group exhibited a significantly decreased activated partial thromboplastin time (aPTT) and prothrombin time (PT) and increased Lp-PLA 2 activity. Compared to the low ox-LDL group, the high ox-LDL group exhibited significantly increased intensities of 17 lysophosphatidylcholines (lysoPCs) and 7 lysophosphatidylethanolamines (lysoPEs). Ox-LDL was inversely correlated with aPTT and PT and positively correlated with Lp-PLA 2 activity. Positive correlations were also found among ox-LDL, Lp-PLA 2 activity, lysoPCs, and lysoPEs. LysoPCs and lysoPEs were inversely correlated with PT and aPTT. The identified plasma metabolites, including amino acids, fatty acid amides, acylcarnitines, and lysophospholipids, were significantly upregulated in the high ox-LDL group., Conclusion: High ox-LDL levels may be involved in the development of a procoagulant state in subjects with borderline hypercholesterolemia by increasing Lp-PLA 2 activity and lysoPC and lysoPE levels., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aim: General population awareness about cardiovascular risk factors is usually low. The aim of the present study was to evaluate the vascular aging of subjects aware and not aware to be hypertensive, hypercholesterolemic, hypertriglyceridemic or diabetics in a general population sample., Methods and Results: We interviewed 1652 subjects without atherosclerotic cardiovascular diseases (M: 46.6%, F: 53.4%) about their awareness of hypertension, hypercholesterolemia, hypertriglyceridemia or type 2 diabetes. Then we compared the augmentation index and pulse wave velocity of subjects aware and not aware of the investigated cardiovascular risk factors. 1049 participants declared not to be hypertensive, while 32 were not sure. Among them, respectively, 23.5% and 50% were hypertensive. Subjects not aware of their hypertension had significantly higher aortic blood pressure than aware ones (p < 0.001). 841 participants declared not to be hypercholesterolemic, while 60 were not sure. Among them, respectively, 18.1% and 40% were hypercholesterolemic. Subjects not aware of their hypercholesterolemia had significantly higher augmentation index than the aware ones (p < 0.05). 1226 participants declared not to be hypertriglyceridemic, while 200 were not sure. Among them, respectively, 19.2% and 44% were hypertriglyceridemic. Subjects not aware of their hypertriglyceridemia had significantly higher TG levels aware ones (p < 0.05), although this seemed to not related to increased arterial stiffness. 1472 participants declared not to be diabetic, while 20 were not sure. Among them, respectively, 2.0% and 25.0% were diabetics. Subjects not aware of their diabetes had significantly higher augmentation index than the aware ones (p < 0.05)., Conclusions: In conclusion, the lack of awareness of hypertension and hypercholesterolemia is relatively frequent in the general population and is associated to significantly higher arterial stiffness., Competing Interests: Declaration of competing interest Authors have no direct nor indirect conflict of interest to declare., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: In the association between hypercholesterolemia (HC) and thrombotic risk platelet hyper-reactivity plays an important role. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) to reduce plasma LDL-cholesterol merges as effective therapeutic strategy to prevent cardiovascular (CV) events. Aim of this study was to verify whether a treatment up to 12 months with the monoclonal antibodies (mAbs) anti-PCSK9 influences platelet function in primary HC., Methods and Results: In patients affected by primary HC (n = 24), all on background of statin and 17 on acetyl salicylic acid (ASA), platelet function parameters were evaluated at baseline up to 12 months of treatment with the mAb anti-PCSK9 alirocumab or evolocumab. From baseline, the treatment with anti-PCSK9 mAbs: i) in ASA HC patients, significantly decreased platelet aggregation detected in platelet-rich plasma by light transmission aggregometry and in whole blood Platelet Function Analyzer-100 assay; ii) in all HC patients, significantly decreased platelet membrane expression of CD62P and plasma levels of the in vivo platelet activation markers soluble CD40 Ligand, Platelet Factor-4, and soluble P-Selectin. Furthermore, CD62P expression, and sP-Selectin, PF-4, sCD40L levels significantly correlated with serum PCSK9., Conclusion: Besides markedly lowering LDL-c levels, our results suggest that HC patients benefit from anti-PCSK9 mAb treatment also for reducing platelet reactivity and increasing platelet sensitivity to the inhibitory effects of aspirin. These effects on platelets could play a role in the reduction of CV event incidence in patients treated with PCSK9 inhibitors., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Potential beneficial effect of probiotic yogurt on the lipid profile has raised much interest. However, the results are inconsistent in this regard. The aim of the study is to determine the effects of probiotic yogurt on serum lipid profile in individuals with mild to moderate hypercholesterolemia., Methods and Results: Online databases including PubMed, Scopus, ISI Web of Science, Cochrane Central Register of Controlled Trials, Science Direct, Google Scholar and Igaku Chuo Zasshi were searched until March 19th 2019. The effect sizes were expressed as the weighted mean difference (WMD) with 95% confidence interval (CI). Seven eligible trials with 274 participants were included in this systematic review. Pooling of 9 effect sizes from these seven articles revealed a significant reduction in total cholesterol and low density lipoprotein cholesterol levels following probiotic yogurt consumption (mean difference: -8.73 mg/dl, 95% CI: -15.98, -1.48, p-value = 0.018 and mean difference: -10.611 mg/dl, 95% CI: -16.529, -4.693, p-value = 0.000, respectively) without significant heterogeneity among the studies (I 2  = 40.6%, p-value = 0.1 and I 2  = 24.2%, p-value = 0.229, respectively). The results showed no significant changes in high density lipoprotein cholesterol and triglyceride levels. Also, none of the variables showed a significant change for sensitivity analysis., Conclusion: Available evidence suggests that probiotic yogurt can significantly reduce total cholesterol and LDL-c in subjects with mild to moderate hypercholesterolemia without a significant effect on HDL-c and triglyceride levels., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: Older stroke survivors are at risk of long-term cognitive impairment, which is associated with a number of modifiable and non-modifiable factors. We aimed to assess the association between the modifiable risk factors, serum cholesterol, low density lipoprotein, high density lipoprotein, serum triglycerides, body mass index (BMI) and smoking status on cognitive function, while controlling for the non-modifiable factors, acute functional impairment, diabetes status and age., Methods: A cross-sectional study from a metropolitan university hospital in Sweden involving older adults (n = 149). Assessments occurred at 20 months post-stroke, using the Mini Mental State Examination and serum blood levels of cholesterol, low density lipoprotein, high density lipoprotein and serum triglycerides., Results: Hierarchical linear regression showed that only acute functional impairment significantly contributed to long-term cognitive impairment in stroke survivors. Only 12% of the sample showed healthy cholesterol levels while the remaining patients showed borderline or high cholesterol levels. In terms of BMI, only 2% of the sample were underweight, 38% were within healthy range and 26% were overweight/obese. Only eight women and four men were smokers, therefore our sample of smokers was likely too small to detect any differences between smokers and non-smokers in regard to cognitive outcomes., Conclusion: Serum cholesterol, low density lipoprotein, high density lipoprotein, serum triglycerides, BMI or smoking status did not influence cognitive outcomes in older stroke surviving individuals. These findings suggest that modification of these factors may not influence cognitive outcomes in stroke-surviving individuals however should be interpreted as preliminary given limitations in the current study., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Autosomal recessive hypercholesterolemia (ARH; OMIM #603813) is a very rare monogenic disorder affecting less than 1 in 1000,000 people and is characterized by very high levels of low-density lipoprotein cholesterol (LDL-C), leading to aggressive and premature atherosclerotic cardiovascular disease if left untreated. Lowering of LDL-C is the main target of the treatment. We report on a 29-year-old male patient born in nonconsanguineous Lithuanian family homo(hemi-)zygous for LDLRAP1 gene variant causing ARH. This variant is not present in population databases and, to our knowledge, has not been reported in scientific literature before., Methods and Results: The earliest clinical sign, noticed at the age of 5 years, was painful and enlarging nodules on Achilles tendons. At the age of 10 years, xanthomas of the metacarpal joint area on both hands emerged. The first lipid panel was performed at the age of 12 years. In accordance with Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolemia (FH), definite FH (type IIA hyperlipoproteinemia) was diagnosed and the treatment with cholestyramine 4 grams per day was initiated. As the patient was 15 years old, direct adsorption of low-density lipoprotein apheresis was started and repeated monthly. At the age of 20 years, along with lipoprotein apheresis, 10 mg of rosuvastatin daily intake was prescribed. At the age of 28 years, the dose of rosuvastatin was increased to 40 mg per day, and 10 mg of ezetimibe daily intake was added. At the age of 28 years, homozygous LDLRAP1 gene variant NM&#95;015627.2:c.488A>C, NP&#95;056442.2:p.(Gln163Pro) causing autosomal recessive hypercholesterolemia was determined by genetic testing., Conclusions: This case report implies that ARH, being an extremely rare disorder, is a severe disease. As there is limited routine testing, including genetic testing, patients suffering from both this disease and FH may remain undiagnosed. Cascade screening and genetic counseling differ for ARH as compared with FH, as the carrier of a pathogenic variant in the LDLRAP1 gene does not have marked total cholesterol and LDL-C elevations. However, genetic testing of the proband and their relatives is essential to evaluate the risk of development of FH and to provide prognosis as well as adequate, timely treatment. To improve the quality of life of patients with FH and prolong their life expectancy, national registries of FH and wider laboratory and genetic testing are undoubtedly necessary. A national FH screening program was set up in Lithuania, which helps to identify, monitor, and treat subjects with FH., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Cholesterol treatment for the primary prevention of cardiovascular disease is based on cardiovascular risk, as assessed by the SCORE (Systematic COronary Risk Evaluation) scale. This study aimed to assess the predictive value and clinical utility of the SCORE scale for preventing cardiovascular events and all-cause mortality in people with dyslipidemia and no lipid-lowering treatment., Methods: Patients with dyslipidemia and no lipid-lowering treatment were included from the ESCARVAL-RISK cohort. Cardiovascular risk was calculated by means of the SCORE scale. All deaths and cardiovascular events were recorded for up to five years of follow-up. We calculated sensitivity, specificity and other predictive values for different cut-off points and assessed the effect of different risk factors on the diagnostic accuracy of the SCORE charts., Results: In the final cohort of 18,853 patients, there were 1565 cardiovascular events and 268 deaths. The risk value recommended to initiate pharmacological treatment (5%) presented a specificity of 86% for death and 90% for cardiovascular events, and a sensitivity of 53% for death and 32% for cardiovascular events. In addition, the scale classified as low risk 62.8% of the patients who suffered a cardiovascular event and 46.6% of those who died. Antithrombotic treatment, diabetes, hypertension, heart failure, peripheral artery disease and chronic kidney disease were associated with a reduction in the predictive capability of the SCORE scale, whereas metabolic syndrome was related to better risk prediction., Conclusions: The predictive capability of the SCORE scale for cardiovascular disease and total mortality in patients with dyslipidemia is limited., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: Extremely high level high-density lipoprotein (HDL) cholesterol had been cautioned as risk factor for all-cause mortality and cardiovascular disease. However, both the physician and the patient may underestimate the risk due to the emphasis on "good cholesterol", resulting in passive treatment or adoption of a less healthy lifestyle. The aim of this study is to re-evaluate the association with longitudinal data to account for fluctuations in HDL cholesterol and covariates., Methods: We conducted a retrospective longitudinal study at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all adults who participated in health check-ups. Outcomes were all-cause mortality and cardiovascular events. HDL cholesterol was repeatedly measured at each visit and categorized into five groups. The time-varying Cox model was applied to longitudinal analyses., Results: We included a total of 83,100 participants; the mean age was 45.5 (standard deviation:12.4) years; 41,013 (49.4%) were male, and 4475 participants belonged to the extremely high level HDL cholesterol group (>90 mg/dl). During a median follow-up of 1746 (interquartile range:740-3112.5) days, 382 (0.5%) participants died, and 2023 (2.4%) experienced cardiovascular events. Although the extremely high level HDL cholesterol group had significantly lower hazard ratios (HRs) for all-cause mortality (HR:0.49, 95%confidence interval(CI):0.26-0.90) and cardiovascular events (HR:0.71, 95%CI:0.54-0.94) compared to the low group (<40 mg/dl), HRs were higher than in the very high level HDL cholesterol group., Conclusions: Our study demonstrated that extremely high level HDL cholesterol has significantly lower risks of all-cause mortality and cardiovascular events compared to low level, but higher risks compared to very high level, as previously reported., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: This study evaluated whether lipoprotein apheresis produces immediate changes in resting perfusion in subjects with severe hypercholesterolemia, and whether there is a difference in the response between peripheral and coronary microcirculations., Background: Lipoprotein apheresis is used in patients with severe hypercholesterolemia to reduce plasma levels of low-density lipoprotein cholesterol., Methods: Quantitative contrast-enhanced ultrasound perfusion imaging of the myocardium at rest and skeletal muscle at rest and during calibrated contractile exercise was performed before and immediately after lipoprotein apheresis in 8 subjects with severe hypercholesterolemia, 7 of whom had a diagnosis of familial hypercholesterolemia. Myocardial perfusion imaging was also performed in 14 normal control subjects. Changes in myocardial work and left ventricular function were assessed by echocardiography. Ex vivo ovine coronary and femoral artery ring tension assays were assessed in the presence of pre- and post-apheresis plasma., Results: Apheresis acutely decreased low-density lipoprotein cholesterol (234.9 ± 103.2 mg/dl vs. 67.1 ± 49.5 mg/dl; p < 0.01) and oxidized phospholipid on apolipoprotein B-100 (60.2 ± 55.2 nmol/l vs. 47.0 ± 24.5 nmol/l; p = 0.01), and acutely increased resting myocardial perfusion (55.1 [95% confidence interval: 77.2 to 73.1] IU/s vs. 135 [95% confidence interval: 81.2 to 189.6] IU/s; p = 0.01), without changes in myocardial work. Myocardial longitudinal strain improved in those subjects with reduced pre-apheresis function. Skeletal muscle perfusion at rest and during contractile exercise was unchanged by apheresis. Acetylcholine-mediated dilation of ex vivo ovine coronary but not femoral arteries was impaired in pre-apheresis plasma and was completely reversed in post-apheresis plasma., Conclusions: Lipoprotein apheresis produces an immediate improvement in coronary microvascular function, which increases myocardial perfusion and normalizes endothelial-dependent vasodilation. These changes are not observed in the periphery. (Acute Microvascular Changes With LDL Apheresis; NCT02388633)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We investigated the association between statin use and site-specific risk of colorectal cancer in individuals with hypercholesterolemia., Methods and Results: This study is based on the National Health Insurance Service-National Health Screening Cohort, conducted during 2002-2015. Statin users were classified as high and low users according to medication possession ratio (MPR). Statin nonusers comprised participants who did not use statins during the entire follow-up period. In total, 17,737 statin users and 13,412 statin nonusers were included in the analysis, with a median follow-up period of 12.7 years. Cox proportional hazards regression models were adopted after stepwise adjustment for confounders to investigate prospective association between statin usage and colorectal cancer risk. In total, 378 (2.3%) of 16,588 male participants and 239 (1.6%) of 14,561 female participants had colorectal cancer during the follow-up period. Compared to nonusers, fully adjusted hazard ratios (HRs) (95% confidence intervals [95% CIs]) for colorectal cancer risk in high statin users were 0.56 (0.42-0.75) in men and 0.64 (0.46-0.90) in women. In men, the fully adjusted HRs for proximal and rectal cancer for high users were 0.29 (0.15-0.56) and 0.52 (0.35-0.78), respectively, compared to those for nonusers. In women, statistical significance was seen only in rectal cancer (HR 0.43 [0.25-0.72]) but not in proximal or distal colon cancer., Conclusions: High statin users with hypercholesterolemia were associated with lower risk of overall colorectal cancer, especially proximal colon cancer in men and rectal cancer in both sexes., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Women minorities have an overall increased lifetime incidence of cerebrovascular disease. The provision of risk factor modification in this group can prove difficult. In a population-based study, we used cluster enrollment to identify vascular risk factors in the female caregivers of stroke survivor study participants., Methods: Obese women caregivers were identified as part of Swipe out Stroke, a Phase I PROBE study assessing the use of SmartPhone based intervention for dietary modification in minority stroke survivors. After written informed consent was obtained, both patients and caregivers were screened for vascular risk factors at study enrollment. Descriptive statistics were used to depict the study population. Continuous baseline variables were compared using 2 sample t-test or Wilcoxon rank-sum test by caregivers and patients. Categorical baseline variables were compared using Fisher's exact test., Results: Thirty-six stroke patients (63.9% African-American, 36.1% Hispanic) and thirteen female caregivers (69.2% African-American, 30.8% Hispanic) were enrolled. Mean age, patients - 54.1 (SD 9.4), caregivers - 51.3 (SD 15.6) years, education, employment status and family history of stroke or obesity did not differ significantly. Compared to stroke patients, female caregivers were significantly less likely to self-report hypertension (69.2 versus 97.2%; P = 0.01) and hyperlipidemia (16.7 versus 60%; P = 0.02). Female caregivers were more likely to have elevated systolic blood pressure (147.6 vs 127.7 mmHg; P = 0.05), total cholesterol (207.5 versus 167 mg/dL; P = 0.01) and low density lipoprotein values (119.5 versus 88 mg/dL; P = 0.03) compared to stroke patients., Conclusions: Using cluster enrollment, we discovered minority female caregivers were more likely to have unknown or poorly controlled vascular risk factors compared to stroke patients. Innovative health screening tools may benefit the extended family of minority patients participating in clinical trials., (Copyright © 2018 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Routine and selective cholesterol screening of children is an effective tool to help identify those with familial hypercholesterolemia. In children found to have elevated levels of cholesterol, secondary causes should be excluded, including hypothyroidism. Thyroid hormone has multiple effects on the regulation of lipid synthesis, absorption, and metabolism. In this case report, we described a 2-year-old with a history of congenital hypothyroidism who was found to have severe hypercholesterolemia. A detailed medical history and appropriate screening tests are important in determining the underlying cause of elevated low-density lipoprotein cholesterol to help inform clinical decision-making., (Published by Elsevier Inc.)

Background: There are no data on the prevalence of non-alcoholic fatty liver disease (NAFLD) in general population samples in Guatemala or in other Central American countries. The prevalence and distribution of NAFLD and its associated risk factors were evaluated in a population-based sample of adults in Guatemala., Methods: Cross-sectional study of 411 men and women 40 years of age or older residing in urban and rural areas of Guatemala. Metabolic outcomes included obesity, central obesity, hypercholesterolemia, diabetes, and metabolic syndrome (MetS). Liver disease outcomes included elevated liver enzymes, elevated Fatty Liver Index (FLI), and elevated FIB-4 score., Results: The overall prevalence of obesity, central obesity, diabetes, and MetS were 30.9, 74.3, 21.6, and 64.2%, respectively. The fully-adjusted prevalence ratios (95% CI) for obesity, central obesity, diabetes, and MetS comparing women to men were 2.83 (1.86-4.30), 1.72 (1.46-2.02), 1.18 (1.03-1.34), and 1.87 (1.53-2.29), respectively. The overall prevalence of elevated liver enzymes (ALT or AST), elevated FLI, and elevated FIB-4 scores were 38.4, 60.1, and 4.1%, respectively. The fully-adjusted prevalence ratios (95% CI) for elevated liver enzymes (either ALT or AST) and elevated FLI score comparing women to men were 2.99 (1.84-4.86) and 1.47 (1.18-1.84), respectively., Conclusions: The prevalence of metabolic abnormalities and liver outcomes in this general population study was very high. The prevalence of metabolic and liver abnormalities was particularly high among women, an observation that could explain the atypical 1:1 male to female ratio of liver cancer in Guatemala., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

Background and Aims: We aimed to test the hypothesis that levels of total and low-density lipoprotein cholesterol are increased after Christmas and that the risk of hypercholesterolemia is increased after the Christmas holidays., Methods: We conducted an observational study of 25,764 individuals from the Copenhagen General Population Study, Denmark, aged 20-100 years. Main outcome measures were mean total and LDL cholesterol levels. Hypercholesterolemia was defined as total cholesterol >5 mmol/L (>193 mg/dL) or LDL-cholesterol >3 mmol/L (>116 mg/dL)., Results: Mean levels of total and LDL cholesterol increased in individuals examined in summer through December and January. Compared with individuals examined in May-June, those examined in December-January had 15% higher total cholesterol levels (p < 0.001). The corresponding value for LDL cholesterol was 20% (p < 0.001). Of the individuals attending the study during the first week of January, immediately after the Christmas holidays, 77% had LDL cholesterol above 3 mmol/L (116 mg/dL) and 89% had total cholesterol above 5 mmol/L (193 mg/dL). In individuals attending the Copenhagen General Population Study in the first week of January, the multivariable adjusted odds ratio of hypercholesterolemia was 6.0 (95% confidence interval 4.2-8.5) compared with individuals attending the study during the rest of the year., Conclusions: Celebrating Christmas is associated with higher levels of total and LDL cholesterol and a higher risk of hypercholesterolemia in individuals in the general population. Thus, a diagnosis of hypercholesterolemia should not be made around Christmas, and our results stress the need for re-testing such patients later and certainly prior to initiation of cholesterol-lowering treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)