Consensus document on diagnosis and management of familial hypercholesterolemia from the Italian Society for the Study of Atherosclerosis (SISA).

AIMS: Familial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism that causes an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Although early diagnosis and treatment of FH can significantly improve the cardiovascular prognosis, this disorder is underdiagnosed and undertreated. For these reasons the Italian Society for the Study of Atherosclerosis (SISA) assembled a Consensus Panel with the task to provide guidelines for FH diagnosis and treatment. DATA SYNTHESIS: Our guidelines include: i) an overview of the genetic complexity of FH and the role of candidate genes involved in LDL metabolism; ii) the prevalence of FH in the population; iii) the clinical criteria adopted for the diagnosis of FH; iv) the screening for ASCVD and the role of cardiovascular imaging techniques; v) the role of molecular diagnosis in establishing the genetic bases of the disorder; vi) the current therapeutic options in both heterozygous and homozygous FH. Treatment strategies and targets are currently based on low-density lipoprotein cholesterol (LDL-C) levels, as the prognosis of FH largely depends on the magnitude of LDL-C reduction achieved by lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment. Addition of novel medications like PCSK9 inhibitors, ANGPTL3 inhibitors or lomitapide in homozygous FH results in a further reduction of LDL-C levels. LDL apheresis is indicated in FH patients with inadequate response to cholesterol-lowering therapies. CONCLUSION: FH is a common, treatable genetic disorder and, although our understanding of this disease has improved, many challenges still remain with regard to its identification and management.

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries.

BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. METHODS: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. FINDINGS: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). INTERPRETATION: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

Obicetrapib on top of maximally tolerated lipid-modifying therapies in participants with or at high risk for atherosclerotic cardiovascular disease: rationale and designs of BROADWAY and BROOKLYN.

BACKGROUND: Obicetrapib, a novel, selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), LDL particles, apolipoprotein (Apo) B, and lipoprotein(a) [Lp(a)] and increases high-density lipoprotein cholesterol (HDL-C) when added to statins with or without ezetimibe. By substantially reducing LDL-C, obicetrapib has the potential to lower atherogenic lipoproteins in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels remain high despite treatment with available maximally tolerated lipid-modifying therapies, addressing an unmet medical need in a patient population at high risk for cardiovascular events. METHODS AND RESULTS: BROADWAY (NCT05142722) and BROOKLYN (NCT05425745) are ongoing placebo-controlled, double-blind, randomized Phase III trials designed to examine the efficacy, safety, and tolerability of obicetrapib as an adjunct to dietary intervention and maximally tolerated lipid-modifying therapies in participants with a history of ASCVD and/or underlying HeFH whose LDL-C is not adequately controlled. The primary efficacy endpoint was the percent change in LDL-C from baseline to day 84. Other endpoints included changes in Apo B, non-HDL-C, HDL-C, Apo A1, Lp(a), and triglycerides in addition to parameters evaluating safety, tolerability, and pharmacokinetics. BROADWAY also included an adjudicated assessment of major adverse cardiovascular events, measurements of glucose homeostasis, and an ambulatory blood pressure monitoring substudy. A total of 2,532 participants were randomized in BROADWAY and 354 in BROOKLYN to receive obicetrapib 10 mg or placebo (2:1) for 365 days with follow-up through 35 days after the last dose. Results from both trials are anticipated in 2024. CONCLUSION: These trials will provide safety and efficacy data to support the potential use of obicetrapib among patients with ASCVD or HeFH with elevated LDL-C for whom existing therapies are not sufficiently effective or well-tolerated.

Efficacy and safety of bempedoic acid in patients with heterozygous familial hypercholesterolemia: analysis of pooled patient-level data from phase 3 clinical trials.

BACKGROUND: Patients with heterozygous familial hypercholesterolemia (HeFH) often cannot reach guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals despite multidrug therapy. OBJECTIVE: To evaluate the efficacy and safety of bempedoic acid as an add-on therapy for lowering LDL-C in patients with HeFH. METHODS: Pooled data from two 52-week phase 3 clinical trials of patients with atherosclerotic cardiovascular disease and/or HeFH receiving maximally tolerated statin therapy (randomized 2:1 to bempedoic acid or placebo) were analyzed by HeFH status. Endpoints included changes from baseline to week 12 (and up to week 52) in LDL-C and other lipid parameters, achievement of LDL-C goals, and safety. RESULTS: A total of 217 (bempedoic acid, 146; placebo, 71) patients with HeFH and 2,792 (bempedoic acid, 1,864; placebo, 928) without HeFH were included (mean baseline LDL-C, 172.8 mg/dL and 102.6 mg/dL, respectively). Bempedoic acid significantly lowered LDL-C at week 12 vs. placebo regardless of HeFH status (with HeFH, -21.2%; without HeFH, -18.2% [both P<0.0001]). Bempedoic acid significantly reduced other lipid parameters and high-sensitivity C-reactive protein vs. placebo regardless of HeFH status (all P≤0.01). Among patients with HeFH treated with bempedoic acid, 32% and 27% achieved LDL-C <100 mg/dL at weeks 12 and 52, respectively. Overall treatment-emergent adverse event incidence was comparable across all four groups (74.7-77.5%). CONCLUSION: Bempedoic acid significantly lowered LDL-C levels vs. placebo and was generally well tolerated in all patients, with no new safety findings in patients with HeFH, despite more intensive lipid-lowering therapy in patients with vs. without HeFH.

Contemporary lipid-lowering management and risk of cardiovascular events in homozygous familial hypercholesterolaemia: insights from the Italian LIPIGEN Registry.

AIMS: The availability of novel lipid-lowering therapies (LLTs) has remarkably changed the clinical management of homozygous familial hypercholesterolaemia (HoFH). The impact of these advances was evaluated in a cohort of 139 HoFH patients followed in a real-world clinical setting. METHODS AND RESULTS: The clinical characteristics of 139 HoFH patients, along with information about LLTs and low-density lipoprotein cholesterol (LDL-C) levels at baseline and after a median follow-up of 5 years, were retrospectively retrieved from the records of patients enrolled in the LIPid transport disorders Italian GEnetic Network-Familial Hypercholesterolaemia (LIPIGEN-FH) Registry. The annual rates of major atherosclerotic cardiovascular events (MACE-plus) during follow-up were compared before and after baseline. Additionally, the lifelong survival free from MACE-plus was compared with that of the historical LIPIGEN HoFH cohort. At baseline, LDL-C level was 332 ± 138 mg/dL. During follow-up, the potency of LLTs was enhanced and, at the last visit, 15.8% of patients were taking quadruple therapy. Consistently, LDL-C decreased to an average value of 124 mg/dL corresponding to a 58.3% reduction (Pt < 0.001), with the lowest value (∼90 mg/dL) reached in patients receiving proprotein convertase subtilisin/kexin type 9 inhibitors and lomitapide and/or evinacumab as add-on therapies. The average annual MACE-plus rate in the 5-year follow-up was significantly lower than that observed during the 5 years before baseline visit (21.7 vs. 56.5 per 1000 patients/year; P = 0.0016). CONCLUSION: Our findings indicate that the combination of novel and conventional LLTs significantly improved LDL-C control with a signal of better cardiovascular prognosis in HoFH patients. Overall, these results advocate the use of intensive, multidrug LLTs to effectively manage HoFH.

Contemporary real-world data from the Italian cohort of patients affected by homozygous familial hypercholesterolaemia demonstrated that the addition of novel, low-density lipoprotein receptor (LDLR)-independent medications to conventional therapies allowed the achievement of unprecedented low-density lipoprotein cholesterol (LDL-C) values with a trend towards a reduction of cardiovascular risk.

Genetic heterogeneity of familial hypercholesterolaemia in two populations from two different countries.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetically determined monogenic disorder of predominantly autosomal dominant inheritance. A number of studies on differences in the genetic profile of patients with FH have demonstrated the importance of a more substantive evaluation of genetic features. The aim of this study was to evaluate the genetic profile of patients with clinical FH among Italian and Russian patients. METHODS: We included 144 Italian and 79 Russian FH patients; clinical diagnosis was based on the same criteria. Patients were divided in: positive to genetic test (one causative variant), inconclusive (only variants of uncertain clinical significance [VUS]), and negative (with likely benign/benign variants, heterozygous variants in LDLRAP1 gene, or without causative variants). RESULTS: The genetic test was positive in 76.4 % of the Italian patients and in 49.4 % of the Russian patients. The presence of VUS alone was detected in 7.6 % and in 19.0 % (p < 0.001), respectively. Among patients with positive genetic diagnosis, pre-treatment LDL-C levels were higher in the Russian cohort (353.5 ± 111.3 vs. 302.7 ± 52.1 mg/dL, p = 0.009), as well as the percentage of treated patients (53.8 % vs. 14.5 %, p < 0.001) and the prevalence of premature coronary heart disease (12.8 % vs. 3.6 %, p = 0.039). Among patients carrying only VUS, mean pre-treatment LDL-C levels were similar between the cohorts (299.5 ± 68.1 vs. 295.3 ± 46.8 mg/dL, p = 0.863). Among pathogenic/likely pathogenic variants and VUS, only 5 % and 4 % was shared between the two cohorts, respectively. CONCLUSION: The genetic background of patients clinically diagnosed with FH in two different countries is characterized by high variability.

Real-World Effectiveness of PCSK9 Inhibitors in Reducing LDL-C in Patients With Familial Hypercholesterolemia in Italy: A Retrospective Cohort Study Based on the AIFA Monitoring Registries.

Background Information on the real-world use of proprotein convertase subtilisin kexin 9 inhibitors (PCKS9is) in familial hypercholesterolemia are limited. We evaluated the pattern of prescription and the long-term efficacy of alirocumab and evolocumab in Italian patients with familial hypercholesterolemia in clinical practice. Methods and Results The data set for analysis was extracted from the PCKS9i Italian Medicines Agency (AIFA) registry and included 2484 patients with heterozygous familial hypercholesterolemia (HeFH) and 62 patients with homozygous familial hypercholesterolemia (HoFH) who were prescribed PCKS9is from February 2017 to December 2021. As the follow-up schedules were not prespecified and could vary, persistence and adherence as well as low-density lipoprotein cholesterol (LDL-C) changes during 2 years of treatment were analyzed in a final cohort of 1299 patients with familial hypercholesterolemia. At baseline, 53.8% of patients with HeFH and 69.4% of patients with HoFH were receiving maximally tolerated lipid-lowering therapies, while 45.9% of patients with HeFH and 30.7% of patients with HoFH reported statin intolerance; mean LDL-C was 197.7±52.3 mg/dL in HeFH and 252.0±106.2 mg/dL in HoFH. The 6-month persistence and adherence to therapy were >85%, and LDL-C reduction reached 58.6% (to 79.7 mg/dL) in HeFH and 57.6% (to 95.1 mg/dL) in HoFH after 24 months of treatment. The European Atherosclerosis Society/European Society of Cardiology LDL-C goals were achieved in 43.3% of patients with HeFH and 37.5% of patients with HoFH. Conclusions PCKS9i prescribed to patients with familial hypercholesterolemia in clinical practice showed LDL-C-lowering efficacy similar to that observed in controlled trials. However, 2 of 5 HeFH cases and 2 of 6 HoFH cases achieved the recommended LDL-C goals. The full achievement of European Atherosclerosis Society/European Society of Cardiology LDL-C goals should require a lower threshold for PCKS9i initiation and a combination of multiple therapies.

Serum antinuclear autoantibodies are associated with measures of oxidative stress and lifestyle factors: analysis of LIPIDOGRAM2015 and LIPIDOGEN2015 studies.

Introduction: Oxidative stress is one of many factors suspected to promote antinuclear autoantibody (ANA) formation. Reactive oxygen species can induce changes in the antigenic structure of macromolecules, causing the immune system to treat them as "neo-antigens" and start production of autoantibodies. This study was designed to evaluate the relationship between oxidative stress markers, lifestyle factors and the detection of ANA. Material and methods: We examined measures of oxidative stress indices of free-radical damage to lipids and proteins, such as total oxidant status (TOS), concentration of protein thiol groups (PSH), and malondialdehyde (MDA), activity of superoxide dismutase (SOD) in 1731 serum samples. The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid (UA) concentration, were also measured and the oxidative stress index (OSI-index) was calculated. All samples were tested for the presence of ANA using an indirect immunofluorescence assay (IIFA). Results: The presence of ANA in women was associated with lower physical activity (p = 0.036), less frequent smoking (p = 0.007) and drinking of alcohol (p = 0.024) accompanied by significant changes in SOD isoenzymes activity (p < 0.001) and a higher uric acid (UA) concentration (p < 0.001). In ANA positive males we observed lower concentrations of PSH (p = 0.046) and increased concentrations of MDA (p = 0.047). Conclusions: The results indicate that local oxidative stress may be associated with increased probability of ANA formation in a sex-specific manner.

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study.

BACKGROUND AND AIMS: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age. METHODS: From the Italian LIPIGEN cohort, we selected 1188 (≥18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation. RESULTS: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives. CONCLUSIONS: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age.

Clinical Approach in the Management of Paediatric Patients with Familial Hypercholesterolemia: A National Survey Conducted by the LIPIGEN Paediatric Group.

Detection and treatment of patients with familial hypercholesterolemia (FH) starting from childhood is fundamental to reduce morbidity and mortality. The activity of National realities such as the LIPIGEN (LIpid transPort disorders Italian GEnetic Network) Paediatric Group, founded in 2018, is a milestone in this context. The aim of this exploratory survey, conducted in October 2021 among Italian lipid clinics included in the LIPIGEN Paediatric Group, was to investigate the current clinical approach in the management and treatment of paediatric patients with suspected FH. A digital questionnaire composed of 20 questions investigating nutritional treatment and nutraceutical and pharmacological therapy for children and adolescents with FH was proposed to the principal investigators of 30 LIPIGEN centres. Twenty-four centres responded to the section referring to children aged < 10 years and 30 to that referring to adolescents. Overall, 66.7% of children and 73.3% of adolescents were given lipid-lowering nutritional treatment as the first intervention level for at least 3-4 months (29.2% and 23.3%) or 6-12 months (58.3% and 53.3%). Nutraceuticals were considered in 41.7% (regarding children) and 50.0% (regarding adolescents) of the centres as a supplementary approach to diet. Lipid-lowering drug therapy initiation was mainly recommended (91.7% and 80.0%). In 83.3% of children and 96.7% of adolescents, statins were the most frequently prescribed drug. We highlighted several differences in the treatment of paediatric patients with suspected FH among Italian centres; however, the overall approach is in line with the European Atherosclerosis Society (EAS) recommendations for FH children and adolescents. We consider this survey as a starting point to reinforce collaboration between LIPIGEN centres and to elaborate in the near future a consensus document on the management of paediatric patients with suspected FH so as to improve and uniform detection, management, and treatment of these patients in our country.

Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention.

INTRODUCTION: Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking. METHODS AND ANALYSIS: The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners' offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed. ETHICS AND DISSEMINATION: This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study's course and findings through regular meetings. TRIAL REGISTRATION NUMBER: NCT05339841.

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance.

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia.

Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH.

Metabolic syndrome is associated with similar long-term prognosis in those living with and without obesity: an analysis of 45 615 patients from the nationwide LIPIDOGRAM 2004-2015 studies.

AIMS: We aimed to evaluate the association between metabolic syndrome (MetS) and long-term all-cause mortality. METHODS AND RESULTS: The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006, and 2015. MetS was diagnosed based on the National Cholesterol Education Program, Adult Treatment Panel III (NCEP/ATP III), and Joint Interim Statement (JIS) criteria. The cohort was divided into four groups: non-obese patients without MetS, obese patients without MetS, non-obese patients with MetS, and obese patients with MetS. Differences in all-cause mortality were analysed using Kaplan-Meier and Cox regression analyses. A total of 45 615 participants were enrolled (mean age 56.3, standard deviation: 11.8 years; 61.7% female). MetS was diagnosed in 14 202 (31%) by NCEP/ATP III criteria and 17 216 (37.7%) by JIS criteria. Follow-up was available for 44 620 (97.8%, median duration 15.3 years) patients. MetS was associated with increased mortality risk among the obese {hazard ratio, HR: 1.88 [95% confidence interval (CI) 1.79-1.99] and HR: 1.93 [95% CI 1.82-2.04], according to NCEP/ATP III and JIS criteria, respectively} and non-obese individuals [HR: 2.11 (95% CI 1.85-2.40) and 1.7 (95% CI 1.56-1.85) according to NCEP/ATP III and JIS criteria, respectively]. Obese patients without MetS had a higher mortality risk than non-obese patients without MetS [HR: 1.16 (95% CI 1.10-1.23) and HR: 1.22 (95% CI 1.15-1.30), respectively in subgroups with NCEP/ATP III and JIS criteria applied]. CONCLUSIONS: MetS is associated with increased all-cause mortality risk in non-obese and obese patients. In patients without MetS, obesity remains significantly associated with mortality. The concept of metabolically healthy obesity should be revised.

Metabolic syndrome (MetS) is used to describe a constellation of metabolic disturbances such as elevated blood glucose, increased levels of triglycerides and decreased level of high density lipoprotein cholesterol. They are often accompanied by elevated blood pressure and central obesity, defined as increased waist circumference. Usually, those metabolic disturbances occur in obese individuals, but sometimes, they can also occur in lean subjects. This relatively recent concept is often referred to as lean MetS. A key conclusion from our paper is that MetS, when it occurs in lean patients, is associated with similarly unfavourable long-term prognosis as in obese patients. Additionally, our analysis shows that lean patients with MetS are less often treated with lipid-lowering drugs despite having higher low density lipoprotein cholesterol levels (LDL-C). An additional finding, which is important from a public health perspective, is that obese patients who do not fulfil MetS criteria have higher long-term all-cause mortality than their lean counterparts without MetS. This finding should be an argument to encourage maintenance of normal body weight.

[Identifying possible homozygous familial hypercholesterolemia patients: an Italian experts' opinion]. / Inquadramento diagnostico del paziente con possibile ipercolesterolemia familiare omozigote: il parere di un gruppo italiano di esperti.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) and massive risk of premature atheromasia and cardiovascular events. HoFH is caused by mutations in several genes, such as LDLR, APOB, PCSK9 and LDLRAP1. If untreated, the average age of death is 18 years old, but fatalities within the first 5 years of age have been recorded. Therefore, early diagnosis and treatment are crucial, in order to prevent and/or delay the cardiovascular complications of LDL-C exposure. Because HoFH is a rare disorder, it is not frequently encountered in daily clinical practice at the primary/secondary unspecialized cardiological centers. Then the availability of practical indications helping to identify HoFH patients or to arise a suspect of HoFH is particularly strategic to promptly start the appropriate lipid-lowering therapy. For such a purpose, a group of Italian experts suggests three useful algorithms to identify cases requiring accurate and specialized clinical evaluation as potential HoFH patients. These cases with suspected HoFH should be addressed to specialized centres for the optimal management of these patients.

High-density lipoprotein revisited: biological functions and clinical relevance.

Previous interest in high-density lipoproteins (HDLs) focused on their possible protective role in atherosclerotic cardiovascular disease (ASCVD). Evidence from genetic studies and randomized trials, however, questioned that the inverse association of HDL-cholesterol (HDL-C) is causal. This review aims to provide an update on the role of HDL in health and disease, also beyond ASCVD. Through evolution from invertebrates, HDLs are the principal lipoproteins, while apolipoprotein B-containing lipoproteins first developed in vertebrates. HDLs transport cholesterol and other lipids between different cells like a reusable ferry, but serve many other functions including communication with cells and the inactivation of biohazards like bacterial lipopolysaccharides. These functions are exerted by entire HDL particles or distinct proteins or lipids carried by HDL rather than by its cholesterol cargo measured as HDL-C. Neither does HDL-C measurement reflect the efficiency of reverse cholesterol transport. Recent studies indicate that functional measures of HDL, notably cholesterol efflux capacity, numbers of HDL particles, or distinct HDL proteins are better predictors of ASCVD events than HDL-C. Low HDL-C levels are related observationally, but also genetically, to increased risks of infectious diseases, death during sepsis, diabetes mellitus, and chronic kidney disease. Additional, but only observational, data indicate associations of low HDL-C with various autoimmune diseases, and cancers, as well as all-cause mortality. Conversely, extremely high HDL-C levels are associated with an increased risk of age-related macular degeneration (also genetically), infectious disease, and all-cause mortality. HDL encompasses dynamic multimolecular and multifunctional lipoproteins that likely emerged during evolution to serve several physiological roles and prevent or heal pathologies beyond ASCVD. For any clinical exploitation of HDL, the indirect marker HDL-C must be replaced by direct biomarkers reflecting the causal role of HDL in the respective disease.

Antibiotic Prescription in the Community-Dwelling Elderly Population in Lombardy, Italy: A Sub-Analysis of the EDU.RE.DRUG Study.

Inappropriate consumption and over-prescription of antibiotics have been extensively reported. Our aim was to specifically evaluate the antibiotic prescribing patterns and appropriateness among the elderly (≥65 years) from the Lombardy region (Italy) in primary care. Antibiotic consumption (as DID: DDD/1000 inhabitants × day) and prevalence rates in 2018 were assessed, and the prescribing quality was evaluated using ESAC-based indicators and WHO-AWaRe criteria. A multivariate logistic regression analysis was performed to evaluate the association between the probability of receiving an antibiotic prescription and patients' and physicians' characteristics. A total of 237,004 antibiotic users were included (mean age ± SD 75.98 ± 7.63; males 42.7%). Antibacterial consumption was equal to 17.2 DID, with values increasing with age in both males and females. The study found that the proportion of patients with at least one antibiotic prescription in 2018 was around 39.1%, with different age-related trends between males and females. Consumption (as DID) of cephalosporines (65-74 years: 1.65; 75-84 years: 2.06; ≥85 years: 2.86) and quinolones (3.88, 4.61, 4.96, respectively) increased with growing age, while consumption of penicillins (6.21, 6.08, 6.04, respectively) and macrolides, lincosamides, and streptogramins (3.25, 2.91, 2.64, respectively) decreased. In 2018, antibiotics considered to have higher toxicity concerns or resistance potential, as reported by WHO-AWaRe tool, were consumed more intensively than those to be used as first choices, independent of age and sex. The probability of receiving an antibiotic prescription was greater in females, in subjects with polypharmacy, in treatment with respiratory drugs, anti-inflammatory agents or glucocorticoids, and with previous hospitalization; but increasing age was less associated with exposition to antibiotics.

The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation.

Activation of T cells relies on the availability of intracellular cholesterol for an effective response after stimulation. We investigated the contribution of cholesterol derived from extracellular uptake by the low-density lipoprotein (LDL) receptor in the immunometabolic response of T cells. By combining proteomics, gene expression profiling, and immunophenotyping, we described a unique role for cholesterol provided by the LDLR pathway in CD8+ T cell activation. mRNA and protein expression of LDLR was significantly increased in activated CD8+ compared to CD4+ WT T cells, and this resulted in a significant reduction of proliferation and cytokine production (IFNγ, Granzyme B, and Perforin) of CD8+ but not CD4+ T cells from Ldlr -/- mice after in vitro and in vivo stimulation. This effect was the consequence of altered cholesterol routing to the lysosome resulting in a lower mTORC1 activation. Similarly, CD8+ T cells from humans affected by familial hypercholesterolemia (FH) carrying a mutation on the LDLR gene showed reduced activation after an immune challenge.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

Evinacumab: a new option in the treatment of homozygous familial hypercholesterolemia.

INTRODUCTION: Familial hypercholesterolemia is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) since birth and an exceedingly high risk of premature cardiovascular disease, especially in the homozygous form (HoFH). Despite the availability of effective cholesterol-lowering drugs, substantial LDL-C and cardiovascular risk reductions in these patients are still problematic, especially in those carrying mutations in the low-density lipoprotein receptor (LDLR) gene. AREAS COVERED: Loss-of-function mutations in angiopoietin-like 3 (ANGPTL3) encoding gene are associated with lower levels of LDL-C and reduced cardiovascular risk; the pharmacological inhibition of ANGPTL3 reduces LDL-C levels independently of LDLR. This approach can thus improve the treatment of HoFH using a monoclonal antibody targeting ANGPTL3 (evinacumab). EXPERT OPINION: Most lipid-lowering agents available so far are insufficient to achieve an appropriate response in HoFH patients. The inhibition of ANGPTL3 with evinacumab halves LDL-C levels in HoFH patients by an LDLR-independent mechanism. The results obtained so far have clearly indicated a promising improvement in the management of these patients. As the reduction of CV risk is proportional to the absolute reduction in LDL-C levels, we can expect that treatment with evinacumab, added to the maximally tolerated lipid-lowering therapy, will turn into a significant clinical benefit.