AIMSFamilial 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 SYNTHESISOur 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.CONCLUSIONFH 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.

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 (P-t < 0.001), with the lowest value (similar to 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.

Background and aims: Inflammation due to the excess of nutrient intake plays an important role in the pathophysiology of metabolic syndrome (MetS). Here, the potential influence of neutrophils and their degranulation markers on MetS improvement upon dietary and behavioral counselling, has been investigated. Specifically, we aimed at investigating their role as potential predictors of metabolic syndrome improvements.Methods and Results: patients with MetS (n = 127) received behavioral and dietary recommendations before follow-up at 6 months. Serum levels of matrix metalloproteinases (MMP)8, MMP9, myeloperoxidase (MPO), tissue inhibitor of MMP (TIMP)-1, TIMP-2, TIMP-3 and resistin were tested at baseline. In the whole cohort, baseline levels of proinflammatory MMP8, MMP9 and MPO increased together with the number of MetS criteria. Seventy-three (57%) patients experienced a reduction in MetS-defining criteria at follow-up. With respect to those with no improvement, such individuals showed lower weight and waist circumference at enrolment, less frequent smoking habits, higher levels of triglycerides and lower circulating MMP8. At logistic regression analysis, baseline MMP8 showed negative predictive ability (odds ratio (OR) 0.979 [0.961-0.997]; p = 0.025) against MetS improvement. Such findings hold true even when included in the backward stepwise logistic regression model confirming MMP8 as an independent predictor (OR 0.970 [0.949-0.993]; p = 0.009). Receiver operating characteristic (ROC) curve confirmed the predictive ability of MMP8 combined in a model including baseline MetS criteria and waist circumference. Bootstrap resampling analysis internally validated our findings.Conclusion: Improvement of MetS is independently associated with baseline low MMP-8 levels, suggesting a pivotal role for inflammation in metabolic alteration.& COPY; 2022 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 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.

Background and Aims: Heterozygous familial hypercholesterolaemia (FH) in women is often diagnosed later and treated less aggressively compared to men. It is unknown whether these differences also apply to homozygous FH (HoFH), given its more severe clinical phenotype. Methods: Using data from the HoFH International Clinical Collaborators (HICC) cross-sectional registry we compared age at diagnosis, prevalence of cardiovascular risk factors, lipid-lowering treatment (LLT), and atherosclerotic cardiovascular (ASCVD) outcomes in women and men with HoFH. Results: We included 751 patients (52% women) from 38 countries. Median [Interquartile range] age at diagnosis was similar in women and men (13[6-26] and 11[5-27] yrs, p=0.85; respectively). More men than women had a smoking history (27% vs 14%, p<0.001), but there were no sex differences for other cardiovascular risk factors. There were no sex differences in the intensity and type of LLT prescribed. Prevalence of ASCVD was 44% at registry entry (table 1). Previous myocardial infarction (16% vs 8%, p<0.001) and PCI (16% vs 9%, p=0.005) were more common in men. No sex differences were observed for other ASCVD or ASCVD interventions. Additionally, age at occurrence of first cardiovascular event, including myocardial infarction, was comparable between the sexes (table 1). Conclusions: Patients with HoFH are at very high risk of premature ASCVD. Although more men had experienced a myocardial infarction, the age at first ASCVD-event and all-cause mortality did not differ by sex, highlighting the causal role of severe LDL-hypercholesterolaemia in the pathogenesis of premature ASCVD in HoFH. This possible loss of the usual female premenopausal cardiovascular protection requires further investigation.

Background and Aims: Hypertriglyceridemia (HTG) is a common form of dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. The severe forms are characterized by very high plasma levels of triglycerides (TG) (> 1000 mg/dL -11.2 mmol/l). Monogenic autosomal recessive forms are characterized by homozygous or compound heterozygous loss-of-function mutations of genes involved in the intravascular lipolysis of the triglyceride-rich lipoproteins, namely lipoprotein lipase (LPL), apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1), and glycerol-3-phosphate dehydrogenase 1 (GPD1). LMF1 has been shown to be essential for the maturation of both LPL and hepatic lipase (HL) to their fully functional forms. Methods: We performed Next Generation Sequencing (NGS) analysis on Ion GeneStudio S5 Plus to study the coding exons and intron/exon boundaries of genes affecting the main pathways of triglyceride synthesis and metabolism. Results: In the majority of subjects no functionally relevant mutations in the LPL, APOC2, APOA5, GPIHBP1 genes were detected. Four patients were found to be carriers of unknown missense variants in LMF1 gene: a) one compound heterozygous carrier for c.787C>T (p.His263Tyr) and c.1381C>T (p.Arg461Cys); b) one homozygous carrier for c.874 G>A (p.Gly292Arg). The other two were heterozygous carriers for c.1351 C/T (p.Arg451Trp) and c.428 C/T (p.Thr143Met) respectively. A functional analysis was carried out to assay LMF1 activity, protein expression and specific activity. Conclusions: The results showed that the Arg461Cys and Gly292Arg dramatically impair LMF1 function, the Arg451Trp does not have an impact, whereas His263Tyr and Thr143Met exhibit moderate effects.

Familial hypercholesterolaemia (FH) is an autosomal dominant dyslipidaemia, characterised by elevated LDL cholesterol (LDL-C) levels in the blood. Three main genes are involved in FH diagnosis: LDL receptor (LDLr), Apolipoprotein B (APOB) and Protein convertase subtilisin/kexin type 9 (PCSK9) with genetic mutations that led to reduced plasma LDL-C clearance. To date, several PCSK9 gain-of-function (GOF) variants causing FH have been described based on their increased ability to degrade LDLr. On the other hand, mutations that reduce the activity of PCSK9 on LDLr degradation have been described as loss-of-function (LOF) variants. It is therefore important to functionally characterise PCSK9 variants in order to support the genetic diagnosis of FH. The aim of this work is to functionally characterise the p.(Arg160Gln) PCSK9 variant found in a subject suspected to have FH. Different techniques have been combined to determine efficiency of the autocatalytic cleavage, protein expression, effect of the variant on LDLr activity and affinity of the PCSK9 variant for the LDLr. Expression and processing of the p.(Arg160Gln) variant had a result similar to that of WT PCSK9. The effect of p.(Arg160Gln) PCSK9 on LDLr activity is lower than WT PCSK9, with higher values of LDL internalisation (13%) and p.(Arg160Gln) PCSK9 affinity for the LDLr is lower than WT, EC50 8.6 ± 0.8 and 25.9 ± 0.7, respectively. The p.(Arg160Gln) PCSK9 variant is a LOF PCSK9 whose loss of activity is caused by a displacement of the PCSK9 P' helix, which reduces the stability of the LDLr-PCSK9 complex.

Background and Aims: Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic disorder characterized by severe LDL hypercholesterolaemia, stenotic aortic valve and root disease, and premature accelerated atherosclerotic cardiovascular disease (ASCVD). Premature cardiovascular death due to HoFH has been reported in children. Here we present a contemporary assessment of the clinical characteristics and life-courses of deceased HoFH patients. Methods: We analysed the data of all deceased patients in the HoFH International Clinical Collaborators (HICC) registry. The HICC registry includes 751 patients with HoFH who were alive in 2010 or later. Results: In total, 37 patients (49% women) were deceased at registry entry. The median [IQR] age of diagnosis was 12 [5-23] and 92% presented with xanthomas. Median [IQR] untreated LDL-cholesterol level was 15.6 [13.2-19.5] mmol/L and last known LDL-cholesterol level 9.4 [5.1-13.4] mmol/L. Most (28 (76%)) patients died of confirmed cardiovascular causes at a median [IQR] age of 32 [17-52] years (Figure 1). The majority (26 (70%)) had experienced (recurrent) ASCVD prior to death, with a median [IQR] age of onset of 28 [16-39] years. The most common diagnoses or interventions were aortic stenosis 15 (41%), myocardial infarction 11 (30%), angina pectoris 11 (30%), aortic valve replacement 8 (22%), CABG 8 (22%) and PCI 7 (19%). Conclusions: Approximately half of the deaths occurred before the third decade of life, mostly from cardiovascular causes. These data stress the potentially life-limiting nature of HoFH and need for early diagnosis and treatment.

Background and Aims: Aim. The treatment of HoFH is rapidly changing in recent times and how such changes may affect LDL-C control and cardiovascular prognosis in HoFH is almost completely unknown. Methods: Methods. Demographic, biochemical characteristics and clinical (including ASCVD and lipid lowering therapies, LLT) were collected from 139 HoFH included in the Italian LIPIGEN-FH registry. A systematic review of literature was performed to estimate the pooled prevalence of ASCVD in HoFH. Results: Results: The LIPIGEN-HoFH included 37 true-HoFH, 11 ARH, 63 CHE/DHE, and 28 clinical HoFH showing a mean untreated LDL-C of 490.7±149.3mg/dl. At last follow-up, the 77% of patients were using innovative therapies (PCSK9i, lomitapide and evinacumab), some in combinations between them and/or with conventional LLT. After 6 years, last visit LDL-C dropped to 124.1±70.8mg/dl with a % reduction from baseline of 58.4±26.9%. The 33.3% of HoFH patients were referring past ASCVD history at baseline and 21.8% experienced incident ASCVD during follow-up (P=NS). Overall, the lifetime prevalence of ASCVD was 41.3% with the mean age at first ASCVD event being 41.4±13.9years. The systematic review included 14 study for a total of 1922 HoFH patients showing a median untreated LDL-C of 579.8±45.7mg/dl. This cohort provided a crude lifetime ASCVD prevalence of 35.0% (95% IC 32.9-37.1) with the first event occurring at 29.1±8.5years. Conclusions: Conclusions: Although in the LIPIGEN cohort we observed a delay in the appearance of first ASCVD event, the cardiovascular risk in HoFH remains very high. These findings underline that a further improvement is necessary in the clinical management of HoFH patients.

Background and Aim: High lipoprotein(a) [Lp(a)] is a well-established cardiovascular (CV) risk factor, but the effect of mildly elevated Lp(a) on CV health is largely unknown. Our aim was to evaluate if Lp(a) is associated with the severity of carotid atherosclerosis (CA) in the specific subset of metabolic syndrome (MetS). Patients and Methods: Subjects with diagnosed MetS and ultrasound-assessed CA were enrolled. Those patients were categorized according to the severity of CA (moderate vs. severe), and the circulating levels of Lp(a) alongside with clinical, anthropometric, and biochemical data were collected. Results: Sixty-five patients were finally included: twenty-five with moderate and forty with severe CA (all with asymptomatic disease). Intergroup comparison showed Lp(a) as the only significantly different variable [6 (2–12) mg/dl vs. 11.5 (6–29.5) mg/dl; p = 0.018]. Circulating levels of Lp(a) were also confirmed as the only variable independently associated with severity of CA at logistic regression analysis [OR 2.9 (95% CI 1.1–7.8); p = 0.040]. ROC curve analysis for Lp(a) confirmed a serum level of 10 mg/dl as the best cut-off value [AUC 0.675 (95% CI 0.548–0.786)]. Although sensitivity and specificity were suboptimal (69.0 and 70.4%, respectively)—likely due to the small sample size—this result is in line with those previously reported in the literature. Conclusion: Lp(a) is independently associated with severity of CA in the subgroup of MetS patients.

[This corrects the article DOI: 10.3389/fgene.2022.912510.].

Background and Aims : Familial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism causing elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. FH is typically caused by deleterious variants of LDLR, APOB or PCSK9 genes and its prevalence is of about 1:300 in the general population. Aim of this study was the genetic characterization of suspected FH patients.Methods: From 2014 to 2019 we collected 186 subjects with suspected FH (122 index cases and 64 relatives, aged ³18 years) who were clinically examined at the Lipid Clinic and tested by Next Generation Sequencing for genes associated with FH (LDLR, APOB, PCSK9, APOE, LDLRAP1, ABCG5, ABCG8, LIPA, CYP27A1, MYLIP).Results: Overall, 107 subjects (54 index patients/53 relatives) resulted to be heterozygous carriers of pathogenic variants of LDLR (103, 96.3%), APOB (3, 2.8%), or PCSK9 (1, 0.9%) genes. Five (likely)pathogenic variants of LDLR were not reported previously. Three of these caused frameshift with the occurrence of a premature termination codon (Gln33Profs*17, Cys243Trpfs*12, Val365Argfs*20). The other two were missense variants (Pro608His, Ala684Asp), involving highly conserved amino acids, which were found to be deleterious by "in silico" analysis (REVEL score 0.962 and 0.817, respectively).Conclusions: Clinical and genetic identification of FH patients represents a challenging task in clinical practice. In the present study we report 5 novel LDLR variants. Three of them can be regarded as deleterious due to the formation of a truncated protein. Clinical phenotypes and "in silico" analysis suggested that novel missense mutations can also be considered pathogenic. Background and Aims : Familial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism causing elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. FH is typically caused by deleterious variants of LDLR, APOB or PCSK9 genes and its prevalence is of about 1:300 in the general population. Aim of this study was the genetic characterization of suspected FH patients. Methods: From 2014 to 2019 we collected 186 subjects with suspected FH (122 index cases and 64 relatives, aged ³18 years) who were clinically examined at the Lipid Clinic and tested by Next Generation Sequencing for genes associated with FH (LDLR, APOB, PCSK9, APOE, LDLRAP1, ABCG5, ABCG8, LIPA, CYP27A1, MYLIP). Results: Overall, 107 subjects (54 index patients/53 relatives) resulted to be heterozygous carriers of pathogenic variants of LDLR (103, 96.3%), APOB (3, 2.8%), or PCSK9 (1, 0.9%) genes. Five (likely)pathogenic variants of LDLR were not reported previously. Three of these caused frameshift with the occurrence of a premature termination codon (Gln33Profs*17, Cys243Trpfs*12, Val365Argfs*20). The other two were missense variants (Pro608His, Ala684Asp), involving highly conserved amino acids, which were found to be deleterious by "in silico" analysis (REVEL score 0.962 and 0.817, respectively). Conclusions: Clinical and genetic identification of FH patients represents a challenging task in clinical practice. In the present study we report 5 novel LDLR variants. Three of them can be regarded as deleterious due to the formation of a truncated protein. Clinical phenotypes and "in silico" analysis suggested that novel missense mutations can also be considered pathogenic.

BACKGROUND:Loss of function variants of LIPG gene encoding endothelial lipase (EL) are associated with primary hyperalphalipoproteinemia (HALP), a lipid disorder characterized by elevated plasma levels of high density lipoprotein cholesterol (HDL-C). OBJECTIVE:Aim of the study was the phenotypic and genotypic characterization of a family with primary HALP. METHODS:HDL subclasses distribution was determined by polyacrylamide gradient gel electrophoresis. Serum content of preβ-HDL was assessed by (2D)-electrophoresis. Cholesterol efflux capacity (CEC) of serum mediated by ABCA1, ABCG1 or SR-BI was assessed using cells expressing these proteins. Cholesterol loading capacity (CLC) of serum was assayed using cultured human macrophages. Next generation sequencing was used for DNA analysis. Plasma EL mass was determined by ELISA. RESULTS:Three family members had elevated plasma HDL-C, apoA-I and total phospholipids, as well as a reduced content of preβ-HDL. These subjects were heterozygous carriers of a novel variant of LIPG gene [c.526 G>T, p.(Gly176Trp)] found to be deleterious in silico. Plasma EL mass in carriers was lower than in controls. CEC of sera mediated by ABCA1 and ABCG1 transporters was substantially reduced in the carriers. This effect was maintained after correction for serum HDL concentration. The sera of carriers were found to have a higher CLC in cultured human macrophages than control sera. CONCLUSION:The novel p.(Gly176Trp) variant of endothelial lipase is associated with changes in HDL composition and subclass distribution as well as with functional changes affecting cholesterol efflux capacity of serum which suggest a defect in the early steps of revere cholesterol transport.

Background Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. Methods The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Findings Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12.0 years (IQR 5.5-27.0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 ( 64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14.7 mmol/L (IQR 11.6-18.4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3.93 mmol/ L, IQR 2.6-5.8) versus non-highincome countries (9.3 mmol/ L, 6.7-12.7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high- income 21% vs non-high- income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24.5 years (IQR 17.0-34.5) versus 37.0 years (29.0-49.0) in high-income countries (adjusted hazard ratio 1.64, 95% CI 1.13-2.38). Interpretation Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved.

Background and aimsFamilial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism that causes elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Despite the availability of effective treatments, FH remains underdiagnosed and undertreated. The aims of the study were to identify putative FH subjects using data from laboratory and cardiology databases, genetically characterize suspected FH patients referred to the Lipid Clinic and monitor attainment of treatment goals in identified patients.Methods and resultsWe retrieved the electronic health records of 221,644 individuals referred to laboratory for routine assessment and of 583 ASCVD patients (age ≤65) who underwent percutaneous transluminal coronary angioplasty (PTCA). We monitored the lipid profiles of subjects with LDL-C ≥ 250 mg/dl identified by laboratory survey (LS-P), PTCA patients and patients from the Lipid Clinic (LC-P). The laboratory survey identified 1.46% of subjects with LDL-C ≥ 190 mg/dl and 0.08% with LDL-C ≥ 250 mg/dl. Probable/definite FH was suspected in 3% of PTCA patients. Molecularly-confirmed FH was found in 44% of LC-P subjects. Five new LDLR mutations were identified. The 50% LDL-C reduction target was achieved by 70.6% of LC-P patients. Only 18.5% of PTCA patients reached the LDL-C < 55 mg/dl target.ConclusionBy using a combined approach based on laboratory lipid profiles, documented ASCVD and Lipid Clinic data, we were able to identify subjects with a high probability of being FH. Attainment of LDL-C goals was largely suboptimal. Efforts are needed to improve FH detection and achievement of lipid targets.

Background and aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH. Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) years, with a median treatment duration of 31.0 (IQR 14.0–40.5) months. At baseline, four (44.4%) patients had hypertension, one (11.1%) had diabetes mellitus, two (22.2%) were active smokers, and five (55.5%) reported ASCVD. The baseline LDL-C was 257.0 (IQR, 165.3–309.2) mg/dL. All patients were on statins plus ezetimibe, three were receiving Lipoprotein apheresis (LA), and one was also receiving proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). The addition of lomitapide (mean dose, 10 mg) resulted in the achievement of a median on-treatment LDL-C of 101.7 mg/dL (IQR, 71.3–138.3; 60.4% reduction from baseline), with a best LDL-C value of 68.0 mg/dL (IQR, 43.7–86.7; 73.5% reduction from baseline). During follow-up, one patient stopped both PCSK9i and LA. Recurrence of ASCVD events was reported in one patient. The median on-treatment aspartate transaminase and alanine transaminase values were 31.1 (IQR, 22.6–48.3) U/L and 31.1 (IQR, 27.2–53.8) U/L, respectively. Among six ARH patients with available fibroscan examination, liver stiffness values recorded at the last visit were within the normal range (median, 4.7 KPa; IQR, 3.6–5.3 KPa). Conclusion: Lomitapide is effective and safe in ARH therapy as well as in classical HoFH.

Background and Aims : In the last decade, the implementation of familial hypercholesterolemia (FH) pathology registries allowed to investigate specific sub-groups as FH subjects <18 years. Here, we report recent advances from the Italian LIPIGEN Paediatric Group, with a focus on the genotype-phenotype relation.Methods: From the LIPIGEN study, we identified 1602 clinically and/or genetically confirmed FH-subjects under 18 years, followed up by 31 Italian LIPIGEN sites, with at least one pre-treatment LDL-C measurement and data about genetic testing.Results: Almost the whole cohort underwent genetic testing. Genetically-confirmed subjects (about 70% of tested individuals) presented higher LDL-C level (mean±SD) compared to subjects with variants of uncertain significance (N=125) or negative diagnosis (N=317) (246.5±102.1 vs 166.4±56.5 vs 159.9±47.7mg/dL; p<0.0001). Among subjects with a genetically-positive diagnosis of FH, 1013 individuals presented one causative mutation (untreated LDL-C =231.6±53.5 mg/dL) in LDLR (N=998) or APOB (N=15) genes, while in 40 subjects two causative mutations “in trans” were detected (untreated LDL-C=623.9±234.7 mg/dL). In heterozygous FH for LDLR, more than 200 different causative variants were detected (three the most frequent: p.Gly549Asp (LDL-C=245.0±50.6 mg/dL), p.Gly592Glu (LDL-C=198.7±50.1 mg/dL), and p.Asp221Gly (LDL-C=212.2±41.2 mg/dL)) and a great variability in the LDL-C values was observed even within the same mutation. Stratifying LDLR mutations by receptor residual activity, a more severe phenotype was confirmed in children/adolescents HeFH with a null-receptor compared to defective-receptor mutation (245.1±52.0 vs 220.2±51.9 mg/dL; p<0.0001).Conclusions: The LIPIGEN paediatric database allow for a better clinical and genetic characterization of FH children/adolescents, providing the basis for further longitudinal investigations. Background and Aims : In the last decade, the implementation of familial hypercholesterolemia (FH) pathology registries allowed to investigate specific sub-groups as FH subjects <18 years. Here, we report recent advances from the Italian LIPIGEN Paediatric Group, with a focus on the genotype-phenotype relation. Methods: From the LIPIGEN study, we identified 1602 clinically and/or genetically confirmed FH-subjects under 18 years, followed up by 31 Italian LIPIGEN sites, with at least one pre-treatment LDL-C measurement and data about genetic testing. Results: Almost the whole cohort underwent genetic testing. Genetically-confirmed subjects (about 70% of tested individuals) presented higher LDL-C level (mean±SD) compared to subjects with variants of uncertain significance (N=125) or negative diagnosis (N=317) (246.5±102.1 vs 166.4±56.5 vs 159.9±47.7mg/dL; p<0.0001). Among subjects with a genetically-positive diagnosis of FH, 1013 individuals presented one causative mutation (untreated LDL-C =231.6±53.5 mg/dL) in LDLR (N=998) or APOB (N=15) genes, while in 40 subjects two causative mutations “in trans” were detected (untreated LDL-C=623.9±234.7 mg/dL). In heterozygous FH for LDLR, more than 200 different causative variants were detected (three the most frequent: p.Gly549Asp (LDL-C=245.0±50.6 mg/dL), p.Gly592Glu (LDL-C=198.7±50.1 mg/dL), and p.Asp221Gly (LDL-C=212.2±41.2 mg/dL)) and a great variability in the LDL-C values was observed even within the same mutation. Stratifying LDLR mutations by receptor residual activity, a more severe phenotype was confirmed in children/adolescents HeFH with a null-receptor compared to defective-receptor mutation (245.1±52.0 vs 220.2±51.9 mg/dL; p<0.0001). Conclusions: The LIPIGEN paediatric database allow for a better clinical and genetic characterization of FH children/adolescents, providing the basis for further longitudinal investigations.

Background and Aims: In 2019, ESC/EAS released new guideline for the management of dyslipidemias further reducing LDL-C targets. New targets appear to be particularly challenging in clinical practice. We evaluated lipid goal attainment in a cohort of high and very-high risk patients.