Search

Aims Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH. Methods A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) ＞190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C ＞225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/pathogenic variant (PV) carriers and predictors of PVs were identified. Results Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease. Conclusions Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.

Aim Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. Method In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. Results The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. Conclusion FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

Primary dyslipidemias are inherited disorders in plasma lipoprotein metabolism that lead to serious cardiovascular and other complications. The Japanese Ministry of Health, Labor and Welfare (MHLW) covers medical expenses, under the Research Program on Rare and Intractable Diseases, for homozygous familial hypercholesterolemia (FH), familial chylomicronemia, sitosterolemia, cerebrotendinous xanthomatosis, lecithin:cholesterol acyltransferase deficiency, Tangier disease, and abetalipoproteinemia. Apolipoprotein A1 deficiency, heterozygous FH, and type III hyperlipoproteinemia are covered by the MHLW Pediatric Chronic Disease Program. Heterozygous FH and type III hyperlipoproteinemia are also important for their relatively common prevalence and, accordingly, high impact on Japanese public health by significant contribution to the overall prevalence of cardiovascular diseases. Therefore, a systemic survey of these diseases is mandatory to estimate their actual situation, such as prevalence, clinical manifestations, and prognoses among the Japanese population. The impact of these rare and intractable diseases on cardiovascular and other complications will likely be higher among Japanese people than other ethnicities because the general Japanese population has many cardioprotective aspects. The current study intends to conduct a multicenter registry of these diseases to assess their demographics and clinical features comprehensively. Methods and Analysis: The Prospective Registry Study of Primary Dyslipidemia is a registry-based prospective, observational, multicenter cohort study in Japan, enrolling patients who fulfill the Japanese clinical criteria of the primary dyslipidemias listed above, from 26 participating institutes from August 2015 to March 2023. A total of 1,000 patients will be enrolled in the study and followed for 10 years. Clinical parameters are collected, including physical and laboratory findings, genetic analysis, drugs, lifestyle management, and clinical events, especially cardiovascular events. The primary endpoint of this study is the new onset of cardiovascular disease and acute pancreatitis, and the secondary endpoint is death from any causes. Ethics and Dissemination: This study complies with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. The institutional review boards have approved this study protocol at all participating institutes. The final results are to be published at appropriate international conferences and in peer-reviewed journals.

A 17-year-old boy with acute coronary syndrome was admitted to our hospital. He had xanthomas over his elbow and Achilles tendon and a high level of low-density lipoprotein cholesterol; therefore, his initial diagnosis was familial hypercholesterolemia. However, a genetic analysis revealed a compound heterozygous mutation in the ABCG5 gene with a high serum level of sitosterol, leading to the diagnosis of sitosterolemia. After lipid-lowering treatment, percutaneous coronary intervention was performed. Furthermore, a persistently high C-reactive protein level and images of large arteries led to a diagnosis of Takayasu arteritis. To our knowledge, this is the first case of sitosterolemia complicated by Takayasu arteritis.

Background Heterozygous familial hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce. Methods In the VRONI study, children aged 5–14 years in Bavaria are invited to participate in an FH screening program during regular pediatric visits. The screening is based on low-density lipoprotein cholesterol measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first-degree relatives, reverse cascade screening is recommended to identify and treat affected family members. Results Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data safety, legal and organizational aspects, which will be outlined in this article. Recruitment started in early 2021, within the first months, more than 380 pediatricians screened over 5200 children. Approximately 50 000 children are expected to be enrolled in the VRONI study until 2024. Conclusions VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nationwide FH screening infrastructure. Furthermore, we aim to validate genetic variants of unclear significance, detect novel causative mutations and contribute to polygenic risk indices (DRKS00022140; August 2020).

A 56-year-old postmenopausal woman with out-of-hospital cardiac arrest caused by acute myocardial infraction was successfully resuscitated by intensive treatments and recovered without any neurological disability. She was diagnosed as having familial hypercholesterolemia (FH) based on a markedly elevated low-density lipoprotein cholesterol (LDL-C) level and family history of premature coronary artery disease. Genetic testing in her family members showed that a variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (c.2004C＞A, p.S668R), which had been previously reported as having uncertain significance, was associated with FH, indicating that the variant is a potential candidate for the FH phenotype. Next-generation sequencing analysis for the proband also showed that there was a heterozygous mutation of the ATP-binding cassette sub-family G member 5 (ABCG5) gene (c.1166G＞A, R389H), which has been reported to increase LDL-C level and the risk of cardiovascular disease. She was also diagnosed as having type 1 CD36 deficiency based on a lack of myocardial uptake of 123 I-labeled 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid in scintigraphy and the absence of CD36 antigen in both monocytes and platelets in flow cytometry. She had a homozygous mutation of the CD36 gene (c.1126-5_1127delTTTAGAT), which occurs in a canonical splice site (acceptor) and is predicted to disrupt or distort the normal gene product. To our knowledge, this is the first report of a heterozygous FH phenotype caused by possibly oligogenic variants of the PCSK9 and ABCG5 genes complicated with type I CD36 deficiency caused by a novel homozygous mutation. Both FH phenotype and CD36 deficiency might have caused extensive atherosclerosis, leading to acute myocardial infarction in the present case.

Background and Aims Familial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. Methods and Results We evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54±13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygotes (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p=1.00) and T36w (p=0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p=0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. Conclusions After 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations. Registration number for clinical trials: NCT04313270 extension.

BACKGROUND Thickening of Achilles tendon (≥9 mm on radiography) is one of the diagnostic criteria for familial hypercholesterolemia (FH). Since FH is associated with premature coronary artery disease (CAD) including acute coronary syndrome (ACS), measurement of Achilles tendon thickness (ATT) is important for early diagnosis of FH. However, clinical significance of mild thickening of Achilles tendon in non-FH patients with CAD is unclear. The present study investigated the association of ATT with coronary lesion severity in early-onset ACS without clinically diagnosed FH. METHODS From outpatients who had a history of ACS under 60 years old, 76 clinically non-FH subjects (71 men and 5 women; mean age at the onset of ACS, 50.5 years) with maximum ATT of

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

Sitosterolemia is a rare form of dyslipidemia that has diverse clinical manifestations, and insufficient knowledge of the disease frequently leads to a delay in diagnosis. We report a case of sitosterolemia in a 26-year-old Chinese woman, characterized by anemia, thrombocytopenia, persistent hypercholesterolemia, premature atherosclerosis, extensive xanthoma, and arthralgia-tenosynovitis. Successive misdiagnoses of Evans syndrome and familial hypercholesterolemia had been made, and the patient had responded minimally to steroid therapy, splenectomy, and statin treatment; therefore, she was referred to our hospital. On admission, a peripheral blood smear revealed the presence of abnormally shaped erythrocytes and giant platelets. Multiple atherosclerotic lesions, sites of tenosynovitis, and carotid sheath xanthomas were identified on ultrasonography. Compound heterozygous mutations of the ABCG5 gene, including a hot variant (c.1,336, exon10 C>T, p.(R446*)) and a novel variant (c.1,325-3(IVS9)_c.1325-2(IVS9)delCA) were separately identified in her parents by pedigree analysis. Plant sterols analysis by high performance liquid chromatography method revealed remarkably elevated plasma plant sterol concentrations after drug withdrawal but reduced rapidly after restarting ezetimibe during follow-up period. After 21 months of treatment with ezetimibe and a low-plant sterol diet, her hematologic abnormalities, tenosynovitis, and hypercholesterolemia had significantly improved; and ultrasonography showed that her skin and carotid sheath xanthomas had resolved or shrunk. This case demonstrates that morphological changes in blood cells on a peripheral blood smear, ultrasonographic findings and ABCG5/ABCG8 gene screening are valuable, and plant sterol analysis in serum is crucial to confirm diagnosis and assess treatment adequacy for sitosterolemia.

Achilles tendon xanthoma (ATX) is one of the typical features of familial hypercholesterolemia (FH). The morphological evaluation of ATX by X-ray radiography is widely recognized; however, the utility of other imaging modalities remains unclear. We herein report two cases of FH in which Doppler ultrasound imaging demonstrated a microvascular flow in ATX that only rarely could be observed in normal Achilles tendons. Neoangiogenesis accompanies chronic inflammation and it may play an important role in the deposition of cholesterol crystals leading to ATX. In addition to the morphological evaluation of ATX, the assessment of neoangiogenesis may therefore be essential for the evaluation of ATX.

International audience; ObjectivesThis study aimed at investigating the additional contribution of coronary artery calcium (CAC) score to SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) risk equation (SAFEHEART-RE) for cardiovascular risk prediction in heterozygous familial hypercholesterolemia (HeFH).BackgroundCommon cardiovascular risk equations are imprecise for HeFH. Because of the high phenotype variability of HeFH, CAC score could help to better stratify the risk of atherosclerotic cardiovascular disease (ASCVD).MethodsREFERCHOL (French Registry of Familial Hypercholesterolemia) and SAFEHEART are 2 ongoing national registries on HeFH. We analyzed data from primary prevention HeFH patients undergoing CAC quantification. We used probability-weighted Cox proportional hazards models to estimate HRs. Area under the receiver-operating characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare the incremental contribution of CAC score when added to the SAFEHEART-RE for ASCVD prediction. ASCVD was defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death, and cardiovascular death.ResultsWe included 1,624 patients (mean age: 48.5 ± 12.8 years; men: 45.7%) from both registries. After a median follow-up of 2.7 years (interquartile range: 0.4-5.0 years), ASCVD occurred in 81 subjects. The presence of a CAC score of >100 was associated with an HR of 32.05 (95% CI: 10.08-101.94) of developing ASCVD as compared to a CAC score of 0. Receiving-operating curve analysis showed a good performance of CAC score alone in ASCVD prediction (AUC: 0.860 [95% CI: 0.853-0.869]). The addition of log(CAC + 1) to SAFEHEART-RE resulted in a significantly improved prediction of ASCVD (AUC: 0.884 [95% CI: 0.871-0.894] for SAFEHEART-RE + log(CAC + 1) vs AUC: 0.793 [95% CI: 0.779-0.818] for SAFEHEART-RE; P < 0.001). These results were confirmed also when considering only hard cardiovascular endpoints. The addition of CAC score was associated with an estimated overall net reclassification improvement of 45.4%.ConclusionsCAC score proved its use in improving cardiovascular risk stratification and ASCVD prediction in statin-treated HeFH.

The aim – clinical, laboratory and genetic parallels of patients with hetero- and homozygous familial hypercholesterolemia (FH) in Ukraine.Materials and methods. 231 FH patients were included in the Ukrainian FH Registry: 8 children (under 18 years of age) and 223 adult patients (197 heterozygous FH (HeFH) patients, 26 homozygous FH (HoFH) patients, verified according to DLCN criteria). The patients underwent general clinical, laboratory, instrumental examinations and genetic testing.Results and discussion. Among HeFH patients against the background of early manifestation of atherosclerosis, the male patients were more likely to have coronary heart disease and peripheral atherosclerosis, xanthomatosis and higher DLCN scores against an increase in % obesity and hypertension among HeFH women on the background of significantly lower DLCN. In the HoFH patients despite the inclusion of mostly reproductive aged females in the Registry, it is among women the most severe variants of FH were registered. They were characterized by a predominance of coronary heart disease, MI, xanthomatosis, the need for myocardial revascularization and prosthetic heart valves on the background of higher DLCN scores, cholesterol, LDL-C and ApoB values ​​up to 1.7±0.2 g/L and Lp (a) up to 119.5±31.4 nmol/L. In HoF patients and the most severe variants of the clinical course, who had levels of «statin naive» cholesterol and LDL above 20 mmol/L a more significant increase in these values were found: ApoB average 3.2±1.1 (maximum – 4.72) g/L and Lp (a) to 121.5±41.5 (maximum – 163) nmol/L and reduction of apoA1 level to 0.9±0.1 g/L.Conclusions. HeFH patients retain gender features of the risk factors profile, which corresponds to the main gender-related trends revealed by the Ukrainian population study with a predominance of coronary heart disease, peripheral atherosclerosis and xanthomatosis on the background of higher scores on DLCN in men. HoFH patients showed a reverse trend, namely among women – the predominance of coronary heart disease, myocardial infarction, xanthomatosis and the need for revascularization on the background of a higher score on DLCN. The cohort of HoFH women revealed the most severe FH cases with LDL-C > 20 mmol/L, which was accompanied in 100 % of cases by early development of coronary heart disease and the need for myocardial revascularization, despite young age (36.5±3.9) and preserved reproductive function. According to HoFH patients genetic testing, pathogenetic mutations were detected in 72.3 % of women and 55.5 % of men (92.3 % in LDLR and 7.7 % in apoB). In the cohort of the most severe patients with LDL and LDL cholesterol > 20 mmol/L, genetic mutations were detected in 100 %

Pediatric dyslipidemia affects approximately 20% of children ages 6 to 19 years. This disease is impacted by and contributes to many factors, including obesity, metabolic syndrome, diabetes, and hypothyroidism. Obesity doubles the risk of dyslipidemia, but 26% to 63% of normal-weight children have lipid abnormalities. Dyslipidemia contributes to pediatric onset of atherosclerotic changes, and early adult cardiovascular complications. Sedentary lifestyle and poor food choices are the primary causes, but familial hypercholesterolemia affects 1 in 200 to 500 individuals. Evidence-based guidelines and screening recommendations are inconsistent among disciplines, there is poor compliance with utilization, and treatment options lack long-term outcome data.

Detecting familial hypercholesterolemia (FH) early and “normalizing” low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular disease prevention in FH. Combining lipid-lowering therapies targeting synergistic/complementary metabolic pathways makes this feasible, even among severe phenotypes. For LDL receptor-dependent treatments, PCSK9 remains the main target for adjunctive therapy to statins and ezetimibe through a variety of approaches. These include protein inhibition (adnectins), inhibition of translation at mRNA level (antisense oligonucleotides or small interfering RNA), and creation of loss-of-function mutations through base-pair editing. For patients with little LDL receptor function, LDL receptor-independent treatment targeting ANGPTL3 through monoclonal therapies are now available, or in the future, antisense/small interfering RNA-based approaches offer alternative approaches. Finally, first-in-human studies are ongoing, testing adenovirus-mediated gene therapy transducing healthy LDLR DNA in patients with HoFH. Further development of the CRISPR cas technology, which has shown promising results in vivo on introducing PCSK9 loss-of-function mutations, will move a single-dose, curative treatment for FH closer.

Visual Abstract, Highlights • A machine-learning model has been developed to improve accuracy on predicting the activity of missense LDLr mutations. • ClinVar was used as database, and the model function was defined by using specific characteristics of the LDLr. • A high-score prediction ML model with specificity of 92.5% and sensitivity of 91.6% has been developed to predict pathogenicity of LDLr variants. • Implementation of high-predicting capacity software constitutes a valuable approach for assessing pathogenicity of LDLr variants to help in the early diagnosis and management of FH disease. • An open-access predictive software (MLb-LDLr) is provided to the scientific community., Summary Untreated familial hypercholesterolemia (FH) leads to atherosclerosis and early cardiovascular disease. Mutations in the low-density lipoprotein receptor (LDLr) gene constitute the major cause of FH, and the high number of mutations already described in the LDLr makes necessary cascade screening or in vitro functional characterization to provide a definitive diagnosis. Implementation of high-predicting capacity software constitutes a valuable approach for assessing pathogenicity of LDLr variants to help in the early diagnosis and management of FH disease. This work provides a reliable machine learning model to accurately predict the pathogenicity of LDLr missense variants with specificity of 92.5% and sensitivity of 91.6%.

Familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), and elevated lipoprotein (a) (Lp[a]) increase risk of premature coronary artery disease (CAD). The objective of this study was to assess the prevalence of FH, FCHL, elevated Lp(a) and their impact on management in patients with premature CAD.We prospectively recruited men ≤ 50 years and women ≤ 55 with obstructive CAD. FH was defined as Dutch Lipid Clinic Network scores ≥ 6. FCHL was defined as apolipoprotein B1.2 g/L, triglyceride and total cholesterol90th population percentile, and family history of premature cardiovascular disease. Lp(a) ≥ 50 mg/dL was considered to be elevated.Among 263 participants, 9.1% met criteria for FH, 12.5% for FCHL, and 19.4% had elevated Lp(a). Among patients with FH, 37.5% had FH-causing DNA variants. Patients with FH, but not other dyslipidemias, were more likely than nondyslipidemic patients to have received lipid-lowering therapy before presenting with CAD (33.3% vs 12.3%, P = 0.04) and combined lipid-lowering therapy after the presentation (41.7% vs 7.7%, P0.001). One year after presentation, 58.3%, 54.5%, and 58.8% of patients with FH, FCHL, and elevated Lp(a) had low-density lipoprotein cholesterol (LDL-C)1.8 mmol/L, respectively, compared with 68.0 % in reference group. Patients with FCHL were more likely to have non-high-density lipoprotein (HDL) and apolipoprotein B above recommended lipid goals (70.0% and 87.9%, respectively).FH, FCHL, and elevated Lp(a) are common in patients with premature CAD and have differing impact on treatment and achievement of lipid targets. Assessment for these conditions in patients with premature CAD provides valuable information for individualized management.

Background Recent studies suggest that cumulative exposure to low-density lipoprotein-cholesterol (LDL-C) leads to the development of atherosclerotic cardiovascular disease (ASCVD). However, few studies have investigated whether this link extends to individuals with familial hypercholesterolemia (FH), a relevant patient population.Methods and Results:We retrospectively investigated the health records of 1,050 patients with clinical FH diagnosis between April 1990 and March 2019. We used Cox proportional hazards models adjusted for established ASCVD risk factors to assess the association between cholesterol-year-score and major adverse cardiovascular events (MACEs), including death from any cause or hospitalization due to ASCVD events. Cholesterol-year-score was calculated as LDL-C max × [age at diagnosis/statin initiation] + LDL-C at inclusion × [age at inclusion - age at diagnosis/statin initiation]. The median follow-up period for MACE evaluation was 12.3 (interquartile range, 9.1-17.5) years, and 177 patients experienced MACEs during the observation period. Cholesterol-year-score was significantly associated with MACEs (hazard ratio, 1.35; 95% confidence interval, 1.07-1.53; P=0.0034, per 1,000 mg-year/dL), independent of other traditional risk factors including age and LDL-C, based on cross-sectional assessment. Cholesterol-year-score improved the discrimination ability of other traditional risk factors for ASCVD events (C-index, 0.901 vs. 0.889; P=0.00473). Conclusions Cumulative LDL-C exposure was strongly associated with MACEs in Japanese patients with FH, warranting early diagnosis and treatment initiation in these patients.

Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents—especially antisense RNA and monoclonal antibodies—targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.

Patient-reported outcomes (PROs) and PRO measures (PROMs) are often used to help clinicians and researchers understand patients' personal concerns, feelings, experiences, and perspectives following the implementation of an intervention. Notably, PROs and PROMs can inform health systems, health policy, and payers on the utility of clinical genetic testing based on each patient's personal values, perspectives, and potential health behaviors subsequent to testing. In this topic synopsis, we discuss the underexplored role of and implications for PROs and PROMs following genetic testing for familial hypercholesterolemia (FH), an autosomal dominant genetic disorder of cholesterol metabolism that can lead to highly premature fatal and nonfatal myocardial infarction and stroke. We also discuss why the use and consideration of patient perspectives, via PROs and PROMs, are critical to the process of optimizing patient care across various FH treatment contexts. As expert clinician groups consider the latest evidence when establishing recommendations for FH genetic testing, there is a ripe opportunity for clinicians and researchers to explore the value and utility of PROs to inform and possibly improve care for patients diagnosed with FH.

Purpose of review Antisense oligomers (ASOs) have been available for decades: however, only recently have these molecules been applied clinically. This review aims to discuss the possible development of antisense-mediated splice correction therapies as precision medicines for familial hypercholesterolemic patients carrying mutations that compromise normal splicing of the low-density lipoprotein receptor (LDLR) gene transcript. Recent findings Three antisense drugs are currently being assessed in ongoing clinical trials for dyslipidemias, aiming to lower the plasma concentrations of lipoproteins that lead to end-organ damage, principally coronary artery disease. Although a handful of drugs may be applicable to many patients with familial hypercholesterolemia (FH), mutation-specific personalised antisense drugs may be even more effective in selected patients. Currently, there is no therapy that effectively addresses mutations in the LDLR, the major cause of FH. Many mutations in the LDLR that disrupt normal pre-mRNA processing could be applicable to splice correction therapy to restore receptor activity. Summary Precision medicine could provide long-term economic and social benefits if they can be implemented effectively and sustainably. Many mutations found in the LDLR gene could be amendable to therapeutic splice correction and we should consider developing a therapeutic ASO platform for these mutations.

Purpose of review To highlight quandaries and review options for the management of familial hypercholesterolemia (FH) during pregnancy. Recent findings Women with FH face barriers to effective care and consequently face significant disease related long term morbidity and mortality.Pregnancy includes major maternal physiological changes resulting in exacerbation of maternal hypercholesterolemia compounded by the current practice of cessation or reduction in the dose of lipid-lowering therapy during pregnancy and lactation that may impact short and long term cardiac morbidity and mortality. Although lipoprotein apheresis is the treatment of choice for high- risk FH patients, reassuring safety evidence for the use of statins during pregnancy is mounting rapidly. However, it will be some time before subtle effects on the development of the offspring can be definitively excluded. Women with homozygous FH or with an established atherosclerotic vessel or aortic disease should be offered therapy with statins during pregnancy if lipoprotein apheresis is not readily available. Pregnancy outcomes tend to be favourable in women with FH. We have reviewed the currently available evidence regarding the risks and benefits of treatment options for FH during pregnancy.

Background and aims: Women with heterozygous familial hypercholesterolemia (FH) are recommended to initiate statin treatment at the same age as men (from 8 to 10 years of age). However, statins are contraindicated when pregnancy is planned, during pregnancy and breastfeeding. The aim of the study was to determine the duration of pregnancy-related off-statin periods and breastfeeding in FH women. Methods: A cross-sectional study using an anonymous online self-administered questionnaire was conducted. Women with FH were recruited through Lipid Clinics in Norway and Netherlands and national FH patient organizations. Results: 102 women with FH (n = 70 Norwegian and n = 32 Dutch) were included in the analysis. Total length of pregnancy-related off-statin periods was estimated for 80 women where data were available, and was median (min-max) 2.3 (0–14.2) years. Lost statin treatment time was estimated for 67 women where data were available, and was median (min-max) 18 (0–100)% at mean (SD) age of 31 (4.3) years at last pregnancy. More women breastfed in Norway (83%) and for longer time [8.5 [1-42] months] compared to the Netherlands [63%, p = 0.03; 3.6 (0–14) months, p < 0.001]. Eighty-six percent of the women reported need for more information on pregnancy and breastfeeding in relation to FH. Conclusions: Young FH women lose years of treatment when discontinuing statins in relation to pregnancy and breastfeeding periods and should be closely followed up to minimize the duration of these off-statin periods. Whether these periods of interrupted treatment increase the cardiovascular risk in FH women needs to be further elucidated.

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

Familial hypercholesterolemia (FH) is a genetic disease associated with an important risk of premature and recurrent atherosclerotic cardiovascular disease (ASCVD). Red blood cell (RBC) parameters such as cell count and hematocrit (HCT) have previously been associated with ASCVD risk in the general population. However, little is known concerning their effect in FH. The aim of the present study is to investigate the effect of the different RBC parameters on the incidence of major adverse cardiovascular events (MACE) in FH patients.In this prospective cohort study, genetically-confirmed FH patients aged between 18 and 65 years and without history of a prior ASCVD event were included. MACE included myocardial infarction, stroke, coronary revascularization, unstable angina or cardiovascular death.A total of 482 subjects (6217 person-years of follow-up) were included in the analysis. Hemoglobin (HB), RBC count, and HCT were significant predictors of MACE risk (HR 1.04 (95% CI 1.01-1.06) p = 0.001, HR 2.69 (95% CI 1.49-4.86) p = 0.001, and HR 1.16 (95% CI 1.08-1.26) p 0.0001, respectively) and these associations remained significant when adjusted for traditional cardiovascular risk factors. In addition, the frequency of recurrent MACE was 4-fold and 7-fold higher in the group above vs below the median for HB (p = 0.002) and RBC count (p = 0.001), respectively.HB, RBC count and HCT were significant predictors of incident and recurring MACE in FH patients. These parameters could therefore be used to further refine the ASCVD risk prediction in this vulnerable population.

Dyslipidemia represents a major risk factor for cardiovascular disease. In addition, severe hypertriglyceridemia is an important cause of acute pancreatitis. Accordingly, the increase in serum lipid levels that is observed during pregnancy has potentially important implications. The management of dyslipidemia in pregnancy is further complicated by the lack of safety data during this period for most of the lipid-lowering agents. In the present review, we discuss the most important lipid disorders in pregnant women and their management. Pregnancy is characterized by increases in both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, which might result in severe complications both for the mother and the fetus. Accordingly, LDL-C and triglyceride levels should be monitored during pregnancy, particularly in women with a history of dyslipidemia. Diet is the mainstay of management of dyslipidemia in pregnant women and apheresis can also be considered in patients with homozygous familial hypercholesterolemia or severe hypertriglyceridemia. However, there is a pressing need for studies that evaluate the safety of lipid-lowering agents during pregnancy.

Proprotein convertase subtilisin/kexin type 9 inhibitors, such as evolocumab, are cholesterol-lowering drugs effective in lowering lipid levels in high-risk patients with primary hypercholesterolemia or mixed dyslipidemia. This study assessed the cost effectiveness of evolocumab in combination with lipid-lowering therapies (LLTs) compared with LLTs alone, from a public healthcare perspective in the Kingdom of Saudi Arabia (KSA). A Markov cohort state transition model was used, incorporating efficacy estimates from the FOURIER clinical trial and baseline cardiovascular event rates observed in clinical practice. Other model inputs were extracted from the literature and Saudi sources. In patients with clinically evident atherosclerotic cardiovascular disease and baseline low-density lipoprotein cholesterol ≥ 70 or ≥ 100 mg/dL, adding evolocumab to a maximally tolerated statin, with or without ezetimibe, was associated with incremental cost-effectiveness ratios (ICERs) of Saudi Arabian riyal (SAR) 109,274 ($US60,708) per quality-adjusted life-year (QALY) gained and SAR75,163 ($US41,757) per QALY gained, respectively. The ICER was SAR22,391 ($US12,440) per QALY gained in patients with heterozygous familial hypercholesterolemia. Sensitivity analysis results were robust to changes in model parameters and fell below the willingness-to-pay threshold of up to three times gross domestic product per capita in 2019 (SAR264,813 [$US147,118]). Evolocumab can be considered a cost-effective treatment option for patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia in the KSA.

Aim. To study the features of the nutritional status, including physical growth, body composition, energy value of the diet and the amount of cholesterol consumed with food, in children with familial hypercholesterolemia (FH).Patients and methods. The study included 39 children (19 girls, 20 boys) with familial hypercholesterolemia, both genetically confirmed (n = 11) and established on the basis of Simon Broome criteria (n = 28), aged 9.9 [6.0; 12.9] years. All children were assessed for physical growth based on the Z-score BMI, Z-score height, Z-score body weight/height calculated using the programs Anthro and Anthro plus; analysis of actual nutrition using a standard application program; study of body composition using the InBody 770 bioimpedance analyzer, the basal metabolic rate measured by indirect calorimetry.Results. 55 % of children with FH had harmonious physical growth, 27 % had a body weight deficit, 18 % were overweight or obese. 53 % of patients consumed more than 200 mg of cholesterol per day, while half of them consumed more than 300 mg of cholesterol per day. The range of excess consumption of cholesterol in comparison to the recommended physiological needs for patints with FH ranged from 24 to 67 %. The fat mass according to the body composition in 47 % of patients with FH is within the normal range, in 39 % it is reduced by 18-74 %, in 14 % it is increased by 14-197 %. The median fat percentage was 17.8 [12.7; 22.4]%. According to indirect calorimetry, it was found that the level of resting energy needs corresponded to age needs in 21 % patients, in 8 % it was decreased of 2-26 %, in 2/3 of children its increase was recorded by 3-69 %. The rate of fat oxidation, on the contrary, was increased in 71 % of children by 3-86 % and reduced only in 6 %.Conclusion. The physical growth of children with FH was mainly average, harmonious, while a third of the children had a mass deficit. The level of the main indicators of lipid metabolism did not depend on the physical growth of patients. This pathology in children with normal body weight or with a body weight deficit often remains undiagnosed.

Increased levels of low-density lipoprotein cholesterol (LDL-C) are recognized as a primary risk factor for atherosclerotic cardiovascular disease, which remains the leading cause of death worldwide. Lowering LDL-C levels clearly reduces the risk of cardiovascular events, with benefits related to both absolute reduction and duration of treatment; however, a threshold below which low LDL-C levels can be dangerous has never been established. Since the discovery of statins, cardiovascular research has focused on developing new lipid-lowering agents. Ezetimibe and proprotein convertase subtilisin–kexin type 9 inhibitors have been found to further reduce LDL-C values and subsequent cardiovascular risk. Novel recently approved inclisiran and bempedoic acid, currently being tested in cardiovascular outcomes studies, are further expanding our pharmacological armamentarium, enabling the clinician to diminish residual risk related to LDL-C. Moreover, new agents are paving the way to successful treatment of homozygous familial hypercholesterolemia. This review summarizes the main characteristics of current and emerging lipid-lowering therapies to assist with comprehensive evidence-based decision making.

The aim – to evaluate clinical and laboratory characteristics of patients of the Ukrainian familial hypercholesterolemia registry taking into account gender differences.Materials and methods. 231 patients with familial hypercholesterolemia were included to the Ukrainian Familial Hypercholesterolemia Registry: 8 children (under 18 years of age) and 223 adult patients (68 men (30.5 %), mean age 43.4±1.3 and 155 women) 69.5 %) – 45.5±1.0 years) with familial hypercholesterolemia verified according to the DLCN criteria. General clinical, laboratory, instrumental examinations and genetic testing were performed.Results and discussion. In the general registry among the patients with familial hypercholesterolemia in the setting of early manifestation of atherosclerosis the male patients with familial hypercholesterolemia were more likely to have coronary artery disease, premature coronary artery disease, cerebral and peripheral atherosclerosis, xanthoma, hypertriglyceridemia, diabetes mellitus, smoking and a history of MI, which caused a higher DLCN score (9.3 points in men against 7.8 points in women, p

Heterozygous familial hypercholesterolemia is associated with a high risk of early ischemic heart disease onset and cardiovascular death. There is almost no data about the prevalence of the disease in the Ukrainian population. The aim of the study was to assess the incidence of familial hypercholesterolemia among patients who were treated in “L.T. Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine” due to early ischemic heart disease. Medical records data of 600 patients treated in the Institute during 2015-2017 were analyzed. Early ischemic heart disease was diagnosed in 89 patients. The disease verification has been conducted either on the basis of coronarography data, or on the basis of previous myocardial infarction with Q wave. To identify patients with familial hypercholesterolemia, the Dutch lipid clinic network criteria were used. The presence of familial hypercholesterolemia was suspected in more than 14.8% of patients with early ischemic heart disease. Among these patients, 2 (2.2%) had definite diagnosis; 27 (30.3%) were likely to have diagnosis, 26 (29.7%) had possible diagnosis and in 34 (38,2%) patients it was unlikely to diagnose them with familial hypercholesterolemia. The term “familial hypercholesterolemia” was not mentioned in the hospital diagnosis. This paper demonstrates that despite frequent occurrence of familial hyper-cholesterolemia, doctors’ alertness towards this disease has been noted to be quite low.

Background: Familial Hypercholesterolemia (FH) is an inherited disease, associated with an increased risk of atherosclerosis, manifested clinically as premature coronary heart disease. FH is biochemically characterized by increased Cholesterol and Low-density Lipoprotein Cholesterol serum levels. The diagnosis is often made using clinical scores however, the definitive FH diagnosis should point out the underlying molecular change, which can be: a point mutation within the three major genes, a number of single nucleotide polymorphisms determining the polygenic etiology, or copy number variations in the Low-density lipoprotein receptor gene. Objective: In the present study we investigated copy number variations as a possible etiological factor for FH in a cohort of patients with documented premature coronary heart disease. Methods: The study population consisted of 150 patients with premature coronary heart disease documented by angiography, all being under lipid-lowering therapy, and 20 apparently healthy controls. Serum lipids were assessed using the Cobas Integra 400 plus and commercial reagents. Copy number variations were evaluated with the SALSA MLPA Probemix P062 LDLR kit. Results: Cholesterol, Triglycerides, Low-density Lipoprotein Cholesterol and High-density Lipoprotein Cholesterol showed no difference between patients and controls. No copy number variations were detected in the investigated regions, namely all 18 exons and the promoter region of the Low-density lipoprotein receptor gene. Conclusions: Even in the presence of negative results, the Familial Hypercholesterolemia genetic diagnosis has to be further pursued in the presence of a clinical diagnosis, as the identification of the molecular etiology may bring additional clinical and therapeutical benefits, as well as open the possibility for “cascade screening”.

Heterozygous familial hypercholesterolemia (HeFH) is a common, autosomal dominant, genetic disease that results in premature atherosclerotic cardiovascular disease secondary to high-level low-density lipoprotein cholesterol (LDL-C) exposure. We present a 68-year-old male patient with HeFH who was diagnosed with acute coronary syndrome at 9 months after coronary artery bypass grafting, although his LDL-C level was decreased to 77 mg/dL from 213 mg/dL. The emergency coronary angiography revealed that all bypass grafts were occluded, and the large atherosclerotic plaque burden was observed even in right internal thoracic artery (RITA) by intravascular ultrasound examination. Emergency percutaneous coronary intervention (PCI) was performed to his RITA bypass graft. After strict LDL-C management with proprotein convertase subtilisin/kexin 9 (PCSK-9) inhibitors, re-stenosis was not observed at the PCI site and the atherosclerotic plaque burden in his graft drastically disappeared. The high-risk HeFH patients, including those suffering from coronary bypass graft stenosis despite receiving medical therapy, might need stricter management of lipid profile with PCSK-9 inhibitors.

Familial hypercholesterolemia (FH) is a monogenic form of severe hypercholesterolemia that, if left untreated, is associated with early onset of atherosclerosis. FH derives from genetic variants that lead to inefficient hepatic clearance of low-density lipoprotein (LDL) particles from the circulation. The FH phenotype is encountered in approximately 1 of every 300 people. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with FH than in normolipidemic individuals and in those with polygenic hypercholesterolemia. FH is usually diagnosed by clinical scores that consider hypercholesterolemia, family history of early ASCVD and hypercholesterolemia, and cutaneous stigmata. Genetic diagnosis is important and should be offered to individuals suspected of FH. Family cascade screening is important to identify asymptomatic hypercholesterolemic individuals. Despite the high risk of ASCVD, this risk is heterogenous in heterozygous FH and depends not only on high LDL cholesterol (LDL-C) but also on other risk biomarkers. Risk can be evaluated by considering biomarkers such as male sex, late-onset therapy (> age 40), LDL-C > 310 mg/dL, low high-density lipoprotein cholesterol, elevated lipoprotein(a), obesity, diabetes, and hypertension by using specific risk equations and by detecting subclinical coronary atherosclerosis. Statins are the main therapy for FH and change the natural history of ASCVD; however, most individuals persist with elevated LDL-C. PCSK9 inhibitors provide robust and safe LDL-C lowering in FH, although elevated costs preclude their widespread use. Newer therapies such as ANGPTL3 inhibitors add intensive LDL-C lowering for refractory forms of FH. Finally, while it is possible to normalize LDL-C in people with FH, the disease unfortunately is still severely underdiagnosed and undertreated.

Resumen Introduccion Gran Canaria es una region de aislamiento genetico para hipercolesterolemia familiar, debido a una mutacion fundadora, p.[Tyr400_Phe402del], en el gen del receptor de LDL (LDLR). Datos iniciales indican que sus portadores podrian tener una alta prevalencia de diabetes. Material y metodos Se recluto a los pacientes mayores de 30 anos con hipercolesterolemia familiar y mutacion confirmada en LDLR en un hospital de tercer nivel de Gran Canaria y se comparo la prevalencia de diabetes y otros datos clinicos entre los portadores de p.[Tyr400_Phe402del] y los de otras mutaciones en LDLR. Resultados El 76,4% de los 89 participantes era portador de p.[Tyr400_Phe402del]. En ese grupo la prevalencia de diabetes fue significativamente mas alta (25 vs. 4%, p = 0,045). Dichos casos tambien tenian mayor prevalencia de enfermedad cardiovascular y niveles mas altos de colesterol LDL y trigliceridos. No hubo diferencias en edad, peso, indice de masa corporal, cintura, edad de inicio y tiempo de tratamiento con estatinas. Sin embargo, si precisaban mas a menudo inhibidores de PCSK9 (51,5 vs. 24%, p = 0,027). Conclusiones La mutacion p.[Tyr400_Phe402del] se asocia a una elevada prevalencia de diabetes, no explicada por factores de riesgo clasicos, como la edad, la obesidad o el uso prolongado de estatinas.

Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor that reduces levels of low-density lipoprotein-cholesterol (LDL-C) in the plasma by inhibition of cholesterol synthesis in hepatic cells, which leads to up-regulation of hepatic LDL receptors. Bempedoic acid is approved as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C. In this case study, we describe a patient with HeFH who had a prior excellent response to statin but unable to take the same, and a less than expected response to PCSK9i, in whom initiation of bempedoic acid led to a substantial reduction of LDL-C. Our findings suggest that patients who are quite responsive to statins may also be quite responsive to bempedoic acid, a medication that works in the same biochemical pathway as HMG-CoA reductase inhibitors. Additionally, this medication may be particularly effective at lowering LDL-C among individuals not on background statin therapy.

Background: The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. However, whether this criteria could appropriately stratify a high-risk Japanese patient with FH remains unknown. Objectives: This study sought to characterize atherosclerotic cardiovascular diseases in IAS-defined Japanese subjects with severe FH. Methods: This study analyzed 380 clinically diagnosed subjects with heterozygous FH without any history of atherosclerotic cardiovascular diseases. Severe FH was defined as untreated low-density lipoprotein cholesterol >400 mg/dL, >310 mg/dL plus 1 high-risk feature, or >190 mg/dL plus 2 high-risk features according to IAS-proposed statement. The occurrence of first and subsequent composite outcomes (cardiac [cardiac death + coronary artery disease + coronary revascularization] and noncardiac events [stroke + peripheral artery disease] was compared between subjects with severe (n = 135) and non-severe (n = 227) FH. Results: Severe FH was identified in 40.3% of study population. They had higher low-density lipoprotein cholesterol (P < 0.001) and lipoprotein(a) (P = 0.03) levels. Moreover, they more frequently received high-intensity statin (P < 0.001), PCSK9 inhibitor (P < 0.001), and lipoprotein apheresis (P = 0.01) than nonsevere FH subjects did, which resulted in a lower on-treatment low-density lipoprotein cholesterol level of subjects with severe FH (113 ± 47.2 vs 130 ± 53.9 mg/dL; P = 0.007). However, during the 7.4-year observational period, subjects with severe FH exhibited a 9.3-, 15.4-, and 5.9-fold greater risk for first composite (P < 0.001), cardiac (P < 0.001), and noncardiac outcomes (P = 0.02), respectively. Multivariate Cox proportional hazard model consistently revealed the 7.8- and 7.9-fold elevated risks of first (P < 0.001) and of subsequent (P < 0.001) composite outcomes in subjects with severe FH. Conclusions: Japanese subjects with severe FH present profound risks of both first and subsequent atherosclerotic cardiovascular diseases in the primary prevention settings. These findings support the clinical applicability of IAS-defined severe FH in Japanese patients, which identifies those who require further stringent antiatherosclerotic management.

Family-based cascade screening from index probands is considered an effective way of identifying undiagnosed individuals with familial hypercholesterolemia (FH). The role of genetic testing of the proband in the success of cascade screening for FH is unknown. We randomized 240 individuals with a clinical diagnosis of FH to genetic testing for FH (n = 160) or usual care with lipid testing alone (n = 80). The primary study endpoint was the proportion of probands with at least one relative enrolled in the study within one year after the notification of results. Proband median age was 59 (47–67) and 71% were female. Only 28 (12%) probands succeeded in enrolling a relative. While the genetic testing group had a higher proportion of probands with relatives enrolled (13.1%) compared with the usual care group (8.8%), this difference was not significant (p = 0.40). In subgroup analyses, enrollment of a relative was higher in the pathogenic variant group (22.7%) compared to the no pathogenic variant (9.5%) and usual care groups (8.8%) (p = 0.04). We observed a low rate of family participation in cascade screening despite repeated recommendations to probands. Compared to usual care, genetic testing did not improve family participation in cascade screening for FH. NCT04526457

Background As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly attributed to disease-causing variants in the low-density lipoprotein receptor (LDLR) gene. The aim of this study was to explore the molecular mechanism of LDLR c.501C>A variant in FH and assess the efficacy of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor treatment for FH patients. Methods The whole-exome sequencing was performed on two families to identify disease-causing variants, which were verified by Sanger sequencing. The function of LDLR variant was further explored in HEK293 cells by Western Blot and confocal microscopy. Besides, the therapeutic effects of PCSK9 inhibitor treatment for two probands were assessed for 3 months. Results All members of the two families with the LDLR c.501C>A variant showed high levels of LDLC. The relationship between the clinical phenotype and LDLR variants was confirmed in the current study. Both in silico and in vitro analyses showed that LDLR c.501C>A variant decreased LDLR expression and LDL uptake. PCSK9 inhibitor treatment lowered the lipid level in proband 1 by 24.91%. However, the treatment was ineffective for proband 2. A follow-up study revealed that the PCSK9 inhibitor treatment had low ability of lipid-lowering effect in the patients. Conclusions LDLR c.501C>A variant might be pathogenic for FH. The PCSK9 inhibitor therapy is not a highly effective option for treatment of FH patients with LDLR c.501C>A variant.

Lipoprotein apheresis plays a vital role in the management of the severe hyperlipidemias that predispose to atherosclerosis. Determinants of efficacy are the acute reduction in lipoproteins achieved by each apheresis procedure, their frequency, and the fractional catabolic rates and hence pool sizes of low-density lipoprotein (LDL) or lipoprotein (a) (Lp(a)) of the patient being treated. A useful criterion of the efficacy of apheresis plus lipid-lowering drug therapy is the decrease in the interval (time-averaged) mean of serum total or LDL cholesterol or Lp(a) between procedures, expressed as the percent decrease in the interval means below the maximal levels of these lipoproteins when off all treatment. Recent advances in lipid-lowering drug therapy may diminish the use of lipoprotein apheresis but will not abolish its unique role as a therapeutic "last chance saloon," especially for children and pregnant women with homozygous familial hypercholesterolemia.

Aims: Despite the established link between familial hypercholesterolemia (FH) and increased risk of coronary heart disease (CHD), its association with other common atherosclerotic and metabolic diseases has not been extensively studied. The aim of this study was to report the prevalence of peripheral arterial disease (PAD) [i.e., common carotid artery disease (CCAD) and lower extremity arterial disease (LEAD)], aortic valve stenosis, chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) in patients with FH. Materials & Methods: This was a cross-sectional study retrieving data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Results: A total of 1,633 adult patients (850 males) with heterozygous FH (HeFH) were included (mean age 51.3±14.6 years at registration and 44.3±15.9 years at diagnosis). Any common carotid artery stenosis (CCAS) was diagnosed in 124 out of 569 patients with available related data (21.8%), while the prevalence of CCAD (defined as a CCAS ≥50%) was 4.2%. The median (interquartile range - IQR) CCAS was 30% (20-40), whereas the median (IQR) carotid intima-media thickness (CIMT) was 0.7 (0.1-1.4) mm. LEAD was reported in 44 patients (prevalence 2.7%). The prevalence of aortic valve stenosis and CKD was 2.0% and 6.4%, respectively. NAFLD was present in 24% of study participants. Conclusions: HeFH is associated with a relatively high prevalence of any CCAS and CCAD. The prevalence of LEAD, CKD and aortic valve stenosis was relatively low, whereas the prevalence of NAFLD was similar to that of the general population.

Familial Hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL-cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients - 342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re-analyzed by next-generation-sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL-cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL-cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL-cholesterol is only mildly increased. This article is protected by copyright. All rights reserved.

[EN] [Introduction and objectives] Our objective was to approximate the prevalence of mutations in candidate genes for familial hypercholesterolemia (FH) in a middle-aged Spanish population and to establish the predictive value of criteria for clinical suspicion in the detection of causative mutations., [EN] [Methods] Unrelated individuals aged ≥ 18 years from the Aragon Workers’ Health Study (AWHS) with high low-density lipoprotein cholesterol (LDL-C) and clinical suspicion of FH (participants with LDL-C concentrations above the 95th percentile, participants with premature cardiovascular disease and/or participants with high LDL-C [130 mg/dL] under statin therapy), assuming that any participant with FH exhibits at leats 1 trait, were selected and the LDLR, APOB, PCSK9, APOE, STAP1 and LDLRAP1 genes were sequenced by next generation sequencing technology., [EN] [Results] Of 5400 individuals from the AWHS, 4514 had complete data on lipid levels and lipid-lowering drugs, 255 participants (5.65%) met the criteria for suspicion of FH, 24 of them (9.41%) were diagnosed with hyperlipoproteinemia(a), and 16 (6.27% of those sequenced) were found to carry causative mutations in candidate genes: 12 participants carried 11 different pathogenic LDLR alleles and 4 participants carried 1 pathogenic mutation in PCSK9. LDL-C concentrations > 220 mg/dL and LDL-C > 130 mg/dL despite statin therapy showed the strongest association with the presence of mutations (P = .011)., [EN] [Conclusions] Our results show that the prevalence of FH in Spain is 1:282 and suggest that the combination of high untreated LDL-C and high levels of LDL-C despite statin therapy are the best predictors of a positive FH genetic test., [ES] [Introducción y objetivos] Nuestro objetivo fue aproximar la prevalencia de mutaciones en los genes candidatos de hipercolesterolemia familiar (HF) en una población española de mediana edad, y determinar el valor predictivo de los criterios clínicos de sospecha de HF en la detección de mutaciones causales., [ES] [Métodos] Se seleccionaron individuos mayores de 18 años no relacionados de la cohorte Estudio de Salud de los Trabajadores de Aragón (AWHS) con colesterol unido a lipoproteínas de baja densidad (cLDL) > percentil 95, con enfermedad cardiovascular prematura o con cLDL > 130 mg/dl con tratamiento hipolipemiante, asumiendo que al menos una de las características estará presente en todos los individuos con HF. En estos participantes se secuenciaron los genes LDLR, APOB, PCSK9, APOE, STAP1 y LDLRAP1 mediante secuenciación masiva., [ES] [Resultados] De 5.400 individuos del AWHS, 4.514 tenían datos lipídicos y registro farmacológico hipolipemiante completo, 255 participantes (5,65%) cumplían los criterios de sospecha de HF, 24 de ellos (9,41%) fueron diagnosticados de hiperlipoproteinemia(a) y 16 (6,27% de los secuenciados) presentaron alguna mutación causal en genes candidatos: 12 participantes portaban 11 alelos patogénicos diferentes en LDLR y 4 participantes portaban una mutación patogénica en PCSK9. Las concentraciones de cLDL > 220 mg/dl y el cLDL > 130 mg/dl a pesar del tratamiento con estatinas mostraron la mayor asociación con la presencia de mutación (p = 0,011)., [ES] [Conclusiones] Nuestros resultados muestran que la prevalencia española de HF es 1:282 y sugieren que una concentración de cLDL elevado, y niveles altos de cLDL a pesar de la terapia con estatinas son los mejores predictores para un diagnóstico genético positivo de HF., Este trabajo contó con el apoyo de subvenciones del Gobierno de Aragón, B14-7R, España y del Ministerio de Economía y Competitividad de España PI15/01983, PI18/01777 y CIBERCV. Estos proyectos son cofinanciados por el Instituto de Salud Carlos III y el Fondo Europeo de Desarrollo Regional (FEDER) de la Unión Europea «Una manera de hacer Europa».

Background: In recent years, two-dimensional speckle tracking echocardiography (2D-STE) has been increasingly used to detect left ventricular myocardial ischemia with high accuracy for a reliable and comprehensive assessment of myocardial function by myocardial strain analysis. The present study aimed to assess whether the longitudinal strain (LS) bull’s eye plot could accurately detect left ventricular myocardial ischemia in homozygous familial hypercholesterolemia (HoFH) patients. Methods: A total of 28 HoHF patients, who underwent 2D-STE and myocardial perfusion imaging (MPI), were classified into two groups as diagnosed by MPI for myocardial ischemia. The myocardial ischemia score by MPI, LS bull’s-eye plot, and strain parameters were analyzed and compared. Results: Among the 28 HoFH patients, MPI detected 30.77% and 2D-STE showed 30.19% ischemic segments in 13 and 15 HoFH patients with myocardial ischemia, respectively. All segmental LSs in the left anterior descending artery (LAD) perfusion territory were significantly decreased in patients with myocardial ischemia. The diagnostic capability of 2D-STE for myocardial ischemia was 85.29%, 95.34%, and 93.91% for sensitivity, specificity and accuracy, respectively. Conclusion: Left ventricular LS bull’s-eye plot can assist rapid and accurate evaluation of myocardial ischemia in HoFH patients. The myocardial ischemia is mainly distributed in the LAD perfusion territory in these patients.

Supplemental Digital Content is available in the text., Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of

Background: Monogenic hypercholesterolemia with Mendelian inheritance is a heterogeneous group of diseases that are characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) leve...