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Hyperlipidemia has been frequently recorded as a side effect of treating HIV patients with protease inhibitors (PI). This study was initiated to analyze the modifications on blood lipids in HIV-patients receiving PI and the safety and efficacy of the treatment with fenofibrate. Total (TC) and HDL-cholesterol, triglycerides (TG), and CD4+ T-cell counts were measured in 30 HAART-naive patients (Group I) before and after PI introduction. In a second phase of the study, the effects of fenofibrate on lipids, CPK, CD4+, and viral load were determined in 13 patients (Group II) with elevated TC or TG. In Group I, 60% of the patients showed TC or TG elevations. Average increments of 31% and 146% in TC and TG respectively (p

Background: The International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and implementation recommendations. We reference examples of strategies from the literature to explore how these implementation recommendations can be tailored into implementation strategies at the local-level for stakeholders guided by a framework proposed by Sarkies and Jones., Methods: Four authors of the IAS guidance selected two published exemplar implementation recommendations for detection, management, and general implementation. Each recommendation was described as an implementation strategy using Proctor's guidance for specifying and reporting implementation strategies. It recommends reporting the actor (who), action (what), action-target (who is impacted), temporality (how often), and dose (how much) for each implementation strategy., Results: Detection: A centralized cascade testing model, mobilized nurses (actor) to relative's homes, after the diagnosis of the proband (temporality), once (dose) to consent, obtain a blood sample and health information (action) on relatives (action-target)., Management: A primary care initiative to improve FH management included an educational session (action) with clinicians (action-target), computer-based reminder message and message to patients to have their cholesterol screened once (dose) at a visit or outreach (temporality) by researchers (actor). General: A partnership between a statewide public pathology provider, local public hospital network, primary health network, government health ministry, and an academic university (actors) was established to implement a primary-tertiary shared care model (action) to improve the detection of FH (action-target)., Conclusions: We demonstrate that implementation recommendations can be specified and reported for different local contexts with examples on monitoring, evaluation, and sustainability in practice., Competing Interests: Declaration of competing interest LKJ: research grants from Amarin and reports consulting fees from Novartis. SSG: reports consulting fees from Esperion. PL: Dr. Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr. Libby's laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk and Genentech. Dr. Libby is on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. RDS: received honoraria related to consulting, research and/or speaker activities from: Abbott, Ache, Amgen, Esperion, Kowa, Libbs, Eli-Lilly, Novartis, Novo-Nordisk, PTC Therapeutics, and Sanofi/Regeneron, outside the submitted work. GFW: research grants and honoraria for lectures and advisory boards from Amgen, Arrowhead, Esperion, Silence Therapeutics, Novartis, and NovoNordisk. MNS: No competing interest declared., (Copyright © 2024. Published by Elsevier Inc.)

Background: Statins are the main strategy to reduce dyslipidemia-related cardiovascular risk. Nevertheless, there is scarce evidence on the real-world statins use in primary care settings in low-middle-income countries., Objective: We conducted a cross-sectional retrospective study using anonymized data routinely collected by community health workers in Brazil aimed to evaluate statin use and associated factors in a primary prevention population with cardiovascular risk enhancers., Methods: Study population consisted of adults with hypertension, diabetes, and/or dyslipidemia. The primary and secondary outcomes were the proportion of individuals self-reporting statins use on any dose and high-dose statins/high-intensity lipid-lowering therapy (LLT), respectively., Results: Of the 2,133,900 adult individuals in the database, 415,766 (19.5%) were included in the study cohort. From this cohort, 89.1% had hypertension, 28.9% diabetes, and 5.5% dyslipidemia. The mean age was 61.5 (standard deviation 14.5) years, 63.4% were female, and 61.0% were of mixed-race. Only 2.6% and 0.1% of individuals self-reported the use of statins and high-dose statins/high-intensity LLT, respectively. Older age (odds ratio [OR] 1.96; 95% confidence interval [CI] 1.88, 2.05, p < 0.001), living in the South region of Brazil (OR 4.39; 95% CI 3.97, 4.85, p < 0.001), heart failure (OR 2.60; 95% CI 2.33, 2.89, p < 0.001), chronic kidney disease (OR 1.49; 95% CI 1.35, 1.64, p < 0.001), and anti-hypertensive medications use (OR 4.38; 95% CI 4.07, 4.71, p < 0.001) were independently associated with statin use., Conclusion: In a real-world evidence study analyzing data routinely collected in a digitized primary care setting, we observed a very low use of statins in a primary prevention population with cardiovascular risk enhancers in Brazil. Socio-demographic factors and co-morbidities were associated with higher statins use rates., (Copyright © 2024. Published by Elsevier Inc.)

Background and Aims: Metabolically healthy (MHO) and unhealthy obesity (MUO) may be transient conditions. This study aimed to quantify and identify predictive factors of metabolic transitions in obesity, exploring influences of age and sex., Methods and Results: We retrospectively evaluated adults with obesity who underwent routine health evaluation. In a cross-sectional analysis of 12,118 individuals (80% male, age 44.3 ± 9.9 years), 16.8% had MHO. In a longitudinal evaluation of 4483 participants, 45.2% of individuals with MHO at baseline had dysmetabolism after a median follow-up of 3.0 (IQR 1.8-5.2) years, whereas 13.3% MUO participants became metabolically healthy (MH). Development of hepatic steatosis (HS, ultrasound) was an independent predictor of MHO conversion to dysmetabolism (OR 2.36; 95% CI 1.43, 3.91; p < 0.001), while HS persistence was inversely associated with transition from MUO to MH status (OR 0.63; 95% CI 0.47, 0.83; p = 0.001). Female sex and older age were associated with a lower chance of MUO regression. A 5% increment in body mass index (BMI) over time increased the likelihood of metabolic deterioration by 33% (p = 0.002) in females and 16% (p = 0.018) in males with MHO. A 5% reduction in BMI was associated with a 39% and 66% higher chance of MUO resolution in females and males, respectively (both p < 0.001)., Conclusion: The findings support a pathophysiological role of ectopic fat depots in metabolic transitions in obesity and identify female sex as an aggravating factor for adiposity-induced dysmetabolism, which has implications for personalized medicine., (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: Experimental studies have linked triglyceride-rich lipoproteins (TRLs) to inflammation, but the extent of this phenomenon in vivo has not been completely elucidated., Objective: We investigated the association between TRL subparticles and inflammatory markers (circulating leukocytes, plasma high-sensitivity C-reactive protein [hs-CRP], and GlycA) in the general population., Methods: This was a cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). TRLs (number of particles per unit volume) and GlycA were measured by nuclear magnetic resonance spectroscopy. The association between TRLs and inflammatory markers was determined by multiple linear regression models adjusted for demographic data, metabolic conditions, and lifestyle factors. Standardized regression coefficients (beta) with 95% confidence intervals are reported., Results: The study population comprised 4,001 individuals (54% females, age 50 ± 9 years). TRLs, especially medium and large subparticles, were associated with GlycA (beta 0.202 [0.168, 0.235], p<0.001 for total TRLs). There was no association between TRLs and hs-CRP (beta 0.022 [-0.011, 0.056], p = 0.190). Medium, large, and very large TRLs were associated with leukocytes, with stronger connections with neutrophils and lymphocytes than monocytes. When TRL subclasses were analyzed as the proportion of the total pool of TRL particles, medium and large TRLs were positively related to leukocytes and GlycA, whereas smaller particles were inversely associated., Conclusions: There are different patterns of association between TRL subparticles and inflammatory markers. The findings support the hypothesis that TRLs (especially medium and larger subparticles) may induce a low-grade inflammatory environment that involves leukocyte activation and is captured by GlycA, but not hs-CRP., (Copyright © 2023. Published by Elsevier Inc.)

Background and Aims: Familial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT., Methods: Hypercholesterolemic individuals ≥60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 × 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75)., Results: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497-6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants., Conclusions: In old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not., Competing Interests: Declaration of competing interest ERC has received honoraria related to speaker activities from Amgen, Ache and Novartis; MHM has received honoraria related to speaker activities from Amgen; VZR has received honoraria related to speaker activities from: Ache, Amgen, Novo-Nordisk and Sanofi; MSB has received honoraria from Boston Scientific and Novo-Nordisk; RDS has received honoraria related to consulting, research and/or speaker activities from: Abbott, Ache, Amgen, Amryt, Astra Zeneca, Biolab, Esperion, Getz Pharma, Kowa, Libbs, Novo-Nordisk, Novartis, Merck, Pfizer, PTC Therapeutics and Sanofi; all other authors have none to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as "Cardiometabolic Disease" (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus. One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD. The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None reports was provided by none. None reports a relationship with none that includes: None has patent pending to none. None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients., Objective: To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH., Methods: Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test., Results: At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (-0.2, 0.4), -0.1 (-0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (-0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group., Conclusion: In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition., Funding: This study was funded and designed by Amgen., Competing Interests: Declaration of Competing Interest Dr D Gaudet reports receiving consulting fees from HDL Therapeutics, Regeneron Pharmaceuticals, and Sanofi; and grant support from Esperion, Gemphire Therapeutics, HDL Therapeutics, Pfizer, Regeneron Pharmaceuticals, Sanofi, and The Medicines Company. Dr Ruzza reports employment with and holding stock in Amgen; and holding pending patent 63/032451 on PCSK9 inhibitors and methods of use thereof to treat cholesterol-related disorders. Mr Bridges reports employment with and holding stock in Amgen. Dr Maruff and Dr Schembri are employees of Cogstate Ltd., the company that provided the cognitive tests in this study. Dr Hamer reports employment with Cardiol Therapeutics Inc. and holding stock in Amgen. Dr Bergeron reports receiving lecture fees from Amgen and HLS Therapeutics Inc.; grant support from Akcea Therapeutics–Ionis Pharmaceuticals, Amgen, Kowa, Novartis, Regeneron Pharmaceuticals, Sanofi, and The Medicines Company; and serving on the advisory boards for Amgen and Novartis. Dr St Pierre–Takeda, Novo Nordisk, and Bausch Health. Dr Kastelein reports consulting fees from AstraZeneca, CiVi Biopharma, CSL Behring, Draupnir Bio, Esperion, Gemphire Therapeutics, Madrigal Pharmaceuticals, Matinas BioPharma, NorthSea Therapeutics, Novo Nordisk, Novartis, Regeneron Pharmaceuticals, REGENXBIO, Staten Biotechnology, 89bio, OMEICOS Therapeutics, Serometrix. Dr Hovingh reports the following: employment with Novo Nordisk; consulting and speakers bureau fees from Aegerion Pharmaceuticals, Amgen, Regeneron Pharmaceuticals, and Sanofi; grant support from Aegerion Pharmaceuticals, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis Pharmaceuticals, Kowa, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi, The Medicines Company; and serving on advisory boards for Aegerion Pharmaceuticals, Amgen, Regeneron Pharmaceuticals, Sanofi. Dr Wiegman reports research support for pharmaceutical trials of lipid-lowering agents from Amgen, Regeneron and Novartis. Dr Raal has received research grants, honoraria, or consulting fees for professional input and/or lectures from Sanofi, Regeneron, Amgen, and Novartis. Dr Santos reports receiving the following: consulting fees and lecture fees from Abbott, Amgen, AstraZeneca, Aché, EMS, Getz Pharma, Libbs, Merck, Merck Sharp & Dohme, PTC Therapeutics, Novo Nordisk, Novartis, Sanofi-Regeneron Pharmaceuticals; grant support from Amgen, Kowa, Esperion, Novartis, Sanofi-Regeneron Pharmaceuticals. The remaining authors have nothing to disclose., (Copyright © 2022 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: LDL appears to drive atherogenesis in overt hypothyroidism, but in subclinical dysfunction, its role is not completely elucidated., Objective: The aim of this study was to evaluate subfractions of LDL in subclinical (SC) thyroid disorders., Methods: Individuals were divided into three groups by baseline thyroid function (SC hypothyroidism, euthyroidism, and SC hyperthyroidism). LDL particle (LDL-P) subfractions were analyzed by Nuclear Magnetic Resonance (NMR) spectroscopy. The association between LDL-P subfractions and thyroid groups and quintiles was evaluated by linear regression models., Results: We evaluated 3304 participants (54.1% women, 51.2% white, mean age 50.6 ± 8.7 years). In the univariate analysis, small LDL particle concentrations (SLDL-P) were not different between SC hypo- and hyperthyroidism compared to euthyroid individuals (p = 0.485 and p = 0.314, respectively). Large LDL-P (LDL-P) levels also did not differ in SC hyperthyroidism and SC hypothyroidism compared to euthyroidism (p = 0.698 and 0.788 respectively). Intermediate LDL-P levels were not different across the groups. These numbers did not materially change in multivariate analysis. However, we also analyzed LDL subfractions according to quintiles of TSH. We showed that in the higher TSH quintile LDL subfractions presented a significantly smaller mean size of LDL subfractions compared to the first quintile., Conclusions: SC thyroid disorders are not associated with significant changes in LDL-P subfractions measured by NMR spectroscopy. However, it seems that the LDL mean size decreases as TSH levels increase, which may represent a more atherogenic lipid profile., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: This analysis describes the protocol of a study with a case-cohort to design to prospectively evaluate the incidence of subclinical atherosclerosis and Cardiovascular Disease (CVD) in Chronic Inflammatory Disease (CID) participants compared to non-diseased ones., Methods: A high-risk group for CID was defined based on data collected in all visits on self-reported medical diagnosis, use of medicines, and levels of high-sensitivity C-Reactive Protein >10 mg/L. The comparison group is the Aleatory Cohort Sample (ACS): a group with 10% of participants selected at baseline who represent the entire cohort. In both groups, specific biomarkers for DIC, markers of subclinical atherosclerosis, and CVD morbimortality will be tested using weighted Cox., Results: The high-risk group (n = 2,949; aged 53.6 ± 9.2; 65.5% women) and the ACS (n=1543; 52.2±8.8; 54.1% women) were identified. Beyond being older and mostly women, participants in the high-risk group present low average income (29.1% vs. 24.8%, p < 0.0001), higher BMI (Kg/m 2 ) (28.1 vs. 26.9, p < 0.0001), higher waist circumference (cm) (93.3 vs. 91, p < 0.0001), higher frequencies of hypertension (40.2% vs. 34.5%, p < 0.0001), diabetes (20.7% vs. 17%, p = 0.003) depression (5.8% vs. 3.9%, p = 0.007) and higher levels of GlycA a new inflammatory marker (p < 0.0001) compared to the ACS., Conclusions: The high-risk group selected mostly women, older, lower-income/education, higher BMI, waist circumference, and of hypertension, diabetes, depression, and higher levels of GlycA when compared to the ACS. The strategy chosen to define the high-risk group seems adequate given that multiple sociodemographic and clinical characteristics are compatible with CID., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by the presence of high levels of total and low-density lipoprotein cholesterol (LDL-C). Statin treatment is recommended for all adults with FH., Objective: Here we have studied the main predictors of the use of lipid-lowering agents at one-year follow-up in a large cohort of FH patients., Methods: Open prospective cohort of individuals resident in São Paulo, Brazil who were enrolled in a FH cascade screening program. We used a multivariate logistic regression analysis to determine predictive variables for the non-adherence of lipid-lowering drugs., Results: A total of 1,360 HF participants were included. At the one-year follow-up (T1), the rates of lipid-lowering treatment were 92%, 76%, and 78% from the genetic positive proband (index cases, IC), genetic negative IC and genetic positive first-degree relatives, respectively. Receiving a positive genetic test for FH (OR: 4.85; CI 95%: 2.97 - 7.93, p value < 0.05), use of lipid-lowering treatment at T0 (OR: 5.01; CI 95%: 3.18 - 7.90, p value < 0.05) and age (OR: 1.04; CI 95%: 1.02 - 1.06) were independently associated with the use of a lipid-lowering drug at T1., Conclusion: Index cases with a positive genetic result increase their prevalence of lipid-lowering medication use. Positive relatives did not have the expected adherence; we could notice a significant increase in the prevalence of treatment starting after a positive genetic test. The independent predictors for lipid-lowering treatment were age, a positive genetic test and previous institution of treatment before the genetic test result., 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 © 2022. Published by Elsevier Inc.)

Background: Among several lipid ratios available, the triglyceride/HDL-cholesterol (TG/HDL-C) may detect individuals at risk of cardiometabolic diseases. However, its reference values for different ethnicities are not well established., Objective: To define sex- and ethnicity-specific reference values for TG/HDL-C ratio in a large sample of healthy multiethnic adults and test its association with cardiometabolic conditions., Methods: An apparently healthy sample (n = 2,472), aged 35-74, free of major cardiovascular risk factors, was used to generate the reference values for the TG/HDL-C. Exclusion criteria were diabetes, elevated blood pressure, obesity, hypercholesterolemia, severe hypertriglyceridemia, and smoking history. Cut-offs based on the reference values were tested in the whole ELSA Brasil study (n = 13,245), stratified by sex and ethnicity, to identify cardiometabolic conditions., Results: TG/HDL-C ratio was higher in men than women, and did not change significantly with age, regardless of sex and ethnicity. Also, black individuals showed lower levels of TG/HDL-C as compared to other ethnic groups. ROC curve showed that the cut-off based on the 75th percentile displayed better sensitivities and specificities for men and women, regardless of ethnicity. Also, the sex- and ethnicity-specific cut-offs based on the 75th percentile were significantly associated with all tested cardiometabolic conditions (hypertension, diabetes, obesity, metabolic syndrome, and insulin resistance). Also, we observed that the use of a single sex-specific cut-off (men: 2.6; women: 1.7) could be used for the different ethnicities with good reliability., Conclusion: The defined TG/HDL-C cut-offs (men: 2.6; women: 1.7) are reliable and showed good clinical applicability to detect cardiometabolic conditions in a multiethnic population., Competing Interests: Conflict of Interest RDS has received honoraria related to consulting, speaker activities, or research from Abbott, Ache, Amgen, Astra Zeneca, Esperion, EMS, Getz pharma, Kowa, Libbs, Novo-Nordisk, Novartis, Merck, MSD, Pfizer, PTC Therapeutics, and Sanofi outside the present work. All other authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2021. Published by Elsevier Inc.)

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by extremely high triglyceride levels due to impaired clearance of chylomicrons from plasma. This paper is the result of a panel discussion with Latin American specialists who raised the main issues on diagnosis and management of FCS in their countries. Overall FCS is diagnosed late on the course of the disease, is characterized by heterogeneity on the occurrence of pancreatitis, and remains a long time in care of different specialists until reaching a lipidologist. Pancreatitis and secondary diabetes are frequently seen, often due to late diagnosis and inadequate care. Molecular diagnosis is unusual; however, loss of function variants on the lipoprotein lipase gene are apparently the most frequent etiology. A founder effect of the glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 gene has been described in the northeast of Brazil. Low awareness of the disease amongst health professionals contributes to inadequate care and an inadequate patient journey., (Copyright © 2021 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Familial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH. This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP)., Methods and Results: In this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135-250) and 161 (133-193) mg/dL; 141 (109-181) and 103 (88-134) mg/dL; and 1.6 (0.8-4.0) and 0.8 (0.4-1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies., Conclusions: Higher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH., Competing Interests: Declaration of competing interest RDS has received honoraria related to consulting, research and or speaker activities from: Abbott, Amgen, Aché, Astra Zeneca, Esperion, GETZ Pharma, Kowa, Libbs, Merck, MSD, Novo-Nordisk, Novartis, PTC Therapeutics, Pfizer, and Sanofi. Others none to declare., (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.)

The novel coronavirus disease (COVID-19) showed increased morbidity and mortality rates and worse prognosis in individuals with underlying chronic diseases, especially cardiovascular disease and its risk factors, such as hypertension, diabetes, and obesity. There is also evidence of possible links among COVID-19, myocardial infarction, and stroke. Emerging evidence suggests a pro-inflammatory milieu and hypercoagulable state in patients with this infection. Despite anticoagulation, a large proportion of patients requiring intensive care may develop life-threatening thrombotic complications. Indeed, the levels of some markers of hemostatic activation, such as D-dimer, are commonly elevated in COVID-19, indicating potential risk of deep vein thrombosis and pulmonary thromboembolism. In this review, we critically examine and discuss aspects of hypercoagulability and inflammation in COVID-19 and the possible benefits of statins in this scenario, with emphasis on their underlying molecular mechanisms. Moreover, we present recommendations on the use of antiviral drugs in combination with statins.

Background and Aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype., Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype., Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH)., Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia (FH) is characterized by high LDL-cholesterol (LDL-C) and early atherosclerotic cardiovascular disease (ASCVD). With a lipid lowering therapy (LLT), most individuals with FH may have a longer ASCVD-free survival. However, there is scant data about older individuals with FH., Methods: We compared characteristics of genetically defined FH older individuals with age-matched non-FH counterparts., Results: From 4111 genotyped individuals, 462 older than 60 years were included (198 positive and 264 negative for FH variants). There were no differences regarding median age [%25; 75%] 66.0 (62.0; 71.0) and 66.0 (62.2; 71.0) years, p = 0.68 for FH and non-FH, respectively. In both groups, there was a higher frequency of females, however, there were more males in the FH group 37.4% vs. 24.2%, p = 0.002. No differences were seen between FH and non-FH in LLT use: 88.5% vs. 91.5%, p = 0.29. Despite a longer LLT duration in FH patients (with 11.0 (7.0; 20.0) vs. 7.0 (3.0; 13.0) years, p < 0.001), treatment was started late in both groups: at 54.0 (47.0; 61.0) and 59.0 (52.0; 64.0) years, p < 0.001, in FH and non-FH, respectively. FH had greater frequencies of previous and early ASCVD (40.9% vs. 27.3%, p = 0.002, and 22.2% vs. 9.0%, p < 0.001). In FH, male sex [HR (95%CI)] 2.67 (1.50-4.73), p = 0.001, and LLT onset age 0.96 (0.93-0.99), p = 0.009, were independently associated with ASCVD., Conclusions: Among hypercholesterolemic older individuals participating in a cascade screening program, the genetic diagnosis of FH was associated with higher ASCVD rates, emphasizing the relevance of a monogenic defect as the cause of long-lasting hypercholesterolemia and ASCVD risk, particularly in men., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Thyroid dysfunction is related to several lipid abnormalities. There is no consensus about concentration of high-density lipoprotein (HDL) in different studies. The aim of this report is to evaluate HDL particle (HDL-P) subfractions across a spectrum of thyroid functions in a Brazilian population., Methods: Individuals were divided into three groups by baseline thyroid function (subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism). HDL-P subfractions were analyzed by Nuclear Magnetic Resonance (NMR) spectroscopy. To examine the association between HDL-P subfractions and thyroid function, we used univariate and multivariate linear regression models adjusted for demographic characteristics, comorbidities, lifestyle factors, and traditional lipid measurement (HDL-C, LDL-C and triglycerides)., Results: Of 3304 participants, 54.1% were women, 51.2% white, with mean age 50.6 ± 8.7 years. HDL-C and triglycerides levels (p = 0.032 and p = 0.016, respectively) were higher in the SC hypothyroid group. There were no statistically significant differences in total cholesterol levels and LDL-C levels. In univariate analysis, small HDL-P subfractions were significantly lower in subclinical hypothyroidism (p = 0.026) whereas intermediate HDL-P were higher in subclinical hyperthyroidism (p = 0.049), compared to euthyroidism. After adjustment for demographic data, SC hypothyroidism was still statistically associated with lower levels of small HDL-P. After adjusting for comorbidities, lifestyle factors, and traditional lipid measurements, SC hypothyroidism had an established association with lower levels of small HDL-P while SC hyperthyroidism was associated with lower levels of large HDL-P., Conclusions: In this large cohort from a Brazilian population, subclinical hypothyroidism was associated with lower small HDL-P subfractions, and subclinical hyperthyroidism with lower large HDL-P subfractions and higher intermediate HDL-P subfractions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol., Methods: In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and 18 F-FDG PET/CT to quantify arterial wall inflammation., Results: A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm 2 , p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks., Conclusion: In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

TG-rich lipoprotein (TRL)-related biomarkers, including TRL-cholesterol (TRL-C), remnant-like lipoprotein particle-cholesterol (RLP-C), and apoC-III have been associated with atherosclerosis. However, their prognostic values have not been fully determined, especially in patients with previous CAD. This study aimed to examine the associations of TRL-C, RLP-C, and apoC-III with incident cardiovascular events (CVEs) in the setting of secondary prevention of CAD. Plasma TRL-C, RLP-C, and total apoC-III were directly measured. A total of 4,355 participants with angiographically confirmed CAD were followed up for the occurrence of CVEs. During a median follow-up period of 5.1 years (interquartile range: 3.9-6.4 years), 543 (12.5%) events occurred. Patients with incident CVEs had significantly higher levels of TRL-C, RLP-C, and apoC-III than those without events. Multivariable Cox analysis indicated that a log unit increase in TRL-C, RLP-C, and apoC-III increased the risk of CVEs by 49% (95% CI: 1.16-1.93), 21% (95% CI: 1.09-1.35), and 40% (95% CI: 1.11-1.77), respectively. High TRL-C, RLP-C, and apoC-III were also independent predictors of CVEs in individuals with LDL-C levels ≤1.8 mmol/l (n = 1,068). The addition of RLP-C level to a prediction model resulted in a significant increase in discrimination, and all three TRL biomarkers improved risk reclassification. Thus, TRL-C, RLP-C, and apoC-III levels were independently associated with incident CVEs in Chinese CAD patients undergoing statin therapy., Competing Interests: Conflict of interest—R.D.S. has received honoraria related to consulting, research, and or speaker activities from: Amgen, Aché, Astra Zeneca, Esperion, Kowa, Merck, Novo-Nordisk, PTC, Pfizer, and Sanofi/Regeneron. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 Cao et al.)

Background and Aims: PCSK9 is an endogenous inhibitor of the LDL receptor pathway. Recently, Mendelian randomization studies have raised a doubt about the diabetogenic risk of PCSK9 inhibitors. Here, we assessed the relationship between plasma PCSK9 levels and the risk of new onset diabetes (NOD)., Methods: Fasting plasma PCSK9 levels were measured at baseline by ELISA in subjects without lipid lowering treatment in IT-DIAB (n = 233 patients with prediabetes, follow-up 5 years) and ELSA-Brasil (n = 1751; 27.5% with prediabetes, follow-up 4 years) prospective cohorts. The primary outcome in both studies was the incidence of NOD. The association of NOD with plasma PCSK9 levels was studied using multivariable Cox models., Results: Plasma PCSK9 levels were not significantly associated with NOD in IT-DIAB (HR (+1SD) 0.96, CI 95% [0.76; 1.21]) and ELSA-Brasil (OR (+1SD) 1.13 [0.89; 1.42]). In ELSA-Brasil, a significant positive association between PCSK9 and worsening of glucose homeostasis, including the progression from normoglycemia to prediabetes, was found (OR (+1SD) 1.17 [1.04; 1.30], p = 0.0074). Plasma PCSK9 concentration was also positively associated with the change in fasting plasma glucose between the first and second visit in ELSA-Brasil (β = 0.053, CI 95% [0.006; 0.10], p = 0.026). Plasma PCSK9 levels positively correlated with total cholesterol in IT-DIAB and ELSA-Brasil, but not with glucose homeostasis parameters, except for a positive correlation with HOMA-IR in ELSA-Brasil., Conclusions: Plasma PCSK9 levels were not significantly associated with NOD risk in longitudinal analyses. These data suggest that inhibition of the PCSK9 extra-cellular pathway should not be deleterious for glucose homeostasis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to evaluate the role of coronary artery calcium (CAC) as a predictor of atherosclerotic cardiovascular disease (ASCVD) (fatal or not myocardial infarction, stroke, unstable angina requiring revascularization, and elective myocardial revascularization) events in asymptomatic primary prevention molecularly proven heterozygous familial hypercholesterolemia (FH) subjects receiving standard lipid-lowering therapy., Background: FH is associated with premature ASCVD. However, the clinical course of ASCVD in subjects with FH is heterogeneous. CAC score, a marker of subclinical atherosclerosis burden, may optimize ASCVD risk stratification in FH., Methods: Subjects with FH underwent CAC measurement and were followed prospectively. The association of CAC with ASCVD was evaluated using multivariate analysis., Results: A total of 206 subjects (mean age 45 ± 14 years, 36.4% men, baseline and on-treatment low-density lipoprotein cholesterol 269 ± 70 mg/dl and 150 ± 56 mg/dl, respectively) were followed for a median of 3.7 years (interquartile range: 2.7 to 6.8 years). CAC was present in 105 (51%), and 15 ASCVD events (7.2%) were documented. Almost one-half of events were hard outcomes, and the others were elective myocardial revascularizations. The annualized rates of events per 1,000 patients for CAC scores of 0 (n = 101 [49%]), 1 to 100 (n = 62 [30%]) and >100 (n = 43 [21%]) were, respectively, 0, 26.4 (95% confidence interval: 12.9 to 51.8), and 44.1 (95% confidence interval, 26.0 to 104.1). In multivariate Cox regression analysis, log(CAC score + 1) was independently associated with incident ASCVD events (hazard ratio: 3.33; 95% CI: 1.635 to 6.790; p = 0.001)., Conclusions: CAC was independently associated with ASCVD events in patients with FH receiving standard lipid-lowering therapy. This may help further stratify near-term risk in patients who might be candidates for further treatment with newer therapies., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The Martin/Hopkins low-density lipoprotein cholesterol equation (LDL-C N ) was previously demonstrated as more accurate than Friedewald LDL-C estimation (LDL-C F ) in a North American database not able to take race into account., Objectives: We hypothesized that LDL-C N would be more accurate than LDL-C F and correlate better with LDL particle number (LDL-P) in a racially diverse Brazilian cohort., Methods: We performed a cross-sectional analysis of 4897 participants in the Brazilian Longitudinal Study of Adult Health, assessing LDL-C F and LDL-C N accuracy via overlap with ultracentrifugation-based measurement among clinical guideline LDL-C categories as well as mg/dL and percent error differences. We analyzed by triglyceride categories and correlated LDL-C estimation with LDL-P., Results: LDL-C N demonstrated improved accuracy at 70 to <100 and <70 mg/dL (P < .001), with large errors ≥20 mg/dL about 9 times more frequent in LDL-C F at LDL-C <70 mg/dL, mainly due to underestimation. Among individuals with LDL-C <70 mg/dL and triglycerides ≥150 mg/dL, 65% vs 100% of ultracentrifugation-based low-density lipoprotein cholesterol calculation fell within appropriate categories of estimated LDL-C F and LDL-C N , respectively (P < .001). Similar results were observed when analyzed for age, sex, and race. Participants at LDL-C <70 and 70 to <100 mg/dL with discordantly elevated LDL-C N vs LDL-C F had a 58.5% and 41.5% higher LDL-P than those with concordance (P < .0001), respectively., Conclusions: In a diverse Brazilian cohort, LDL-C N was more accurate than LDL-C F at low LDL-C and high triglycerides. LDL-C N may avoid underestimation of LDL-C and better reflect atherogenic lipid burden in low particle size, high particle count states., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease., Objective: We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status., Methods: Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24-104 weeks' duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non-familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75 mg every 2 weeks (Q2W) to 150 mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70 mg/dL in very high cardiovascular risk; ≥100 mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150 mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age (<65, ≥65 to <75, ≥75 years) and baseline hypertension or smoking status., Results: Alirocumab reduced LDL-C by 23.7% (75/150 mg vs ezetimibe + statin) to 65.4% (150 mg vs placebo + statin) from baseline to Week 24 vs control. Subgroup analyses confirmed no significant interactions in response to alirocumab between age group, hypertension, or smoking status. Overall rates of treatment-emergent adverse events were similar between alirocumab and control groups., Conclusions: In this pooled analysis from 10 trials, alirocumab led to substantial LDL-C reductions vs control in every age group and regardless of hypertension or smoking status. Alirocumab was well tolerated in all subgroups., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: The cross-sectional observational International ChoLesterol management Practice Study study assessed achievement of European Society of Cardiology/European Atherosclerosis Society low-density lipoprotein cholesterol (LDL-C) targets in patients outside Western Europe., Objective: The aim of the study was to assess LDL-C goal achievement in International ChoLesterol management Practice Study participants with familial hypercholesterolemia (FH)., Methods: A total of 334 patients (aged ≥18 years) with definite or probable FH (Dutch Lipid Clinic Network score ≥6; 43.1% genetically confirmed) who had been receiving stable lipid-modifying therapy (LMT) for ≥3 months were enrolled., Results: The mean ± standard deviation age of the patients was 58.5 ± 13.1 years, 49.1% were male, and 48.2% had coronary artery disease. Most were receiving statin (∼99%). Of these, 57.6% were on high-intensity statin therapy, 49.1% on the highest dose available, and 13.0% used a statin together with a cholesterol absorption inhibitor (CAI). Mean ± standard deviation LDL-C level was 5.6 ± 3.0 mmol/L before LMT and 3.3 ± 2.0 mmol/L at enrollment. Overall, 32.0% of patients achieved their LDL-C target. Target achievement rates were 36.6% for patients with coronary artery disease, and 27.5% for those without, and 27.9%, 28.0%, and 37.5% for patients treated with a statin plus CAI, highest-dose statin (no CAI), and lower-dose statin (no CAI), respectively., Conclusions: LDL-C target achievement rates were low in patients with FH, even in those receiving intensive LMT. Factors that are likely to have contributed to the low LDL-C target achievement rates include high baseline LDL-C, inadequate statin dosages, and low use of CAI. Many patients would have been eligible for proprotein convertase subtilisin/kexin type 9 inhibitor therapy., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Patients with familial hypercholesterolaemia (FH) may require proprotein convertase subtilisin/kexin-type 9 (PCSK9) mAb as add-on therapy to achieve LDL-cholesterol (LDL-C) goals. However, the current cost of these therapies means that choosing suitable patients is based on consensus or clinical judgement rather than a quantitative risk assessment. We used the SAFEHEART Risk Equation (RE) to estimate the number needed to treat (NNT) at different risk thresholds and baseline LDL-C to identify those FH patients more likely to derive the greatest benefit from PCSK9 mAb., Methods: Five-year event rates were calculated using the SAFEHEART-RE for every patient, overall and across LDL-C strata. A 60% reduction of LDL-C after theoretical treatment with PCSK9 mAb was assumed. Individual absolute risk simulating the effects of PCSK9 inhibition was calculated using the SAFEHEART-RE and, in a similar way, by using the Cholesterol Treatment Trialists' (CTT) Collaboration criteria. Absolute risk reduction and NNTs were calculated., Results: Of the total SAFEHEART population, 2,153 were FH cases aged 18 years or older, on maximum tolerated lipid lowering treatment. NNTs were dependent of both baseline predicted risk and baseline LDL-C level ranging from 44 to 17 for those with 5-year risk of ≥1 to ≥5. The smallest NNT (12) was observed among those with 5-year risk of ≥5% and LDL-C ≥160 mg/dl. Using the CTT criteria produced similar results., Conclusions: The SAFEHEART-RE may provide a useful quantitative tool for rationalising the selection of FH patients who might derive greater absolute benefits from PCSK9 mAb., (Copyright © 2019. Published by Elsevier B.V.)

We report for the first time the efficiency and safety of a 49-month compassionate use of the microsomal transfer protein inhibitor lomitapide in a child with homozygous familial hypercholesterolemia. On average, 20 mg of lomitapide caused a 37% reduction in low-density lipoprotein cholesterol levels on top of ezetimibe and atorvastatin. The drug was well tolerated with no changes in liver enzymes and occurrence of steatosis on hepatic ultrasound. The patient presented adequate growth and sexual maturation. Nonetheless, there was progression in either subclinical atherosclerotic carotid or aortic valve diseases. Further studies are necessary to test the impact and safety of lomitapide in children with homozygous familial hypercholesterolemia., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Familial apolipoprotein A-I (apoA-I) deficiency (FAID) involving low levels of both apoA-I and high-density lipoprotein (HDL) cholesterol is associated with accelerated atherosclerosis., Objective: The objective of this study was to define distinctive patterns in the lipidome of HDL subpopulations in FAID in relationship to antiatherogenic activities., Methods: Five HDL subfractions were isolated by ultracentrifugation from plasma of FAID Caucasian patients (n = 5) and age-matched healthy normolipidemic Caucasian controls (n = 8), and the HDL lipidome (160 molecular species of 9 classes of phospholipids and sphingolipids) was quantitatively evaluated., Results: Increased concentrations of numerous molecular species of lysophosphatidylcholine (up to 12-fold), ceramides (up to 3-fold), phosphatidylserine (up to 34-fold), phosphatidic acid (up to 71-fold), and phosphatidylglycerol (up to 20-fold) were detected throughout all five HDL subpopulations as compared with their counterparts from controls, whereas concentrations of phosphatidylethanolamine species were decreased (up to 5-fold). Moderately to highly abundant, within their lipid class, species of phosphatidylcholine, sphingomyelin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and ceramide featuring multiple unsaturations were primarily affected by apoA-I deficiency; their HDL content, particularly that of phosphatidylcholine (34:2), was strongly correlated with HDL function, impaired in FAID. Metabolic pathway analysis revealed that sphingolipid, glycerophospholipid, and linoleic acid metabolism was significantly affected by FAID., Conclusion: These data reveal that altered content of specific phospholipid and sphingolipid species is linked to deficient antiatherogenic properties of HDL in FAID., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: There is a lack of information on the health care of familial hypercholesterolemia (FH)., Objective: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere., Methods: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark., Results: The estimated percentage of patients diagnosed with the condition was low (overall <3%) in all countries, compared with ∼15% in the UK. Underdetection of FH was associated with government expenditure on health care (ϰ = 0.667, P < .05). Opportunistic and systematic screening methods, and the Dutch Lipid Clinic Network criteria were most commonly used to detect FH; genetic testing was infrequently used. Noninvasive imaging of coronary calcium and/or carotid plaques was underutilized in risk assessment. Patients with FH were generally not adequately treated, with <30% of patients achieving guideline recommended low-density lipoprotein cholesterol targets on conventional therapies. Treatment gaps included suboptimal availability and use of lipoprotein apheresis and proprotein convertase subtilsin-kexin type 9 inhibitors. A deficit of FH registries, training programs, and publications were identified in less economically developed countries. The demonstration of cost-effectiveness for cascade screening, genetic testing, and specialized treatments were significantly associated with the availability of subsidies from the health care system (ϰ = 0.571-0.800, P < .05)., Conclusion: We identified important gaps across the continuum of care for FH, particularly in less economically developed countries. Wider implementation of primary and pediatric care, telehealth services, patient support groups, education/training programs, research activities, and health technology assessments are needed to improve the care of patients with FH in these countries., (Copyright © 2019 National Lipid Association. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and includes a spectrum of abnormalities ranging from steatosis to cirrhosis. In this review, we address recent evidence and limitations of studies that evaluated the association of NAFLD with atherosclerotic cardiovascular disease. NAFLD is considered an ectopic fat deposit associated with metabolic (insulin resistance, hyperglycemia and dyslipidemia), inflammatory, coagulation and blood pressure disturbances. Prospective studies have associated NAFLD presence and severity, particularly steatohepatitis and fibrosis, with an increased risk of cardiovascular disease. However, these studies are limited by heterogeneity concerning NAFLD diagnostic criteria and disease severity stratification, as well as by the presence of confounding factors. In addition, genetic variants predisposing to NAFLD, such as the PNPLA3 I148M mutation, were not consistently associated with an increased risk of cardiovascular events. Therefore, currently, it is not possible to prove a causal relation between NAFLD and cardiovascular disease. Furthermore, there is presently no evidence that NAFLD diagnosis can be used as a tool to improve cardiovascular risk stratification and modify treatment. Specific treatments for NAFLD are being developed and must be tested prospectively in adequately designed trials to determine the potential of reducing both hepatic and cardiovascular diseases and to prove whether NAFLD is indeed a cause of atherosclerosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aims: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C-lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile., Methods: In this double-blind trial, HeFH patients (LDL-C >160 mg/dL) on maximal tolerated LDL-lowering therapy were randomized to mipomersen 200 mg once weekly (n = 104), mipomersen 70 mg thrice weekly (n = 102), or placebo in matching frequency (n = 103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment., Results: Mipomersen 200 mg once weekly and mipomersen 70 mg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p < 0.001). Lipoprotein(a) was significantly lowered by 27.7% (p < 0.001) with thrice-weekly dosing. Injection-site reactions and flu-like symptoms led to discontinuation in 21.2% (200 mg), 17.6% (70 mg), and 5.8% (placebo) of participants. Alanine transaminase was elevated (≥3× upper limit of normal at least once) in 21.2%, 21.6%, and 1.0% of subjects, respectively., Conclusions: Mipomersen 200 mg once weekly and 70 mg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder associated with high cardiovascular burden of disease. FH prevalence may vary widely across populations and data in race/ethnically diverse and admixed populations is scarce. ELSA-Brasil epidemiology may be widely generalizable in this regard, and we calculated the ELSA-Brasil FH prevalence and its variation according to age, sex and race/ethnicity., Methods: In 14,460 individuals aged from 35 to 75 years from the ELSA-Brasil cohort baseline, we classified FH according to the Dutch Lipid Clinic Network criteria score ≥6 (probable and definite FH). LDL-C levels were adjusted for statin use. We calculated the overall ELSA-Brasil FH prevalence and the weighted prevalence for age, sex and race/ethnic categories. We extrapolated those frequencies to the Brazilian population weighting for age-sex-race/ethnicity according to the 2015 Statistics and Geography Brazilian Institute survey., Results: The overall FH prevalence per 1000 individuals in ELSA-Brasil was 3.8 (2.9, 4.9) or 1 in 263. The age/sex/race-ethnicity-weighted FH prevalences were: male, 3.0 (1.7, 4.4) or 1 in 333; female, 4.1 (3.0, 5.2) or 1 in 244 (p<0.001). White race prevalence was 2.4 (1.9, 3.0) or 1 in 417; Brown, 4.9 (4.0, 5.9) or 1 in 204; and Black 6.4 (41.1, 8.7) or 1 in 156 (p<0.001). The weighted extrapolation for the Brazilian population derived similar magnitude frequencies., Conclusions: FH affects 1 in 263 in ELSA-Brasil and affects disproportionally more Brown (1 in 204), and Black (1 in 156), than White (1 in 417). Weighted extrapolation for the Brazilian population derived similar magnitude frequencies., (Copyright © 2018 Elsevier B.V. All rights reserved.)