Diagnosis Of Familial Hypercholesterolemia Research Articles

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

Effectiveness and Safety of Lipid-Lowering Drug Treatments in Japanese Patients with Familial Hypercholesterolemia: Familial Hypercholesterolemia Expert Forum (FAME) Study.

Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high serum levels of low-density lipoprotein (LDL)-cholesterol (LDL-C), tendon and skin xanthomas, and premature coronary artery disease (CAD). In Japan, detailed information on the current status of drug therapies for patients with FH has not been reported so far, and their efficacy and safety have not been clarified. After the introduction of ezetimibe, which can further reduce serum LDL-C levels on top of statins, the changes of management for FH patients with these drugs are of particular interest. The current study aimed to evaluate the clinical status of FH heterozygotes and homozygotes, especially focusing on the real-world lipid-lowering drug therapy, attained serum LDL-C levels, and cardiovascular events at registration and during the follow-up. Methods: The FAME Study enrolled 762 heterozygous (including 17 newly diagnosed cases) and 7 homozygous FH patients from hospitals and clinics nationwide. Diagnosis of FH was based upon the criteria defined in the Study Report in 2008 of the Research Committee on Primary Hyperlipidemia supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Health, Labor and Welfare. Data analysis was primarily carried on heterozygous FH patients. Results: Xanthoma or thickening of the Achilles tendon was observed in more than 80% of the patients. CAD was recorded in 23% of patients. Patients with parental and sibling CAD accounted for 47% and 24%, respectively. At baseline, patients without CAD who had LDL-C ＜100 mg/dL accounted for 12.3% and those with CAD who had attained the target (LDL-C ＜70 mg/dL) in the secondary prevention accounted for only 1.8%. In the multiple logistic analysis, male sex, age ＞40, heterozygous FH score ＞20, hypertension, and sibling CAD were significantly and positively associated with prevalent CAD, whereas serum HDL-cholesterol levels showed a significant inverse association with CAD. Patients treated with statin alone, statin＋ezetimibe, statin＋resin, or statin＋probucol accounted for 31.1%, 26.3%, 4.0%, and 3.7%, respectively. Patients treated with three-drug combination (statin＋ezetimibe＋resin or statin＋ezetimibe＋probucol) accounted for 7.5%. Statins and ezetimibe were used in 88.0% and 48.0% at the baseline, respectively. Although high-intensity statins were mainly prescribed, statin doses were much lower than those reported in Western countries. The addition of ezetimibe resulted in ~20% reduction in serum LDL-C. CAD was diagnosed in 17 patients with 21 episodes during follow-up. The Cox hazard model analysis demonstrated that male sex, CAD at the baseline, and parental CAD were related to the development of atherosclerotic cardiovascular disease (ASCVD) events. Furthermore, an increase in serum HDL-C was associated with a significant reduction of ASCVD events, while serum LDL-C and triglyceride levels were not related to ASCVD events. Conclusion: The prevalence of CAD in Japanese patients with heterozygous FH is still very high. In most of the cases, the target level of serum LDL-C was not achieved for primary and secondary prevention of CAD, suggesting that a more aggressive LDL-C lowering and appropriate management of residual risks are necessary.

Efficacy of PCSK9 inhibitors in the treatment of heterozygous familial hypercholesterolemia: A clinical practice experience

PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose. To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting. SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020. 433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6-3.0). Median LDL-C level prior to PCSK9 inhibitors was 145mg/dL (IQR 125-173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41-70) p<0.001, in men and women, achieving a median LDL-C level of 62mg/dL (IQR 44-87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated. PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.

Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia.

To investigate whether genotyping could be used as a cost-effective screening step, preceding next-generation sequencing (NGS), in molecular diagnosis of familial hypercholesterolaemia (FH) in Swedish patients. Three hundred patients of Swedish origin with clinical suspicion of heterozygous FH were analysed using a specific array genotyping panel embedding 112 FH-causing mutations in the LDLR, APOB and PCSK9 genes. The mutations had been selected from previous reports on FH patients in Scandinavia and Finland. Mutation-negative cases were further analysed by NGS. In 181 patients with probable or definite FH using the Dutch lipid clinics network (DLCN) criteria (score ≥ 6), a causative mutation was identified in 116 (64%). Of these, 94 (81%) were detected by genotyping. Ten mutations accounted for more than 50% of the positive cases, with APOB c.10580G>A being the most common. Mutations in LDLR predominated, with (c.2311+1_2312-1)(2514)del (FH Helsinki) and c.259T>G having the highest frequency. Two novel LDLR mutations were identified. In patients with DLCN score < 6, mutation detection rate was significantly higher at younger age. A limited number of mutations explain a major fraction of FH cases in Sweden. Combination of selective genotyping and NGS facilitates the clinical challenge of cost-effective genetic screening in suspected FH. The frequency of APOB c.10580G>A was higher than previously reported in Sweden. The lack of demonstrable mutations in the LDLR, APOB and PCSK9 genes in ~1/3 of patients with probable FH strongly suggests that additional genetic mechanisms are to be found in phenotypic FH.

Identification of familial hypercholesterolemia in acute coronary syndrome patients: are we missing the mark?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Patients (P) with familial hypercholesterolemia (FH) have considerable elevation in levels of low-density lipoprotein (LDL) cholesterol and a higher risk of premature coronary artery disease (CAD) and acute coronary syndromes (ACS). However, even in a hospital setting with a high volume of ACS P, the diagnosis of FH frequently goes undetected. The aim of this study was to evaluate the application of the Dutch Lipid Clinic Network (DLCN) Criteria in P admitted for ACS and analyse ACS recurrence, hospitalization and mortality in a 30-day follow-up. Methods Retrospective evaluation of P with ACS admitted to a tertiary center from 2005 to 2019. Data from the digital files including family history and laboratory tests was analysed and P were followed up for 30 days for hospitalization, recurrent ACS, all cause mortality and cardiovascular (CV) death. Evaluation of tendinous xanthomata, arcus cornealis and genetic analysis was not undertaken. Results 3811 P were evaluated, mean age 63 ± 13 years, 28% female gender, 1497 P (39%) with active or previous smoking habits, 847 P (22%) with diabetes mellitus, 419 P (11%) with family history of coronary disease, 1340 P (35%) with premature CAD, 53 P (1.4%) with premature cerebral or peripheral vascular disease and 522 (14%) with previous ACS. The mean LDL cholesterol level was 125 ± 43 mg/dL, the mean high-density lipoprotein (HDL) cholesterol level was 40 ± 16 mg/dL and the mean triglyceride level was 132 ± 89 mg/dL. The diagnosis at hospital admission was unstable angina (UA) in 189 P (5%), non-ST-segment elevation myocardial infarction (NSTEMI) in 1024 P (27%) and ST-segment elevation MI (STEMI) in 2598 P (68%). The hospital mortality rate was 4.3% (163P). Applying the DLCN criteria, 3089 P (81%) had a score of &amp;lt;3 ("unlikely FH"), 675 P (17.7%) a score of 3 to 5 ("possible FH"), 41 P (1.1%) a score of 6 to 8 ("probable FH") and 1 P (0.03%) a score of &amp;gt;8 ("definite FH"). Stratifying according to ACS type: among UA, 31 P (16%) had "possible FH" and 4 P (2.1%) had "probable FH". Among NSTEMI, 145 P (14.2%) had "possible FH", 9 P (0.9%) "probable FH" and 1 P (0.03%) had "definite FH". Finally, among STEMI P, 497 P (19.1%) had "possible FH" and 28 P (1.1%) had "probable FH". In a 30-day follow-up, there was an all cause mortality of 2% (78 P) and a CV death of 1.3% (49P), while the all cause hospitalization rate was 3.5% (134P) and the admission rate for recurrent ACS was 1.7% (65P). The DLCN criteria score was significantly correlated with CV death (OR 1.25, CI 95% 1.04-1.50, p = 0.020) and admission for recurrent ACS (OR 1.19, CI 95% 1.04-1.36, p = 0.04). Conclusion Application of the DLCN criteria in P admitted for ACS revealed 675 P (17.7%) with "possible FH" and 41 P (1.1%) with "probable FH" as well as show significant correlation with CV death and recurrent ACS. Routine assessment of these criteria can be an accessible tool to stratify likelihood of FH and proceed accordingly to genetic testing.

Improving the identification of patients with a genetic diagnosis of familial hypercholesterolaemia in primary care: A strategy to achieve the NHS long term plan

Background and aimsWe aimed to validate a nurse-led process using electronic health records to identify those at risk of familial hypercholesterolaemia (FH) for genetic diagnosis in primary care. MethodsThose at risk of FH were identified using searches developed and refined locally and implemented in primary care by a trained nurse; they were invited for further assessment and genetic testing if indicated. Family members at risk of FH were identified and invited for cascade testing. ResultsIn total 94,444 patient records were screened (expected prevalence of FH (1 in 250); 377). Of 176 records which already had a diagnostic for FH, 15 had been genetically confirmed and one was undergoing DNA testing. A further 572 (0.61%) were identified as high risk of FH. After desktop screening, 113 (15%) were invited for further assessment. Of these, 73 individuals attended the primary care clinic (64%) of whom 61 (54%) underwent proband genetic testing. Pathogenic variants were detected in 22 cases (36%) and variants of unknown significance in a further 4 cases; a total of 26 probands (43%) were therefore referred for family cascade testing. ConclusionsAn optimised FH identification pathway, based on the NICE CG71 recommendations for systematic searching of primary care electronic health records, can be deployed successfully in primary care settings.

The Spectrum of Low-Density Lipoprotein Receptor Mutations in a Large Turkish Cohort of Patients with Familial Hypercholesterolemia.

Background: Monogenic hypercholesterolemia with Mendelian inheritance is a heterogeneous group of diseases that are characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) levels, and the most common form of this disorder is autosomal-dominant familial hypercholesterolemia (FH). Methods: A total of 104 index cases with the clinical diagnosis of FH were included in this study. Low-density lipoprotein receptor (LDLR) was sequenced using the Sanger sequencing method. Results: Pathogenic/likely pathogenic variants were detected in LDLR in 55 of the 104 cases (mutation detection rate = 52.8%). Thirty different variants were detected in LDLR, three of which were novel. The total cholesterol and LDL-C values of the patients in the group of premature termination codon (PTC) mutation carriers were significantly higher than those of the patients in the group of non-PTC mutation carriers. A total of 87 patients (17 pediatric and 70 adult cases) were diagnosed with cascade genetic screening. Statin treatment was recommended to all 87 patients and was accepted and initiated in 70 of these patients. Conclusions: This study is the largest patient cohort that evaluated FH cases in the Turkish population. Herein, we revealed the LDLR mutation spectrum for a Turkish population and compared the cases in the context of genotype-phenotype correlation. Genetic screening of individuals with suspected FH not only helps to establish their diagnosis, but also facilitates early diagnosis and treatment initiation in other family members through cascade screening.

SCREENING FOR GENETIC MUTATIONS IN LDLR GENE WITH FAMILIAL HYPERCHOLESTEROLEMIA IN THE MONGOLIAN POPULATION

Abstract Objective: The objective of this study was to characterize LDLR (low density lipoprotein receptor) gene mutation in patients with familial hypercholesterolemia. Design and method: Methods: This cross-sectional study was included subjects aged from 20 to 64 years, with a clinical diagnosis of familial hypercholesterolemia. Clinical diagnosis of familial hypercholesterolemia was based on Dutch Lipid Clinic Network diagnostic criteria. Possible and probable familial hypercholesterolemia were defined as a total score was 3–5 and 6–8 points. Ten ml of venous blood samples were collected from all the subjects and used for biochemical and genetic analysis. Deoxyribonucleic acid was isolated from peripheral blood samples and precise primers were designed for LDLR gene which includes 18 exons. Polymerize chain reaction test was followed by deoxyribonucleic acid sequence analysis. Results: Results: A total of 89 subjects included in the study of which, 32 (36%) were men and 57 (64%) were women. The mean age of the participants was 46.5 ± 7.8 years. In our study, we found the following 3 LDLR mutations: S265R mutation in Exon-6, C308Y mutation Exon-8 and V502 M mutation in Exon-10. Conclusions: Conclusion: This was the first study to identify genetic mutations in LDLR gene in Mongolia. We conclude that screening of family hypercholesterolemia among the Mongolian population is very important to identify individuals who are prone to develop the atherosclerotic cardiovascular disease.

Molecular Genetic Approach and Evaluation of Cardiovascular Events in Patients with Clinical Familial Hypercholesterolemia Phenotype from Romania.

This study identifies the genetic background of familial hypercholesterolemia (FH) patients in Romania and evaluates the association between mutations and cardiovascular events. We performed a prospective observational study of 61 patients with a clinical diagnosis of FH selected based on Dutch Lipid Clinic Network (DLCN) and Simon Broome score between 2017 and 2020. Two techniques were used to identify mutations: multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing. The mutation rate was 37.7%, i.e., 23 patients with mutations were identified, of which 7 subjects had pathogenic mutations and 16 had polymorphisms. Moreover, 10 variants of the low-density lipoprotein receptor (LDLR) gene were identified in 22 patients, i.e., one variant of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in six patients, and one variant of the apolipoprotein B (APOB) gene in three patients. Of the LDLR gene variants, four were LDLR pathogenic mutations (c.81C > G, c.502G > A, c.1618G > A mutations in exon 2, exon 4, exon 11, and exon 13–15 duplication). The PCSK9 and APOB gene variants were benign mutations. The pathogenic LDLR mutations were significant predictors of the new cardiovascular events, and the time interval for new cardiovascular events occurrence was significantly decreased, compared to FH patients without mutations. In total, 12 variants were identified, with four pathogenic variants identified in the LDLR gene, whereas 62.3% of the study population displayed no pathological mutations.

Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region.

Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.

Detección de hipercolesterolemia familiar a través de datos analíticos centralizados. Programa DETECTA HF HUELVA

BackgroundFamilial Hypercholesterolemia is the most frequent genetic cause of premature coronary heart disease. The delay in the diagnosis prevents the correct early treatment. There are no effective screening strategies at the national level that ensure a correct diagnosis. ObjectiveTo determine the capacity of a centralized laboratory for the diagnosis of Familial Hypercholesterolemia through the creation of a health program for population screening in the province of Huelva. MethodActive search of patients with primary hypercholesterolemia through the blood tests carried out in the reference laboratories with results of low-density lipoprotein cholesterol greater than 200mg/dl and assessment in the Lipid Unit of Huelva to identify index cases, with subsequent family cascade screening. Results37,440 laboratory tests with lipid profile were examined. After screening, 846 individuals were seen in the Lipid Unit, of which they were diagnosed according to criteria of the Dutch Lipid Clinic Network as possible 654 and probable/definitive 192 individuals, representing 1.74% and 0.51% of the general population examined respectively. ConclusionsThe point prevalence of Familial Hypercholesterolemia in patients submitted to laboratory lipid profile tests was 1:195, higher compared to the prevalence of Familial Hypercholesterolemia in the general population (based on 1 in 200-300). The opportunistic search strategy of the index case through a laboratory alert and centralized screening is an efficient strategy to implement a national screening for the diagnosis of Familial Hypercholesterolemia.

Mutational Spectrum of LDLR and PCSK9 Genes Identified in Iranian Patients With Premature Coronary Artery Disease and Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a common, yet underdiagnosed, genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol levels, which can increase the risk of early-onset coronary artery disease (CAD). In the present study, we screened the nucleotide variations of the LDLR and PCSK9 genes, as well as a part of the APOB gene, in Iranian patients with FH and premature CAD to find the genetic cause of the disorder. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. Direct DNA sequencing was applied to screen the whole coding exons and exon–intron boundaries of the LDLR and PCSK9 genes and the main parts of their introns, together with exon 26 of the APOB gene. The pathogenicity of the identified mutations was investigated via either segregation analyses in the family or in silico predictive software. Six different point mutations (p.Cys148Tyr, p.Cys216Tyr, p.Cys302Trp, p.Cys338Trp, p.Leu479Gln, and p.G593Afs∗72) in LDLR and a double mutation (p.Asp172His and p.Ala53Val) in both LDLR and PCSK9 genes were identified in seven families with clinically diagnosed FH (43%), whereas no pathogenic mutations were found in eight families with clinically diagnosed FH. This study is the first to identify 1 pathogenic mutation in the LDLR gene (c.1014C > G [p.Cys338Trp]) and to cosegregate it from the affected individual in the family. No mutations were found in the APOB gene, whereas several silent mutations/polymorphisms were identified in the LDLR and PCSK9 genes. Genetic testing and reports on nucleotide alterations in the Iranian population are still limited. Our findings not only further confirm the significant role of FH in the incidence of premature CAD but also enlarge the spectrum of LDLR and PCSK9 variations and exhibit the heterogeneity of FH in Iranians. In patients with no mutation in the examined genes, the disease could be begotten either by a polygenic cause or by gene defects occurring in other related genes and regions not targeted in this study.

Prevalence of familial hypercholesterolemia in Attica region, Greece

Background: Dyslipidemias are one of the major modifiable risk factors for cardiovascular disease. Familial hypercholesterolemia (FH) is the most common genetic metabolic disorder; it is estimated that around 14-34 million people worldwide have FH but only 25% of FH patients have been diagnosed. Aim: The aim of the present study was to explore the prevalence of FH in Attica region, Greece.Methods: Attica region was divided into 8 regional units. A predesigned questionnaire was used to collect demographic and clinical data. Data analysis was performed by using the Statistical Package for the Social Sciences (SPSS), ver. 20.Results: The studied sample consisted of 1578 Greek inhabitants of Attica region. The majority of the sample was women (59.9%). The mean age of the studied participants was 47.1 (±14.9) years. According to Simon Broome criteria, the probability of an FH diagnosis as unlikely is determined in 98.7% of the studied sample, probable in 0.8% of the participants or definite in 0.5% of the participants, based on this data, the prevalence of FH in Attica region, Greece is 1:200. Qualitative factors found to be associated with the onset of the disease were medication (p-value = 0.001) and hypolipidemic therapy (p-value = 0.001). The quantitative factors found to be associated with disease onset were body mass index (p-value = 0.044), and systolic (p-value = 0.001) and diastolic (p-value = 0.007) pressure.Conclusions: Based on our data, the prevalence of FH in Attica region, Greece is 1:200. Early identification of contributing factors in FH development and proper treatment is vital and reduce the risk of premature and severe atherosclerotic disease.

Familial Hypercholesterolemia: A Narrative Review on Diagnosis and Management Strategies for Children and Adolescents.

Familial hypercholesterolemia (FH) is a relatively common inherited disorder caused by deleterious mutation(s) in the low-density lipoprotein (LDL) receptor or its associated genes. Given its nature as a heritable disease, any useful screening scheme, including universal, and cascade screening, allows for the early identification of patients with FH. Another important aspect to note is that early diagnosis associated with appropriate treatment can promote better prognosis. However, most clinical diagnostic criteria for adults have adopted clinical elements, such as physical xanthomas and family history, both of which are usually obscure and/or difficult to obtain in children and adolescents. Moreover, LDL cholesterol levels fluctuating considerably during adolescence, hindering the timely diagnosis of FH. In addition, recent advancements in human genetics have revealed several types of FH, including conventional monogenic FH, polygenic FH caused by common single nucleotide variations (SNV) accumulation associated with elevated LDL cholesterol, and oligogenic FH with multiple deleterious genetic variations leading to substantially elevated LDL cholesterol. The aforementioned findings collectively suggest the need for amassing information related to genetics and imaging, in addition to classical clinical elements, for the accurate diagnosis of FH in this era of personalized medicine. The current narrative review summarizes the current status of the clinical and genetic diagnosis of FH in children and adolescents, as well as provide useful management strategies for FH in children and adolescents based on currently available clinical evidence.

Classifying Familial Hypercholesterolaemia: A Tree-based Machine Learning Approach

Familial hypercholesterolaemia is the most common and serious form of inherited hyperlipidaemia. It has an autosomal dominant mode of inheritance, and is characterised by severely elevated low-density lipoprotein cholesterol levels. Familial hypercholesterolaemia is an important cause of premature coronary heart disease, but is potentially treatable. However, the majority of familial hypercholesterolaemia individuals are under-diagnosed and under-treated, resulting in lost opportunities for premature coronary heart disease prevention. This study aims to assess performance of machine learning algorithms for enhancing familial hypercholesterolaemia detection within the Malaysian population. We applied three machine learning algorithms (random forest, gradient boosting and decision tree) to classify familial hypercholesterolaemia among Malaysian patients and to identify relevant features from four well-known diagnostic instruments: Simon Broome, Dutch Lipid Clinic Criteria, US Make Early Diagnosis to Prevent Early Deaths and Japanese FH Management Criteria. The performance of these classifiers was compared using various measurements for accuracy, precision, sensitivity and specificity. Our results indicated that the decision tree classifier had the best performance, with an accuracy of 99.72%, followed by the gradient boosting and random forest classifiers, with accuracies of 99.54% and 99.52%, respectively. The three classifiers with Recursive Feature Elimination method selected six common features of familial hypercholesterolaemia diagnostic criteria (family history of coronary heart disease, low-density lipoprotein cholesterol levels, presence of tendon xanthomata and/or corneal arcus, family hypercholesterolaemia, and family history of familial hypercholesterolaemia) that generate the highest accuracy in predicting familial hypercholesterolaemia. We anticipate machine learning algorithms will enhance rapid diagnosis of familial hypercholesterolaemia by providing the tools to develop a virtual screening test for familial hypercholesterolaemia.

Proprotein convertase subtilisin/kexin type 9 inhibitor utilization and low-density lipoprotein-cholesterol control in familial hypercholesterolemia

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved in August 2015 as an adjunct to maximally tolerated statin treatment in those with familial hypercholesterolemia (FH). ObjectiveTo assess PCSK9 inhibitor utilization patterns and cholesterol control in the high-risk FH population. MethodsThis study was a retrospective analysis of a large administrative database that includes privately insured and Medicare Advantage patients. Individuals with diagnosis codes for FH from October 2016–September 2019 were identified. Differences in PCSK9 inhibitor utilization between various groups were evaluated using multivariable logistic regression. ResultsDuring the study period, 1:371 people enrolled in medical/pharmacy plans had a diagnosis of FH. While 62.5% (n = 33,649) had medication fills for statins (without PCSK9 inhibitors), only 2.0% (n = 1062) had medication fills for PCSK9 inhibitors (with or without other medications). Compared to men, women were more likely to be untreated (OR 1.23, 95% confidence interval (CI):1.18–1.28, p < 0.01) but more likely to be treated with PCSK9 inhibitors (OR 2.18, 95%CI:1.90–2.49, p < 0.01). Compared to those younger than 55 years of age, older individuals were more likely to be treated (OR 1.64, 95%CI:1.56–1.72, p < 0.01) but less likely to be treated with PCSK9 inhibitors (OR 0.40, 95%CI:0.34–0.47, p < 0.01). Lastly, those with household incomes ≥$40,000 were more likely to be treated with PCSK9 inhibitors than those with lower household incomes (OR 1.69, 95%CI:1.41–2.02, p < 0.01). ConclusionPCSK9 inhibitor utilization in FH remains low. Significant differences exist based on demographic factors. Female sex, higher household incomes, and younger age were associated with increased PCSK9 inhibitor utilization.

The Effect of Statins in Children and Adolescents With Familial Hypercholesterolemia: A Systematic Review.

Familial hypercholesterolemia (FH) is a genetic disorder that causes elevated low-density lipoprotein-cholesterol (LDL-C) levels. If undiagnosed and untreated in childhood, affected individuals can suffer premature health complications. Statins reduce the risks of complications for adults, but less is known about children. This systematic review examined the effectiveness of statin therapy for lowering LDL-C levels in children with FH. Medline Ovid, Embase, CINAHL, and Allied Health Literature Plus were searched for studies that examined the effectiveness of stains in children ages 1-18 years with heterozygous FH. Of the 706 articles identified, 10 were included in the review. Statin therapy significantly reduced LDL-C levels in pediatric patients with FH. Statins were safe and well-tolerated with minimal adverse effects. Pediatric providers should be familiar with diagnosis, treatment, and management of FH to successfully lower LDL-C levels and avoid potential long-term health effects. Evidence suggests statins are safe and effective in children with FH.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.

Lipid-lowering therapy and low-density lipoprotein cholesterol goal achievement in patients with acute coronary syndromes: The ACS patient pathway project

Background and aimsPost-acute coronary syndrome (ACS) patients are at very high risk for recurrent events and mortality, despite the availability of effective pharmacological approaches. Aim of this survey was to evaluate the compliance to ESC/EAS guidelines during the management of ACS patients and the effectiveness of secondary prevention in seven European countries. MethodsBy means of an online questionnaire, data on 2775 ACS patients (either acute case or follow-up patients) were collected, including data on lipid profile, medications, follow-up visit planning, screening for familial hypercholesterolemia. ResultsLipid profiles were obtained for 91% of ACS patients in the acute phase, mostly within the first day of hospitalization (73%). During hospitalization, 93% of the patients received a lipid-lowering treatment; at discharge, only 66% of the patients received a high intensity statin therapy. At the first follow-up, most of the patients (77.6%) had LDL-C >70 mg/dL; among them, 41% had no change in their lipid-lowering therapies. Similar data were obtained during the second follow-up visit. The analysis of a subgroup of patients with at least 2 follow-up visits and known LDL-C levels showed that the percentage of patients at goal increased from 9% to 32%, and patients with LDL-C <100 mg/dL raised from 23% to 72%. Among acute cases, 44 were admitted with a diagnosis of familial hypercholesterolemia (FH); only 18% of the remaining patients were screened for FH. ConclusionsContemporary lipid management of very high CV risk patients is sub-optimal despite available treatments. Greater efforts are warranted to optimize cardiovascular prevention.

Lipid profile of male and female patients under 18 years old with a diagnosis of familial hypercholesterolemia: An analysis from the lipigen paediatric cohort

Background and Aims: Familial hypercholesterolemia (FH) is one of the most common genetic disorder in childhood, yet is often undetected. High levels of low-density lipoprotein cholesterol (LDL-C) are present since birth, leading to early atherosclerosis. In 2018, the LIPIGEN paediatric group has been set up within LIPIGEN Network to improve detection, diagnosis and management of paediatric FH patients.