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Background: The causal relationship between familial hypercholesterolemia (FH) and various vitamin deficiencies has not yet been elucidated. Therefore, this study investigated the cause-and-effect relationship between FH and the risk of multiple vitamin deficiencies in humans. Methods: Mendelian randomization (MR) analysis was performed by extracting six datasets for FH, FH with ischemic heart disease (IHD), and vitamin deficiency (vitamin A, thiamine, other B-group vitamins, and vitamin D) from the FinnGen study, covering a total of 329,115; 316,290; 354,932; 354,949; 355,411 and 355,238 individuals, respectively. Results: FH was suggestively associated with higher odds of thiamine deficiency [inverse variance weighted odds ratio (ORIVW) 95% confidence interval (CI): 1.62 (1.03, 2.55), P = 0.036] and vitamin D deficiencies [ORIVW CI: 1.35 (1.04, 1.75), P = 0.024], low-density lipoprotein receptor (LDLR) rs112898275 variant, rs11591147 and rs499883 in proprotein convertase subtilisin/kexin 9 (PCSK9), rs9644862 in cyclin-dependent kinase inhibitor 2 B antisense RNA1 (CDKN2B-AS1), and rs142834163 in dedicator of cytokinesis 6 (DOCK6) and rs115478735 in ABO blood group (ABO) strongly influenced the risk of thiamine deficiency, while the rs7412 variant in apolipoprotein E (APOE) mostly influenced the risk of vitamin D deficiency. FH with IHD was suggestively associated with higher odds of vitamin D deficiency (ORIVW, weighted median [WM][95%CI]: 1.31 [1.05, 1.64]; 1.47 [1.10, 1.97]) (P = 0.018; 0.010) without any single significant SNPs observed. Conclusion: FH was positively associated with increased risks of thiamine and vitamin D deficiencies, revealing a prospective and unfortunate complication of FH. [ABSTRACT FROM AUTHOR]

Aim: To examine the long‐term results and treatment effectiveness of liver transplantation (LT) in the treatment of homozygous familial hypercholesterolemia (HoFH) in children and adolescents. Method: Patients who underwent LT due to HoFH between 2007 and 2023 were included in the study. The patients' demographic data, clinical findings, preoperative and postoperative laboratory examinations, transplantation complications, and postoperative disease courses were evaluated. Results: There were five boys with an average age of 6.2 (median: 6, range 4–10) years in the study. The average total cholesterol level of the patients before transplantation was 923 (median: 950, range: 780–1002) mg/dL and the average LDL‐cholesterol level was 864 (median: 852, range: 770–957) mg/dL. No patients died of transplant‐related complications. After an average follow‐up of 9.2 (median: 9, range: 1.5–16) years, the average total cholesterol level of the patients was 197 (median: 164, range: 137–359) mg/dL, and the average LDL‐cholesterol level was 138 (median: 92, range: 85–313) mg/dL. Four (80%) patients developed atherosclerotic cardiovascular disease during follow‐up, and two (40%) died of this cause. Conclusion: LT in the treatment of HoFH did not help our patients reach the target LDL‐cholesterol level after transplantation and did not prevent the development of cardiovascular disease. Therefore, LT alone is not curative in the treatment of HoFH. [ABSTRACT FROM AUTHOR]

Background The familial hypercholesterolemia (FH) diagnosis is based on clinical and genetic criteria. A relevant proportion of FH patients fulfilling the criteria for definite FH have negative genetic testing. Increasing the identification of true genetic-based FH is a clinical challenge. Deepening the analysis of lipoprotein alterations could help increase the yield of genetic testing. We evaluated whether the number, size, and composition of lipoproteins assessed by 1H-NMR could increase the identification of FH patients with pathogenic gene variants. Methods We studied 294 clinically definite FH patients, 222 (75.5%) with positive genetic testing, as the discovery cohort. As an external validation cohort, we studied 88 children with FH, 72 (81%) with positive genetic testing. The advanced lipoprotein test based on 1H-NMR (Liposcale®) was performed at baseline after a lipid-lowering drug washout of at least 6 weeks. The association of variables with genetic variants was evaluated by random forest and logistic regression. Areas under the curve (AUCs) were calculated. A predictive formula was developed and applied to the validation cohort. Results A formula derived from nuclear magnetic resonance (NMR) lipoprotein analyses improved the identification of genetically positive FH patients beyond low-density lipoprotein (LDL)-cholesterol levels (AUC = 0.87). The parameters contributing the most to the identification formula were LDL particle number, high-density lipoprotein size, and remnant cholesterol. The formula also increases the classification of FH children with a pathogenic genetic variation. Conclusion NMR lipoprotein profile analysis identifies differences beyond standard lipid parameters that help identify FH with a positive pathogenic gene variant, increasing the yield of genetic testing in FH patients. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) is a common monogenic autosomal dominant disorder, primarily mainly caused by pathogenic mutations in the low-density lipoprotein receptor (LDLR) gene. Through phenotypic-genetic linkage analysis, two LDLR pathogenic mutations were identified in FH families: c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr). Materials and methods: Whole exome sequencing was conducted on the proband with familial hypercholesterolemia to identify the target gene and screen for potential pathogenic mutations. The suspicious responsible mutation sites in 14 family members were analyzed using Sanger sequencing to assess genotype-phenotype correlations. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to evaluate LDLR mRNA and protein expression. In parallel, bioinformatics tools were employed to predict structural and functional changes in the mutant LDLR. Results: Immunofluorescence analysis revealed no significant difference in the intracellular localization of the p.Gly343Ser mutation, whereas protein expression of the p.Ala627Thr mutation was decreased and predominantly localized in the cytoplasm. Western blotting has showed that protein expression levels of the mutant variants were markedly declined in both cell lysates and supernatants. Enzyme linked immunosorbent assay has demonstrated that LDLR protein levels in the supernatant of cell culture medium was not significant different from those of the wild-type group. However, LDLR protein levels in the cell lysate of both the Gly343Ser and Ala627Thr variants groups were significantly lower than those in the wild-type group. Bioinformatic predictions further suggested that these mutations may affect post-translational modifications of the protein, providing additional insight into the mechanisms underlying the observed reduction in protein expression. Conclusions: In this study, we identified two heterozygous pathogenic variants in the LDLR gene, c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr), in a family with familial hypercholesterolemia. We also conducted preliminary investigations into the mechanisms by which these mutations contribute to disease pathology. [ABSTRACT FROM AUTHOR]

Background: We assessed long-term real-world effectiveness and safety of lomitapide in patients with homozygous familial hypercholesterolemia (HoFH). Methods: Retrospective case series of six patients with HoFH treated with lomitapide in an Italian clinic. Changes in low-density lipoprotein cholesterol (LDL-C) during lomitapide treatment were assessed. The effect on LDL-C of PCSK9 inhibitors, apheresis and lomitapide was evaluated. Additionally, high-density lipoprotein cholesterol (HDL-C), gastrointestinal tolerability, hepatic steatosis/elasticity, transaminases, and cardiovascular events and symptoms were assessed. Results: Median age at HoFH clinical and molecular diagnoses was 25 (range 2–49) and 40 (29–71) years, respectively. Five (83.3%) had prior cardiovascular events. One patient received apheresis, which was subsequently discontinued. All patients received PCSK9 inhibitors but discontinued due to minimal effectiveness. Median (range) age at lomitapide initiation was 44 (28–73) years, with a median 47 (18–85) months' treatment (mean dose 17.5 [5–40] mg/day). Mean (SD) baseline LDL-C was 263.2 (148.1) mg/dL, which decreased by 80% at nadir (52.8 [19.2] mg/dL) and 69% at last follow-up (81.3 [30.5] mg/dL). Four patients (66.7%) achieved LDL-C < 70 mg/dL sometime during follow-up, all of whom also achieved LDL-C < 55 mg/dL. Adverse events (AEs) were generally mild to moderate, hepatic steatosis was either absent or mild/moderate and hepatic elasticity remained normal in all but two patients (> 70 years old). All patients with reported cardiovascular symptoms had improvements in symptoms, and all patients reported stabilization or regression of intima-media thickness and atheromatous plaques. Conclusions: These long-term, real-world data demonstrate that lomitapide substantially reduced LDL-C for up to seven years. Most patients achieved LDL-C goal at some point, consistent with published Phase III trial and real-world evidence data. No patient discontinued lomitapide treatment. Further long-term follow-up in a larger patient population will be important to determine cardiovascular and other outcomes. [ABSTRACT FROM AUTHOR]

Background: Studying patients carrying identical-by-descent (IBD) pathogenic gene variants allows us to control for the disease-causing genetic background and to more accurately document the impact of modifiers. Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels and premature atherosclerosis and is often caused by defects in the LDLR gene. There is a high prevalence of FH in French Canada as a result of a founder effect from France in the 17th century. Several FH patients currently living in French Canada (founder population) and in France (colonizing population) carry IBD FH-causing variants. The expression of FH is affected by environmental and genetic modifiers, and patients with IBD variants may present different characteristics. Methods: In this study, we compared FH clinical expression patients carrying IBD LDLR pathogenic variants living in France or Canada. Four IBD variants, namely c.259T>G p.(Trp87Gly), c.2000G>A p.(Cys667Tyr), c.682G>A p.(Glu228Lys), and c.1048C>T p.(Arg350*), were selected. Untreated plasma lipid profiles, the apolipoprotein E (APOE) genotype, cardiovascular risk factors, and the occurrence of symptomatic ASCVD were compared in 105 adult carriers (30 from France and 75 from French Canada). Results: All parameters were similar between the two populations, except for untreated total cholesterol (10.14 ± 1.89 mmol/L vs. 8.65 ± 1.84 mmol/L, p = 0.0006) and LDL-c concentrations (7.94 ± 1.86 mmol/L vs. 6.93 ± 1.78 mmol/L, p = 0.016), which were significantly higher in FH patients living in France, an observation that was revealed across all studied LDLR variants. Conclusions: This study illustrates that FH patients sharing IBD pathogenic LDLR variants that have evolved in different geographic, cultural, and socio-economic environments for hundreds of years differ in terms of cholesterol levels, highlighting the importance of better understanding the interplay between genetic and environmental modulators of FH expression. [ABSTRACT FROM AUTHOR]

Background and Objectives: The proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab are recently developed promising drugs used for treatment of familial hypercholesterolemia (FH). This systematic review and meta-analysis aimed to thoroughly evaluate the efficacy and safety of evolocumab and alirocumab among pediatric patients with FH. Materials and Methods: A comprehensive search was conducted in PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov from inception through July 2024 to identify primary interventional studies among pediatric patients with FH. Meta-analyses were performed if appropriate. Statistics were analyzed using Review Manager version 5.4 and Stata version 16.0. Results: Fourteen articles reporting nine unique studies were included. There were three randomized controlled trials (RCTs) assessing evolocumab or alirocumab involving a total of 320 pediatric patients, one cross-over trial and five single-arm or observational studies. Pooled results showed significant efficacy of evolocumab/alirocumab in reducing low-density lipoprotein cholesterol (LDL-C) (weighted mean difference [WMD]: −37.92%, 95% confidence interval [CI]: −43.06% to −32.78%; I2 = 0.0%, p = 0.60), apolipoprotein B (WMD: −33.67%, 95% CI: −38.12% to −29.22%; I2 = 0.0%, p = 0.71), and also lipoprotein(a) (WMD: −16.94%, 95% CI: −26.20% to −7.69%; I2 = 0.0%, p = 0.71) among pediatric patients with FH. The efficacies of evolocumab/alirocumab on LDL-C reduction within pediatric patients with heterozygous FH (HeFH) were consistent between studies, whereas in patients with homozygous FH (HoFH), it varied dramatically. Pediatric patients with the null/null variant may respond to the treatment. PCSK9 inhibitors were generally well tolerated within most pediatric patients, in line with previous studies among adult populations. Conclusions: The PCSK9 inhibitors evolocumab/alirocumab significantly reduced LDL-C and some other lipid parameters, such as apolipoprotein B, in pediatric patients with HeFH. These drugs may be appropriate as a potential therapy for pediatric patients with HoFH who cannot achieve LDL-C targets with other treatments. Evolocumab/alirocumab was generally well tolerated in the pediatric population. [ABSTRACT FROM AUTHOR]

Background and Objectives: Familial hypercholesterolemia (FH) is a genetic disease that is massively underdiagnosed worldwide. Affected patients are at high risk of cardiovascular events at young ages. Early intervention in childhood could help prevent heart attacks and cerebral strokes in these patients. Materials and Methods: We conducted an interventional study including 10 patients that previously underwent genetic testing for familial hypercholesterolemia. These patients received lifestyle and diet recommendations that they followed for a year before being reevaluated. Results: Patients with negative genetic testing were able to achieve lower levels in their lipid panel values compared to the patients with positive genetic testing, with lifestyle changes alone. LDL-cholesterol levels decreased by 18.5% in patients without FH while patients genetically confirmed with FH failed to achieve lower LDL-cholesterol levels without medication. Conclusions: Genetic testing for FH is not always part of screening algorithms for FH. Some studies even advise against it. Our study proved the importance of genetic testing for FH when suspecting this disorder and choosing the treatment course for patients. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by significantly elevated levels of low-density lipoprotein (LDL) cholesterol, which plays a major role in the progression of atherosclerosis and leads to a heightened risk of premature atherosclerotic cardiovascular disease. Methods: We have carried out an observational study on a group of 17 patients treated at the Outpatient Lipid Clinic from 2019 to 2024. Result: The most frequent mutation observed was found in the LDL receptor (LDLR) gene, which was identified in ten patients (58.8%). Five patients were identified to have a mutation in the apolipoprotein B (APOB) gene, whereas two patients had two points mutations, one in the LDLR, and the other in the APOB gene. The average age of patients with LDLR mutation was 54.8 (12.3); for APOB mutation it was 61.4 (9.3) and for patients with two points mutation it was 61.5 (14.8). The study results showed that at Week 12, individuals with LDLR-defective heterozygotes who were given alirocumab 150 mg every two weeks experienced a 63.0% reduction in LDL cholesterol levels. On the other hand, individuals with APOB heterozygotes experienced a 59% reduction in LDL cholesterol levels. However, in patients with double heterozygous for mutations in LDLR and APOB genes, there was a hyporesponsiveness to alirocumab, and the reduction in LDL-C was only by 23% in two individuals. Conclusions: In patients with a single mutation, there was a greater response to treatment with alirocumab in contrast to patients with double heterozygous mutation, who did not respond to treatment with PCSK9 inhibitors. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is the most significant inherited risk factor for coronary heart disease (CHD). Current guidelines focus on monogenic FH, but the polygenic form is more common and less understood. This study aimed to assess the clinical utility of an 8-SNP LDLC polygenic score in a central Romanian cohort. The cohort included 97 healthy controls and 125 patients with premature (P)CHD. The weighted LDLC polygenic risk score (wPRS) was analyzed for associations with relevant phenotypic traits, PCHD risk, and clinical FH diagnosis. The wPRS positively correlated with LDLC and DLCN scores, and LDLC concentrations could be predicted by wPRS. A trend of increasing LDLC and DLCN scores with wPRS deciles was observed. A +1 SD increase in wPRS was associated with a 36% higher likelihood of having LDLC > 190 mg/dL and increases in LDLC (+0.20 SD), DLCN score (+0.16 SD), and BMI (+0.15 SD), as well as a decrease in HDLC (−0.14 SD). Although wPRS did not predict PCHD across the entire spectrum of values, individuals above the 90th percentile were three times more likely to have PCHD compared to those within the 10th or 20th percentiles. Additionally, wPRS > 45th percentile identified "definite" clinical FH (DLCN score > 8) with 100% sensitivity and 45% specificity. The LDLC polygenic score correlates with key phenotypic traits, and individuals with high scores are more likely to have PCHD. Implementing this genetic tool may enhance risk prediction and patient stratification. These findings, the first of their kind in Romania, are consistent with the existing literature. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have represented an important change in the management of hypercholesterolemia, although, until now, they have barely been used. Without PCSK9i, many patients with atherosclerotic cardiovascular disease (CVD) or those at very high risk do not reach their therapeutic LDLc objectives. Objective: The analysis aimed to examine the clinical and biochemical characteristics of subjects receiving PCSK9i treatment in the Dyslipidemia Registry of the Spanish Atherosclerosis Society. Methods: All consecutive subjects aged ≥ 18 years from different Lipid Units included in the Dyslipidemia Registry of the SEA were analyzed. Inclusion criteria consisted of unrelated patients aged ≥ 18 at the time of inclusion with hypercholesterolemia (LDL-C ≥ 130 mg/dL or non-HDL-C ≥ 160 mg/dL after the exclusion of secondary causes) who were studied for at least two years after inclusion. Participants' baseline and final visit clinical and biochemical characteristics were analyzed based on whether they were on primary or secondary prevention and whether they were taking PCSK9i at the end of follow-up. Results: Eight hundred twenty-nine patients were analyzed, 7014 patients in primary prevention and 1281 in secondary prevention at baseline. 4127 subjects completed the required follow-up for the final analysis. The median follow-up duration was 7 years (IQR 3.0–10.0). Five hundred patients (12.1%) were taking PCSK9i at the end of the follow-up. The percentage of PCSK9i use reached 35.6% (n = 201) and 8.7% (n = 318) in subjects with and without CVD, respectively. Subjects on PCSK9i and oral lipid-lowering agents with and without CVD achieved LDLc reductions of 80.3% and 75.1%, respectively, concerning concentrations without lipid-lowering drugs. Factors associated with PCSK9i use included increasing age, LDLc without lipid-lowering drugs and the Dutch Lipid Clinic Network (DLCN) score. However, hypertension, diabetes, smoking, and LDLc after oral lipid-lowering drugs were not independent factors associated with PCSK9i prescription. In subjects with CVD, the use of PCSK9i was higher in men than in women (an odds ratio of 1.613, P = 0.048). Conclusions: Approximately one-third of CVD patients received PCSK9i at the end of follow-up. The use of PCSK9i was more focused on baseline LDLc concentrations rather than on CVD risk. Women received less PCSK9i in secondary prevention compared to men. [ABSTRACT FROM AUTHOR]

Background: Heterozygous familial hypercholesterolemia (HeFH) is a genetic condition that is associated with a high risk of atherosclerotic cardiovascular disease (ASCVD) due to elevated lipid levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody inhibitors have been shown to reduce low‐density lipoprotein cholesterol (LDL‐C) substantially. This study aimed to assess the real‐world effectiveness of PCSK9 inhibitor therapy among patients with HeFH. Methods: Retrospective cohort study of patients with probable or definite HeFH on a PCSK9 inhibitor at a specialized lipid clinic between 2015 and 2022. The primary objective was the proportion of patients who attained a ≥50% reduction in LDL‐C after 12 months of treatment. Results: In total, 141 patients were screened and 95 were included. Mean age was 63 years, 51% were female, and mean baseline LDL‐C level was 4.0 mmol/L (155 mg/dL). A majority of patients (60%) had statin intolerance, and 73% were on ezetimibe. The most common PCSK9 inhibitor was evolocumab (94%). Overall, 74% of patients achieved a ≥50% reduction in LDL‐C after 12 months of therapy. Mean LDL‐C concentration decreased to 1.7 mmol/L (66 mg/dL) (approximately 59% reduction from baseline) after 12 months of follow‐up but increased to 1.9 mmol/L (73 mg/dL) after ≥24 months of follow‐up. Similar trends were observed in non‐high‐density lipoprotein cholesterol and apolipoprotein B. Lipoprotein(a) was significantly reduced by 45% over 12 months. Twelve percent of patients permanently discontinued therapy. Barriers to PCSK9i use were mostly related to cost. Conclusions: In a real‐world cohort of HeFH patients, most of which were intolerant to statins, a high majority were able to achieve a ≥50% reduction in LDL‐C after 12 months of PCSK9 inhibitor therapy (mean reduction of approximately 59%), which is similar to clinical trial data of patients with ASCVD. A significant reduction in non‐high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) were also observed. [ABSTRACT FROM AUTHOR]

Background: Xanthomas are papulo-nodular, yellow, soft, painless, dermal-based non-neoplastic cutaneous lesions that comprise of localized aggregates of lipid-laden histiocytes. Case report: A thirteen-year-old adolescent girl presented with multiple, large, bilateral, nodules present over elbows, posterior aspect of heel, and knees for five years. Fine needle aspiration cytology was performed, and the smears showed numerous foamy histiocytes, a few benign spindle cells, and foreign-body giant cells against a lipidaceous background. Her maternal aunt and grandmother also had xanthelasma palpebrarum. Serum lipid levels were advised and were markedly deranged in all three of them. Based on the corroborative clinical, biochemical, and cytopathological findings, a final diagnosis of familial hypercholesterolemia (FH) was rendered. Conclusion: The present case sheds light on the importance of prompt cytopathological diagnosis of xanthomatous lesions, especially in children and adolescents, as it can help prevent morbidity and mortality due to associated premature adverse cardiovascular and cerebrovascular events if left undiagnosed. [ABSTRACT FROM AUTHOR]

Background Detecting total cholesterol in dried blood spots could aid in identifying individuals with a high likelihood of familial hypercholesterolemia and could be used as a screening measure. This study aims to assess the diagnostic accuracy of dried blood spots on Whatman 903 paper cards using a manual enzymatic technique. Methods: A total of 394 samples were collected as serum and dried blood spots were compared. Cholesterol was determined in serum using the automated reference method, while cholesterol on paper was measured using a manual enzymatic method. Within- and between-day diagnostic variability were analyzed. The correlation between both methods was assessed using Passing–Bablok regression and Bland–Altman plot. Internal validation of our correlation formula was performed on 149 samples, along with external validation of the formula proposed by Corso et al. Results: The within- and between-day coefficient of variation was found to be lower than 10.14% and 14.09%, respectively. Passing–Bablok regression indicated a precision of 0.803 and an accuracy of 0.96. Internal validation precision was measured at 0.716. The resulting positive and negative predicted values were 0.77 and 0.92, respectively, vs. 0.46 and 0.96 from the external formula. Conclusions: Total cholesterol analysis in dried blood spots demonstrates high precision and reproducibility. This method reliably enables the incorporation of this biological marker into neonatal screening for familial hypercholesterolemia detection. [ABSTRACT FROM AUTHOR]

Purpose: Familial hypercholesterolemia (FH) leads to elevated low-density lipoprotein cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). Since the first functional and morphologic changes of the arterial wall occur in childhood, treatment should start early in childhood to mitigate the elevated risk of ASCVD. Pediatricians play an important role in the detection and care of children with FH. In this study, we aim to explore potential gaps in FH care amongst Dutch pediatricians, in order to enhance their knowledge and awareness of detecting and treating children with FH. Methods: An anonymous online survey, deployed using Google Forms, including 26 closed and semi-closed questions on FH care in children was distributed by the Dutch Association of Pediatrics via a newsletter to which the majority of the practicing Dutch pediatricians subscribe. In addition, we requested that the pediatric departments of all Dutch hospitals in the Netherlands distribute this survey personally among their employed pediatricians. Respondents were instructed to answer the questions without any help or use of online resources. Results: Between September 1st, 2023 and November 1st, 2023, 158 (an estimated 11% response rate) Dutch pediatricians completed the survey. They reported a median (IQR) of 15.0 (6.0–22.0) years of experience as a pediatrician, and 34 (21.5%) were working in academic hospitals. The majority (76.6%) of pediatricians correctly identified a typical FH lipid profile but 68 (43.0%) underestimated the true prevalence of FH (1:300). Underestimation and unawareness of the increased risk of FH patients for ASCVD were reported by 37.3% and 25.9% of pediatricians, respectively. Although 70.9% of the pediatricians correctly defined FH, only 67 (42.4%) selected statins and ezetimibe to treat severe hypercholesterolemia. Conclusions:The results of this study suggest significant gaps in knowledge and awareness of FH in children among Dutch pediatricians. FH care in children needs improvement through educational and training initiatives to mitigate the life-long risk of ASCVD from early life. What is Known: • Familial hypercholesterolemia (FH) leads to elevated LDL-cholesterol levels, which increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). • The process of atherosclerosis starts in childhood • Pediatricians play an important role in the detection and treatment of children with FH. What is New: • Our results highlight significant gaps in care for children with FH amongst pediatricians and this may lead to suboptimal detection and treatment. • FH care in children needs improvement by educational initiatives to ultimately prevent ASCVD in adulthood. [ABSTRACT FROM AUTHOR]

There is a gap of knowledge about the clinical and pathophysiological implications resulting from the interaction between primary hyperlipidemias and type 2 diabetes (T2D). Most of the existing evidence comes from sub-analyses of cohorts; scant information derives from randomized clinical trials. The expected clinical implications of T2D in patients with primary hyperlipidemias is an escalation of their already high cardiovascular risk. There is a need to accurately identify patients with this dual burden and to adequately prescribe lipid-lowering therapies, with the current advancements in newer therapeutic options. This review provides an update on the interactions of primary hyperlipidemias, such as familial combined hyperlipidemia, familial hypercholesterolemia, multifactorial chylomicronemia, lipoprotein (a), and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). During pregnancy, physiological changes elevate cholesterol and triglyceride levels to support fetal development, which can exacerbate pre-existing conditions and lead to complications such as pre-eclampsia, gestational diabetes, and increased ASCVD risk for both mother and child. Effective management strategies are necessary, especially for pregnant women with inherited forms of dyslipidemia (i.e., familial hypertriglyceridemia, hyperchylomicronemia), where personalized dietary adjustments are crucial for successful pregnancy outcomes. Pharmacological interventions and lipoprotein apheresis may be necessary for severe cases, though their use is often limited by factors such as cost, availability, and potential fetal risks. Despite the promise of advanced therapies, their widespread application remains constrained by limited studies and high costs. Thus, a personalized, multidisciplinary approach is essential for optimizing outcomes. This review provides a comprehensive overview of current strategies and evidence-based practices for managing dyslipidemia during pregnancy, emphasizing the balance of maternal and fetal health. Additionally, it discusses the physiological changes in lipid metabolism during pregnancy and their implications, particularly for women with inherited forms of dyslipidemia. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular diseases are the leading cause of mortality worldwide, with a significant impact on socioeconomic aspects. Various biomarkers have been studied in relation to the diagnosis, progression, and prognosis of atherosclerotic disease, with lipoprotein (a) [Lp (a)] standing out as an important predictor of cardiovascular risk. This observational study aimed to clarify the association between Lp (a) levels and the severity of significant multivessel coronary lesions in acute myocardial infarction (AMI) patients. Materials and Methods: Conducted at the Clinical Emergency County Hospital of Craiova, Romania, the study involved 256 young patients divided into two groups based on Lp (a) levels: Group A (Lp (a) < 30 mg/dL) and Group B (Lp (a) ≥ 30 mg/dL). Patients included young adults up to 55 years for males and 60 years for females, excluding those with familial hypercholesterolemia. Results: The study revealed a significant association between elevated Lp (a) levels and the presence of multivessel coronary lesions. Patients with Lp (a) concentrations ≥ 30 mg/dL exhibited a higher prevalence of multivessel disease compared to those with lower levels. Discussion: The findings suggest that elevated Lp (a) levels are a crucial biomarker for the risk of coronary artery disease, particularly in young patients with AMI. The study emphasizes the need for aggressive lipid management strategies and personalized treatment approaches, considering the significant role of Lp (a) in atherosclerosis and AMI. Conclusions: Lipoprotein A levels above 30 mg/dL are associated with a higher prevalence of multivessel coronary lesions. Multivariate analysis revealed that higher Lp (a) levels and lower HDL levels are linked to an increased risk of multivessel coronary lesions. [ABSTRACT FROM AUTHOR]

Abstract Background Familial hypercholesterolemia (FH) is a prevalent genetic disorder with global implications for severe cardiovascular diseases. Motivated by the growing recognition of the need for early diagnosis and treatment of FH to mitigate its severe consequences, alongside the gaps in understanding the economic implications and equity impacts of FH screening, this study aims to synthesize the economic evidence on the cost-effectiveness of FH screening and to analyze the impact of FH screening on health inequality. Methods We conducted a systematic review on the economic evaluations of FH screening and extracted information from the included studies using a pre-determined form for evidence synthesis. We synthesized the cost-effectiveness components involving the calculation of synthesized incremental cost-effectiveness ratios (ICERs) and net health benefit (NHB) of different FH screening strategies. Additionally, we applied an aggregate distributional cost-effectiveness analysis (DCEA) to assess the impact of FH screening on health inequality. Results Among the 19 studies included, over half utilized Markov models, and 84% concluded that FH screening was potentially cost-effective. Based on the synthesized evidence, cascade screening was likely to be cost-effective, with an ICER of $49,630 per quality-adjusted life year (QALY). The ICER for universal screening was $20,860 per QALY as per evidence synthesis. The aggregate DCEA for six eligible studies presented that the incremental equally distributed equivalent health (EDEH) exceeded the NHB. The difference between EDEH and NHB across the six studies were 325, 137, 556, 36, 50, and 31 QALYs, respectively, with an average positive difference of 189 QALYs. Conclusions Our research offered valuable insights into the economic evaluations of FH screening strategies, highlighting significant heterogeneity in methods and outcomes across different contexts. Most studies indicated that FH screening is cost-effective and contributes to improving overall population health while potentially reducing health inequality. These findings offer implications that policies should promote the implementation of FH screening programs, particularly among younger population. Optimizing screening strategies based on economic evidence can help identify the most effective measures for improving health outcomes and maximizing cost-effectiveness.

Abstract Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have represented an important change in the management of hypercholesterolemia, although, until now, they have barely been used. Without PCSK9i, many patients with atherosclerotic cardiovascular disease (CVD) or those at very high risk do not reach their therapeutic LDLc objectives. Objective The analysis aimed to examine the clinical and biochemical characteristics of subjects receiving PCSK9i treatment in the Dyslipidemia Registry of the Spanish Atherosclerosis Society. Methods All consecutive subjects aged ≥ 18 years from different Lipid Units included in the Dyslipidemia Registry of the SEA were analyzed. Inclusion criteria consisted of unrelated patients aged ≥ 18 at the time of inclusion with hypercholesterolemia (LDL-C ≥ 130 mg/dL or non-HDL-C ≥ 160 mg/dL after the exclusion of secondary causes) who were studied for at least two years after inclusion. Participants’ baseline and final visit clinical and biochemical characteristics were analyzed based on whether they were on primary or secondary prevention and whether they were taking PCSK9i at the end of follow-up. Results Eight hundred twenty-nine patients were analyzed, 7014 patients in primary prevention and 1281 in secondary prevention at baseline. 4127 subjects completed the required follow-up for the final analysis. The median follow-up duration was 7 years (IQR 3.0–10.0). Five hundred patients (12.1%) were taking PCSK9i at the end of the follow-up. The percentage of PCSK9i use reached 35.6% (n = 201) and 8.7% (n = 318) in subjects with and without CVD, respectively. Subjects on PCSK9i and oral lipid-lowering agents with and without CVD achieved LDLc reductions of 80.3% and 75.1%, respectively, concerning concentrations without lipid-lowering drugs. Factors associated with PCSK9i use included increasing age, LDLc without lipid-lowering drugs and the Dutch Lipid Clinic Network (DLCN) score. However, hypertension, diabetes, smoking, and LDLc after oral lipid-lowering drugs were not independent factors associated with PCSK9i prescription. In subjects with CVD, the use of PCSK9i was higher in men than in women (an odds ratio of 1.613, P = 0.048). Conclusions Approximately one-third of CVD patients received PCSK9i at the end of follow-up. The use of PCSK9i was more focused on baseline LDLc concentrations rather than on CVD risk. Women received less PCSK9i in secondary prevention compared to men.

Background and aim: Many children with an FH mutation also exhibit elevated lipoprotein(a) levels, which is an independent risk factor for atherosclerotic cardiovascular disease. Studies have reported higher levels of lipoprotein(a) in adult and middle-aged women than men. There is limited knowledge on the concentration and change of lipoprotein(a) levels in children with genetic FH, and therefore we investigated sex-differences in lipoprotein(a) level and change in lipoprotein(a) in girls and boys with genetically confirmed FH. Methods: Medical records were reviewed retrospectively in 438 subjects with heterozygous FH that started follow-up below the age of 19 years at the Lipid Clinic, Oslo University Hospital in Norway, and of these we included 386 subjects with at least one Lp(a) measurement. Results: Mean (SD) age at baseline was 13.8 (7.3) years and the age was similar between sexes. Girls had a higher lipoprotein(a) level than boys at baseline: median (25–75 percentile) 223 (108–487) vs. 154 (78–360) mg/L, respectively (p 0.05). Conclusions: We found an increase in Lp(a) levels in children with genetic FH with age, and higher levels in girls than boys, which could impact risk assessment and future ASCVD. Further research is needed to elucidate whether subjects with FH could benefit from lipoprotein(a)-lowering therapies that are under current investigations.

Background: Individuals with homozygous familial hypercholesterolemia (HoFH) have a severe clinical problem in their first decade of life, which is not usually present in heterozygous FH (HeFH) individuals. For this latter group of patients, FH diagnosis is mostly severely delayed with a significant increase in the risk of angina, myocardial infarction, peripheral artery disease, stroke, and cardiovascular and all-cause mortality. Methods: This study used various bioinformatics tools to analyze microarray data and identify critical miRNAs and their target genes associated with FH and its severity. Differentially expressed serum miRNAs from direct hybridization microarray data in three groups of subjects: healthy, HeFH, and HoFH. The differential expressed miRNAs were determined according to a log of fold-change (LFC) 0.5 and of p

Background and aims: Familial hypercholesterolemia (FH) is an inherited disease associated with hypercholesterolemia, and dietary treatment is part of the treatment. We aimed to assess the dietary pattern in relation to the Healthy Nordic Food Index (HNFI) in adults with and without heterozygous FH (HeFH), and to examine the associations between dietary quality and biomarkers related to cardiovascular disease in adults with HeFH. Methods: We included 205 adults (≥18 years) with HeFH who received follow-up at the Lipid Clinic in Oslo and compared them to controls (n = 228). Dietary intake was assessed using a food frequency questionnaire and dietary quality was assessed using the HNFI. Blood samples were analysed for levels of blood lipids, plasma fatty acids (FAs), and markers of inflammation and platelet activation. Results: The HeFH patients (median 60 years; 50.2 % female; 25.9 % in secondary prevention) had lower intake of total and saturated fat compared to controls (32.6 energy percent (E%) vs. 34.9 E%, and 9.6 E% vs 12.0 E%, respectively; p

Background Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder characterized by severe hypercholesterolemia and significantly elevated levels of serum low-density lipoprotein cholesterol (LDL-C). Patients with FH are at an increased risk of premature atherosclerotic cardiovascular disease, and early detection and treatment can improve their survival rates. Objective This study aims to explore the clinical value and significance of screening for FH among patients with hypercholesterolemia in community populations. Methods During the period from July to December 2023, a total of 164 patients diagnosed with hyperlipidemia and exhibiting LDL-C levels ≥4.90 mmol/L underwent gene sequencing at Department of Cardiology, the Affiliated Suzhou Hospital of Nanjing Medical University and its 5 community health centers within the medical alliance. Based on quartile intervals of LDL-C levels, the patients were stratified into four groups: Q1 group (LDL-C ≤5.10 mmol/L, n=43), Q2 group (5.10 mmol/L≤LDL-C≤5.32 mmol/L, n=40), Q3 group (5.32 mmol/L≤LDL-C≤5.67 mmol/L, n=41), and Q4 group (LDL-C≥5.67 mmol/L, n=40). Baseline data and laboratory test results of the patients were collected. Results A total of 164 patients with hypercholesterolemia were included, with a prevalence of awareness of dyslipidemia at 39.02% (64/164), and 21.95% (36/164) of the patients had previously taken lipid-lowering medications. The comparison of total cholesterol (TC) and LDL-C among Q1 to Q4 groups showed statistically significant differences (P0.05) . Conclusion In community populations with hypercholesterolemia and LDL-C ≥ 4.9 mmol/L, the rate of FH gene mutations is relatively high, and the rate of other primary (genetic) lipid metabolism gene mutations is also high. Screening for FH among patients with hypercholesterolemia in community populations has significant clinical importance and value.

Double filtration plasmapheresis (DFPP) is a semi‐selective blood purification modality derived from the plasma exchange modality. DFPP can be applied to a variety of refractory disorders including metabolic disorders, organ transplants, rheumatic disorders, neurological disorders, and dermatologic disorders. Familial hypercholesterolemia and lipoprotein (a) hyperlipoproteinemia are major chronic metabolic disorders. Lipoprotein apheresis (LA) is applied for those patients to remove low‐density lipoprotein cholesterol (LDL‐C) and lipoprotein (a) (Lp(a)). DFPP is used as one of the modalities in LA. In addition to removing LDL‐C and Lp(a), DFPP has pleiotropic effects such as removal of lipid metabolism‐related substances, C‐reactive protein lowering effect, removal of adhesion molecules, removal of inflammatory cytokines, and anti‐oxidative effect. This article summarizes the pleiotropic effects of DFPP based on recent clinical articles. [ABSTRACT FROM AUTHOR]

In the present study, a systematic literature review was conducted to examine the prevalence of homo- and heterozygous forms of Familial hypercholesterolemia among different racial and ethnic groups. Familial hypercholesterolemia (FH) is an inherited disorder characterised by elevated blood levels of cholesterol and low-density lipoprotein (LDL), which increases the risk of cardiovascular disease. Databases PubMed, Web of Science, and Elsiever were searched and only peer-reviewed articles with a large number of contributors and sufficient prevalence and ethnicity data were included. Diagnosis of FH was based on genetic testing or clinical criteria. The results of the study indicate inadequate and untimely diagnosis of FH, resulting in inadequate treatment. To date, only 9% of countries have statistical data on the prevalence of FH in the general population. In order to develop effective prevention strategies for cardiovascular diseases associated with FH, further research is needed to obtain accurate epidemiological data, including the race and ethnicity of patients. This will allow optimisation of strategies to reduce the burden of preventable cardiovascular disease associated with FH.

Background: Familial hypercholesterolemia (FH) is a genetic lipid disorder characterized by increased concentrations of low-density lipoprotein cholesterol (LDL-C) in the circulatory system, resulting in a markedly increased vulnerability in the development of atherosclerotic cardiovascular disease at an early age. The prevalence of FH in a Sri Lankan setting was identified in a tertiary hospital laboratory and a primary care family practice laboratory by performing opportunistic screening for index cases using laboratory criteria as a starting point. Methodology: This study assessed the prevalence of FH using the Dutch Lipid Clinic Network (DLCN) Criteria score. The evaluation was conducted over 6 months in both a tertiary hospital laboratory and a primary care laboratory. Once patients were identified by high LDL, the patients were recruited to the study and assessed clinically. Secondary causes were excluded, and clinical evaluations of the patients were done to see if they had clinical features of FH. Results: Of the total of 3039 serum lipid profiles that were reviewed, there were 42 (1.38%) lost to follow-up. There were 72 samples with high LDL (190 mg/dL) ≥4.9 mmol/L (190 mg/dL). Of the patients with LDL >4.9 mmol/L, 16 (0.52%) cases with identified secondary causes (untreated hypothyroidism [n = 13], nephrotic syndrome [n = 3], and no secondary investigations [n = 14]) were excluded. In total, the point prevalence of likely phenotypical FH based on DLCN (probable or confirmed) and an LDL-C >4.9 mmol/L was calculated as approximately 14/3039 (1:217). Conclusions: The point prevalence of FH in patients undergoing lipid profile testing in a tertiary hospital laboratory and a primary care laboratory was 1:217 which is comparable with the prevalence of FH in the general population in the world (based on 1 in 200–250). Based on the laboratory criteria, initiating screening for FH in resource-limited settings could be an effective screening strategy to identify patients with FH. Until national screening programs are established, the laboratory as an avenue to trigger screening for FH is useful in lower-middle-income countries like Sri Lanka.

Abstract Background Familial hypercholesterolemia (FH) poses a substantial risk of cardiovascular diseases. The recent approval of evinacumab signifies a breakthrough in FH management. This review synthesizes evidence from diverse clinical trials, examining evinacumab’s efficacy, safety, and broader impact on hypercholesterolemia. Body As highlighted by multiple trials, Evinacumab demonstrates robust efficacy in reducing LDL-C levels, particularly in refractory cases. Its sustained impact, evidenced by enduring reductions in LDL-C levels throughout extended treatment periods, positions it as a potential long-term solution. While the safety profile appears favorable, instances of deaths underline the importance of holistic clinical management and ongoing surveillance. The clinical implications are profound, suggesting evinacumab’s potential inclusion in guidelines for managing severe lipid disorders. Conclusion Future research directions emphasize inclusivity, diversity, and real-world applications to establish sustained efficacy and safety across diverse populations. Integrating evinacumab into clinical guidelines requires evidence-based recommendations, necessitating collaboration between researchers, clinicians, and guideline developers.

Abstract Background Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing. Objective The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants. Methods Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members. Results A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance. Conclusion This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.

Familial hypercholesterolemia (FH) is a genetic disease that leads to elevated low-density lipoprotein cholesterol levels and risk of coronary heart disease. Current therapeutic options for FH remain relatively limited and only partially effective in both lowering low-density lipoprotein cholesterol and modifying coronary heart disease risk. The unique characteristics of nucleic acid therapies to target the underlying cause of the disease can offer solutions unachievable with conventional medications. DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH. Recent advances are overcoming obstacles to clinical translation of nucleic acid--based medications, including greater stability of the formulations as well as site-specific delivery, making gene-based therapy for FH an alternative approach for treatment of FH. [ABSTRACT FROM AUTHOR]

This document discusses novel and promising therapies for diabetic dyslipidemia, which is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) in diabetic patients. The dyslipidemia of diabetes is characterized by high triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol, and elevated levels of apolipoprotein B (apoB). Current guidelines recommend statins as the primary therapy for lowering LDL cholesterol, but there are other therapies being explored, such as bempedoic acid, inhibitors of apolipoprotein C-III, angiopoietin-like 3 (ANGPTL3), and lipoprotein(a). These therapies show promise in reducing ASCVD events, but further clinical trials are needed to confirm their efficacy and safety. [Extracted from the article]

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased LDL-cholesterol levels. About 85% of FH cases are caused by LDLR mutations encoding the low-density lipoprotein receptor (LDLR). LDLR is synthesized in the endoplasmic reticulum (ER) where it undergoes post-translational modifications and then transported through Golgi apparatus to the plasma membrane. Over 2900 LDLR variants have been reported in FH patients with limited information on the pathogenicity and functionality of many of them. This study aims to elucidate the cellular trafficking and functional implications of LDLR missense variants identified in suspected FH patients using biochemical and functional methods. Methods: We used HeLa, HEK293T, and LDLR-deficient-CHO-ldlA7 cells to evaluate the subcellular localization and LDL internalization of ten LDLR missense variants (p.C167F, p.D178N, p.C243Y, p.E277K, p.G314R, p.H327Y, p.D477N, p.D622G, p.R744Q, and p.R814Q) reported in multiethnic suspected FH patients. We also analyzed the functional impact of three variants (p.D445E, p.D482H, and p.C677F), two of which previously shown to be retained in the ER. Results: We show that p.D622G, p.D482H, and p.C667F are largely retained in the ER whereas p.R744Q is partially retained. The other variants were predominantly localized to the plasma membrane. LDL internalization assays in CHO-ldlA7 cells indicate that p.D482H, p.C243Y, p.D622G, and p.C667F have quantitatively lost their ability to internalize Dil-LDL with the others (p.C167F, p.D178N, p.G314R, p.H327Y, p.D445E, p.D477N, p.R744Q and p.R814Q) showing significant losses except for p.E277K which retained full activity. However, the LDL internalization assay is only to able evaluate the impact of the variants on LDL internalization and not the exact functional defects such as failure to bind LDL. The data represented illustrate the hypomorphism nature of variants causing FH which may explain some of the variable expressivity of FH. Conclusion: Our combinatorial approach of in silico, cellular, and functional analysis is a powerful strategy to determine pathogenicity and FH disease mechanisms which may provide opportunitites for novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to evaluate the serum level of miRNA-27 expression in patients with familial hypercholesterolemia (FH). Material and methods: miRNA-27a/b levels in serum were compared between 39 patients with heterozygous FH (HeFH = 20) and homozygous FH (HoFH = 19), and 20 healthy subjects (control group). The expression level of miRNA-27a/b was measured using real-time PCR. Results: miRNA-27a/b expression in heFH patients (fold change: 2.21 ±0.69, p = 0.001) and in the subgroup of hoFH (fold change: 3 ±1.19, p = 0.001) was significantly higher compared to healthy people. In the comparison between HoFH and HeFH, the HoFH group had a significantly higher level of miRNA-27a/b expression (FC: 1.84 ±1.19, p = 0.009). Conclusions: We observed higher miRNA-27a/b expression in patients with FH than in healthy individuals. In comparison with HoFH and HeFH groups, the former had a higher expression level of miRNA-27a/b, which indicates the potential of miRNA-27a/b as a candidate marker for the severity of disease in individuals with FH. [ABSTRACT FROM AUTHOR]

Background: Real-world data on the use of lipid-lowering therapy (LLT) in clinical practice show that about 80% of (very) high-cardiovascular (CV)-risk patients disregard the 2019 European Society of Cardiology (ESC) Guidelines' recommendations on dyslipidemias. The availability of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9mAb) should reduce this gap. Our aim was to provide data on PCSK9mAb use in clinical practice, investigating the achievement of the ESC Guidelines' recommendations in the real world. Methods: Between April 2018 and December 2022, patients who started on PCSK9mAb therapy (140 mg of evolocumab or 75 mg or 150 mg of alirocumab, subcutaneous injection every 2 weeks) were included in a prospective registry. Our cohort consisted of 256 patients: 95 (37.1%) were women (mean age: 65.43 ± 11.12 yrs), 53 (20.7%) were at high CV risk, and 203 (79.3%) were at very high CV risk. Results: After one year of PCSK9mAb treatment, nearly 60% of patients demonstrated full adherence to the ESC Guidelines' recommendations, defined as achieving at least a 50% reduction in low-density lipoprotein cholesterol (LDL-C) levels along with reaching LDL-C target levels (≤55 and ≤70 mg/dL for very high and high risk, respectively). Concomitant high-dose statin therapy emerged as the primary predictor of LDL-C target attainment. Heterozygous familial hypercholesterolemia (HeFH), statin intolerance, and female gender were associated with a significant lower probability of achieving LDL-C target levels. Conclusions: Our analysis confirms that PCSK9mAb treatment is safe and effective, enabling 60% of our cohort to fully achieve the LDL-C guideline recommendations. The use of high-intensity statins emerged as a significant predictor of efficacy. Conversely, familial hypercholesterolemia and female gender were identified as predictors of therapeutic failure. Hence, it is crucial to address disparities in cardiovascular disease prevention between genders and to enhance strategies for managing elevated LDL-C in HeFH patients. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low‐density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood–brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr−/−) mice. We noticed that microgliosis was more severe in the hippocampus of middle‐aged LDLr−/− mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr−/− mice already showed increased microgliosis and decreased immunocontent of claudin‐5 in the prefrontal cortex (PFC). Subsequently, 6‐month‐old male C57BL/6 wild‐type and LDLr−/− mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr−/− mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non‐treated LDLr−/− mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region‐specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6‐month‐old LDLr−/− mice exhibited a slight but not significant increase in IBA‐1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr−/− mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH. [ABSTRACT FROM AUTHOR]

The IMPACT-FH study implemented strategies (packet, chatbot, direct contact) to promote family member cascade testing for familial hypercholesterolemia (FH). We evaluated the impact of genetic counseling (GC) on medical outcomes, strategy selection, and cascade testing. Probands (i.e., patients with FH) were recommended to complete GC and select sharing strategies. Comparisons were performed for both medical outcomes and strategy selection between probands with or without GC. GEE models for Poisson regression were used to examine the relationship between proband GC completion and first-degree relative (FDR) cascade testing. Overall, 46.3% (81/175) of probands completed GC. Probands with GC had a median LDL-C reduction of −13.0 mg/dL (−61.0, 4.0) versus −1.0 mg/dL (−16.0, 17.0) in probands without GC (p = 0.0054). Probands with and without GC selected sharing strategies for 65.3% and 40.3% of FDRs, respectively (p < 0.0001). Similarly, 27.1% of FDRs of probands with GC completed cascade testing, while 12.0% of FDRs of probands without GC completed testing (p = 0.0043). Direct contact was selected for 47 relatives in total and completed for 39, leading to the detection of 18 relatives with FH. Proband GC was associated with improved medical outcomes and increased FDR cascade testing. Direct contact effectively identified FH cases for the subset who participated. [ABSTRACT FROM AUTHOR]

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

Purpose of Review: Familial Hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevation of severely elevated plasma low-density lipoprotein cholesterol. Atherosclerotic cardiovascular disease (ASCVD) risk accelerates after age 20. Early diagnosis allows for treatment of children with FH and creates an opportunity to identify affected relatives through reverse cascade screening (RCS). Historically, cascade screening has had little impact on identifying individuals with FH. Recent Findings: Universal cholesterol screening (UCS) to identify youth with FH, beginning at 9–11 years-of-age, is currently recommended in the U.S. The European Atherosclerosis Society has called for UCS worldwide, emphasizing the need for educational programs to increase awareness amongst healthcare professions. Underdiagnoses and undertreatment of FH remain high. Improved rates of UCS and a systematic approach to RCS are needed. Summary: The absence of a coordinated RCS program limits the benefits of UCS. Further research is needed to identify barriers to cholesterol screening in youth. [ABSTRACT FROM AUTHOR]

The article discusses the use of evinacumab as a potential therapeutic target for treating homozygous familial hypercholesterolaemia (HoFH). HoFH is a rare genetic condition characterized by extremely high levels of LDL-cholesterol and a high risk of cardiovascular disease. Current treatments are generally ineffective in lowering LDL-cholesterol to recommended levels. Evinacumab, an antibody that inhibits ANGPTL3, has shown promise in reducing LDL-cholesterol levels in patients with HoFH. The article presents data from a phase III trial demonstrating the long-term efficacy and safety of evinacumab in reducing LDL-cholesterol levels in HoFH patients. The study also discusses the mode of action of evinacumab and its potential role in the management of other conditions related to high cholesterol. [Extracted from the article]

Background: Familial hypercholesterolemia (FH) is one of the most prevalent dyslipidemia disorders. This study investigated the demographic and lifestyle characteristics of patients with FH referred to a dyslipidemia clinic. Methods: This 5-year, single-center cross-sectional study focused on patients with low-density lipoprotein cholesterol (LDL-C) levels higher than 190 mg/dL referred to a dyslipidemia clinic in Tehran, Iran, between 2017 and 2022. The study examined their demographics, physical activity, and anxiety within the FH cohort. Results: A total of 1724 patients were referred to the dyslipidemia clinic. Of these patients, 44 were diagnosed with definite FH. The mean age and LDL-C level of the FH cohort were 38.84±16.85 years and 315.95±81.73 mg/dL, respectively. A significant correlation was found between LDL-C and body mass index (BMI) (correlation coefficient = -0.31, P=0.031) and total sleep duration (correlation coefficient = -0.40, P<0.000). No correlation was observed between age and physical activity or LDL-C levels. Additionally, no significant correlation was detected between the Dutch score and patients' LDL-C, BMI, age, or physical activity. Regression analysis indicated that BMI and total sleep duration were independent predictors of LDL-C in the FH cohort. Conclusion: Investigating and identifying patients' demographic and lifestyle characteristics is the first step in planning efficient and effective management strategies for chronic diseases, such as FH. Establishing a patient registry for chronic diseases enhances understanding of the target population and enables healthcare providers to design and implement appropriate preventive and control strategies. [ABSTRACT FROM AUTHOR]

Despite the availability of statins and lifestyle modifications, many patients with Dyslipidemia struggle to achieve optimal low-density lipoprotein cholesterol (LDL-C) control. PCSK9 inhibitors offer a promising new therapeutic option with superior LDL-C lowering efficacy compared to statins. However, data on their real-world use, particularly in Iran, is limited. This study aims to address this gap by investigating the one-year effects of evolocumab on lipid profiles and potential cardiovascular outcomes in Iranian patients with Familial Hypercholesterolemia (FH).This single-center, prospective study evaluated evolocumab effectiveness in lowering LDL-C in 50 Iranian adults with FH. Participants with a documented LDL-C > 190 mg/dL on existing cholesterol medications (excluding PCSK9 inhibitors) and a clinical FH diagnosis was included. After baseline assessments (medical history, demographics, lipid profile), evolocumab was administered subcutaneously every two weeks for one year. Follow-up assessments at year one measured changes in LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. The study enrolled 50 participants with an average age of 55 years old (range 35-80 years).Treatment with evolocumab led to significant improvements in lipid profiles at all follow-up points compared to baseline. On average, LDL-C levels decreased by 105.24 mg/dL, triglycerides decreased by 59.20 mg/dL, and HDL-C levels increased by a modest but significant 4.5 mg/dL after one year(p<0.001). Subgroup analysis revealed no statistically significant interactions between baseline demographics (age, sex, BMI) or lifestyle habits (smoking, alcohol) and changes in lipid levels(p>0.05). However, a significant interaction emerged between baseline lipid levels and their corresponding reductions, suggesting greater improvement in patients with higher baseline values(p<0.05). It is noteworthy that no new cardiovascular events were reported during the study period. This study demonstrates the effectiveness of evolocumab in improving lipid profiles in Iranian patients with FH. The observed reductions in LDL-C and triglycerides, along with a modest increase in HDL-C, suggest potential benefits for cardiovascular risk reduction. The absence of new cardiovascular events during the study is encouraging, but further research with larger and longer-term follow-up is needed to confirm these findings and assess the long-term safety and impact on quality of life. [ABSTRACT FROM AUTHOR]

Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors is lower in women compared to men. Women achieve the guideline-recommended LDL-C levels less often than men. Greater cholesterol burden is particularly prominent in women with familial hypercholesterolemia. In clinical practice, women and men with dyslipidemia present with different cardiovascular risk profiles and disease manifestations. The concentrations of LDL-C, lipoprotein(a), and other blood lipids differ between women and men over a lifetime. Dissimilar levels of LLT target molecules partially result from sex-specific hormonal and genetic determinants of lipoprotein metabolism. Hence, to evaluate a potential need for sex-specific LLT, this comprehensive review (i) describes the impact of sex on lipoprotein metabolism and lipid profile, (ii) highlights sex differences in cardiovascular risk among patients with dyslipidemia, (iii) presents recent, up-to-date clinical trial and real-world data on LLT efficacy and safety in women, and (iv) discusses the diverse medical needs of women and men with dyslipidemia and increased cardiovascular risk. [ABSTRACT FROM AUTHOR]

Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.] [ABSTRACT FROM AUTHOR]

Alirocumab (Praluent®), a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that has been co-developed by Regeneron Pharmaceuticals, Inc. and Sanofi (formerly sanofi-aventis), is approved globally for use in adults with established cardiovascular disease, primary hyperlipidemia [including heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH)]. In November 2023, based on clinical data in patients aged 8–17 years, alirocumab received its first pediatric approval in the EU as an adjunct to diet alone, or in combination with a statin and/or other low-density lipoprotein cholesterol (LDL-C)-lowering therapies, in pediatric patients aged ≥ 8 years with HeFH. Alirocumab was approved a few months later in the US for use as an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged ≥ 8 years with HeFH to reduce LDL-C. This article summarizes the milestones in the development of alirocumab leading to this first pediatric approval for HeFH. [ABSTRACT FROM AUTHOR]

• Familial hypercholesterolemia (FH) is underdiagnosed and undertreated in Slovakia. • FH and at-risk individuals must be detected before the first cardiovascular event. • Pediatric screening is effective in identifying parents at risk of FH. • Dutch lipid clinic network criteria are insufficient at present to catch FH early. • Most enrolled parents required lipid-lowering therapy, but were untreated. In Slovakia, a mandatory national universal pediatric total cholesterol (TC) screening program is in place to identify cases of familial hypercholesterolemia (FH). However, the program's effectiveness has not been systematically assessed. This study aimed to estimate the prevalence of FH among parents of children that had elevated TC levels identified during screening. This prospective, non-interventional, observational study enrolled parents of 11-year-old children who underwent TC screening in 23 selected pediatric outpatient clinics between 2017 and 2018. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria and targeted next-generation sequencing. The primary objective was to estimate the proportion of children with a TC level of >188 mg/dL (>4.85 mmol/L) who had a parent with a confirmed diagnosis of FH. A total of 112 parents of 56 children with an elevated TC level were enrolled. Five children (8.9%) had a parent in whom FH was genetically confirmed. Without genetic analysis, all five parents would only be diagnosed with "possible FH" by DLCN criteria. Of parents, 83.9% (n = 94/112) had an low-density lipoprotein cholesterol (LDL-C) level of >116 mg/dL (>3 mmol/L), but only 5.3% (n = 5/94) received lipid-lowering therapy. Among the five parents with genetically confirmed FH, all had an LDL-C level >116 mg/dL (>3 mmol/L), with a mean (±SD) of 191 (±24) mg/dL (4.94 [±0.61] mmol/L). Only two of these parents received lipid-lowering therapy. The present study demonstrates the significance of mandatory universal pediatric TC screening in identifying families with FH and other at-risk families in need of lipid-lowering therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

• Universal cholesterol screens in childhood identify familial hypercholesterolemia. • Pediatric index cases identified 3.55±1.87 family members with FH. • Genetic counseling and genetic testing are underutilized in pediatric FH. Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder causing elevated low density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. Universal cholesterol screening in childhood leads to children serving as the index case for their family, but efficacy of cascade screening and genetic counseling in this population is not well understood. The institutional pediatric lipid clinic database was queried from 2011 to 2022 for subjects <18 years who met clinical HeFH diagnostic criteria (N = 256). Median peak LDL-C was 198 mg/dL (interquartile range 179–238 mg/dL) and 69.5 % of subjects were the index case. The number of new HeFH cases identified per index case was 3.55 ± 1.87. Genetic counseling was offered to 38.7 % of subjects and genetic testing was completed by 10.9 %, 53.6 % of whom had a pathogenic or likely pathogenic genetic variant for HeFH. Our findings highlight the effectiveness of cascade screening from pediatric index cases identified through universal screening. However, genetic counseling and genetic testing may be underutilized in this population. [ABSTRACT FROM AUTHOR]

• We present a novel approach to the adaptation of implementation recommendations from clinical guidelines into implementation strategies, using care of familial hypercholesterolaemia as an example. • We provide guidance on how implementation strategies can be tailored to local-contexts by key partners. • We draw upon existing programs in the literature to highlight how the application of this process is feasible. The International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and implementation recommendations. We reference examples of strategies from the literature to explore how these implementation recommendations can be tailored into implementation strategies at the local-level for stakeholders guided by a framework proposed by Sarkies and Jones. Four authors of the IAS guidance selected two published exemplar implementation recommendations for detection, management, and general implementation. Each recommendation was described as an implementation strategy using Proctor's guidance for specifying and reporting implementation strategies. It recommends reporting the actor (who), action (what), action-target (who is impacted), temporality (how often), and dose (how much) for each implementation strategy. Detection: A centralized cascade testing model, mobilized nurses (actor) to relative's homes, after the diagnosis of the proband (temporality), once (dose) to consent, obtain a blood sample and health information (action) on relatives (action-target). Management: A primary care initiative to improve FH management included an educational session (action) with clinicians (action-target), computer-based reminder message and message to patients to have their cholesterol screened once (dose) at a visit or outreach (temporality) by researchers (actor). General: A partnership between a statewide public pathology provider, local public hospital network, primary health network, government health ministry, and an academic university (actors) was established to implement a primary-tertiary shared care model (action) to improve the detection of FH (action-target). We demonstrate that implementation recommendations can be specified and reported for different local contexts with examples on monitoring, evaluation, and sustainability in practice. [ABSTRACT FROM AUTHOR]

• Kidney transplantation is not curative for FLD patients and renal disease develops again over time. • Elevated TG and non-HDL-C may promote the formation of LpX and accelerate renal function decline. • Markers of anemia may be early predictors of renal function decline in patients with FLD. • Corneal opacity has early onset, and its progression is not influenced by other disease outcomes. • Dyslipidemia should be controlled with lifestyle and pharmacological interventions. Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low high-density lipoprotein cholesterol (HDL-C) levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent two kidney and one liver transplantations. Results show that elevated triglyceride and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis. [Display omitted] [ABSTRACT FROM AUTHOR]

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The COVID-19 pandemic lockdowns affected the lifestyles of children and adolescents, leading to an increase in childhood obesity. Paediatric patients with familial hypercholesterolemia (FH) may be more susceptible to lockdown effects due to their increased cardiovascular risk. However, data are lacking. We investigated the effect of lockdowns on the metabolic profile of paediatric patients with FH. Blood lipids and anthropometry measured in September 2021–April 2022 were retrospectively compared with pre-pandemic values. Thirty participants were included (1–16 years; 57% female). From baseline to post-pandemic, median [P25, P75] blood LDL-C concentration was 125 [112, 150] mg/dL vs. 125 [100, 147] mg/dL (p = 0.894); HDL-C was 58 [52, 65] mg/dL vs. 56 [51, 61] mg/dL (p = 0.107); triglycerides were 64 [44, 86] mg/dL vs. 59 [42, 86] mg/dL (p = 0.178). The BMI z-score did not change significantly (0.19 [−0.58, 0.89] vs. 0.30 [−0.48, 1.10], p = 0.524). The lack of deterioration in metabolic profiles during lockdowns is positive, as some deterioration was expected. We speculate that patients and caregivers were successfully educated about healthy lifestyle and dietary habits. Our results should be interpreted with caution since the study sample was small and heterogeneous. Multicentre research is needed to better understand the impact of lockdowns on this population. [ABSTRACT FROM AUTHOR]