Probable Familial Hypercholesterolemia Research Articles

Prevalence of genetically diagnosed familial hypercholesterolemia in Vietnamese patients with premature acute myocardial infarction.

Familial hypercholesterolemia (FH) is a genetic disorder that results in elevated low-density lipoprotein cholesterol (LDL-C) levels, which manifest early in the first decades of life. It is a major cause of premature coronary artery disease worldwide, leading to significant public health challenges. The prevalence of genetically determined FH in patients with premature coronary artery disease remains underestimated, particularly in developing countries. This study aimed to assess the prevalence of genetically defined FH in Vietnamese patients with premature acute myocardial infarction (AMI) in the Vietnamese population. This cross-sectional study enrolled 218 consecutive patients diagnosed with premature AMI who underwent coronary angiography. The low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 genes were analyzed by next-generation sequencing. FH was diagnosed according to Dutch Lipid Clinic Network criteria. Among the patients with premature AMI who underwent coronary angiography, the mean age was 46.9 ± 6.1 years, with a predominance of males (83.9%). The prevalence of potential FH diagnosed using Dutch Lipid Clinic Network criteria was 14.7% (definite FH, 6.0%; probable FH, 8.7%). Pathogenic or likely pathogenic variants in LDLR, apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 were found in 9 of 218 patients (4.1%), all of which were causative mutations in LDLR. Patients with premature AMI and FH had significantly greater LDL-C levels (217.6 vs 125.7 mg/dL) and more severe coronary artery lesions, as assessed by the Gensini score (100.3 vs 60.5), than did those in the No FH group. The prevalence of genetically determined FH among Vietnamese patients with premature AMI is relatively high. Screening and diagnosis of hereditary conditions in patients with premature AMI are essential to improve early detection and management and reduce the burden of coronary artery disease in this population.

Improved Efficiency of the Clinical Diagnostic Criteria for Familial Hypercholesterolemia in Children: A Comparison of the Japan Atherosclerosis Society Guidelines of 2017 and 2022.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels, which increases the risk of premature coronary artery disease. Early detection and treatment are vital, especially in children. To improve FH diagnosis in children, the Japan Atherosclerosis Society (JAS) released new guidelines in July 2022. This study assessed and compared the sensitivity and specificity of the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. From September 2020 to March 2023, 69 children with elevated plasma LDL-C levels (≥ 140 mg/dL) were included in a pediatric FH screening project in Kagawa. The children were evaluated using genetic testing alongside the clinical diagnostic criteria from the JAS pediatric FH guidelines of 2017 and 2022. Using the JAS pediatric FH 2017 criteria, eight children were diagnosed as FH-positive and 61 children as FH-negative. The JAS pediatric FH 2022 criteria identified 15 children with definite FH, 31 with probable FH, and 23 with possible FH. Genetic testing detected FH pathogenic variants in 24 children. The sensitivity and specificity for the JAS pediatric FH 2017 criteria were 0.292 and 0.978, respectively. For the JAS pediatric FH 2022 criteria, the sensitivity was 0.542 for definite FH with a specificity of 0.956, and 0.917 for probable FH with a specificity of 0.467. The clinical diagnostic criteria of the JAS pediatric FH 2022 guidelines demonstrated improved diagnostic efficiency compared with those of 2017, as evidenced by the increased sensitivity while preserving specificity.

Efficacy of targeted screening for familial hypercholesterolemia in children and adults aged <44 years: retrospective, prospective observational study

BACKGROUND: Considering the high cardiovascular risk in patients with familial hypercholesterolemia (FH), early diagnosis and treatment are the basis for the prevention of vascular accidents. In the absence of universal screening, the results of more targeted diagnostics are of interest — the search for lipid metabolism disorders in young relatives of patients with atherosclerotic vascular diseases.
 OBJECTIVE: To determine the effectiveness of targeted screening for identifying patients with FH, which will justify its widespread use in clinical practice.
 MATERIALS AND METHODS: At the start of the observational study, 584 patients were identified from the vascular centers of the Krasnoyarsk Regional Hospital, Krasnoyarsk Interdistrict Clinical Hospital No. 20 named after. I.S. Berzon, who had lipid profile data and early cardiovascular events (all forms of coronary heart diseases), including reconstructive vascular interventions up to 55 years in men and up to 60 years in women in the case of first-degree relatives and up to 50 years in second-degree relatives. The study examined patients’ relatives aged 44 years. To diagnose FH in participants aged 16 years, the scale developed by a network of Dutch lipid clinics was used; in participants aged 16 years, the S. Broome criteria were used. Targeted screening and lipid parameters in individuals with probable, possible, and definite FH were analyzed. Data processing was performed using Microsoft Excel and Statistica v. 12.0 (USA). Parametric (calculation of the median and 25th and 75th quartiles) and nonparametric (statistical significance of differences was determined using the Mann–Whitney and χ2 tests) methods were used.
 RESULTS: The study examined 70 children and 104 adults aged 44 years whose first- and/or second-degree relatives suffered premature vascular events. In the general group of participants, 42 (24.14%) patients had FH (of which 18 were 17 years old) and 37 (21.2%) had hyperlipoproteinemia (a). Definite FH was documented in 16 (9.1%) patients, probable in another 16, and possible in 9. Hyperlipoproteinemia (a) was found in 37 (21.2% of general group) patients, including 12 children (17.1% of pediatric group).
 CONCLUSION: Not more than 30% of the population are aware of the hereditary nature of lipid metabolism disorders and atherosclerotic diseases. Targeted screening is the least expensive and most effective tool for identifying patients with FH and hyperdipoproteinemia (a).

Prevalence and Clinical Characteristics of Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome according to the Current Japanese Guidelines: Insight from the EXPLORE-J study.

Little data exists for evaluating the prevalence and patient characteristics of familial hypercholesterolemia (FH) according to the latest 2022 guidelines for FH published by the Japan Atherosclerosis Society (JAS), which revised the Achilles tendon thickness (ATT) threshold from 9.0 mm in both sexes to 8.0 mm in men and 7.5 mm in women. This study used a nationwide registry of patients with acute coronary syndrome (ACS) to evaluate the prevalence of FH according to the latest diagnostic criteria for FH and to investigate the application of Achilles tendon imaging in the diagnosis of FH.A previous prospective observational study at 59 Japanese centers involving consecutive patients with ACS who were managed between April 2015 and August 8, 2016 was conducted to explore lipid management and persistent risk in patients hospitalized for ACS (EXPLORE-J). The study population consisted of 1,944 EXPLORE-J enrollees. According to the diagnostic criteria for FH in the 2022 JAS guidelines, the prevalence of probable or definite was among patients with ACS was 6.6% (127/1944). Among patients with premature ACS (male, age ＜55 years; female, age ＜65 years), the prevalence of FH was 10.1% (43/427). The mean ages were of the probable FH and definite FH groups were 59.9 and 61.0 years, respectively, while the mean age of the possible-or-unlikely FH group was 66.4 years (significantly older). Relative to the possible-or-unlikely FH group, the low-density lipoprotein cholesterol (LDL-C) levels were similar in the probable FH group and and significantly higher in the definite FH group. The prevalence of FH was considerably higher than previously reported, especially for patients with premature ACS. The age and LDL-C levels of the patients in the probable FH and definite FH groups were similar.

Genetic testing for familial hypercholesterolemia in a Finnish cohort of patients with premature coronary artery disease and elevated LDL-C levels.

Based on Finnish LDLR-founder variations, the prevalence of familial hypercholesterolemia (FH) in Finland is estimated to be at least 1:600. Patients with FH have increased risk of premature coronary artery disease (CAD) and thus the prevalence of FH is expected to be higher in this subgroup. To assess the prevalence of monogenic FH in a Finnish cohort of patients with premature CAD and elevated low-density lipoprotein cholesterol (LDL-C) levels. Among 28,295 patients undergoing angiography at Heart Hospital at Tampere University Hospital between 2007 and 2017, we identified 162 patients diagnosed with premature CAD (men aged <55 years and women aged <60 years) and history of high LDL-C (≥5 mmol/L) levels without secondary causes of hypercholesterolemia. Clinical probability of FH was estimated, and genetic testing of FH was carried out in 80 patients with informed consent. Of the 80 patients with premature CAD and history of high LDL-C levels, 70% were men; the age at diagnosis of CAD for male and female patients was 48 and 53 years, respectively. In total, 58 (73%) patients had probable (n = 54) or definite (n = 4) FH based on Dutch Lipid Clinic Network criteria. A pathogenic variant of FH was found in five (6%) patients. Prevalence of the genetically verified FH was 1:16. The FH variant was found in 75% of patients with definite FH. The prevalence of genetically verified FH was 1:16 among patients with premature CAD and elevated LDL-C level, which is 38 times higher than the estimated prevalence of 1:600 in the general Finnish population.

Assessment of Low-density Lipoprotein Cholesterol Levels and Non-invasive Vascular Health in School-aged Children: A Study in Ogasa District, Shizuoka Prefecture.

The present study assessed low-density lipoprotein cholesterol (LDL-C) levels in school-aged children from the Ogasa District of Shizuoka Prefecture and evaluated the utility of non-invasive vascular tests, namely flow-mediated dilation (FMD) and intima-media thickness (IMT), in pediatric patients with familial hypercholesterolemia (FH). We analyzed the lipid test results of 8,568 students screened for prevention of lifestyle-related diseases and 78 children under 15 years old with cholesterol levels exceeding 220 mg/dL who visited Chutoen General Medical Center. We examined the LDL-C distribution from school-age screenings and conducted FMD and IMT assessments on those meeting the 2022 Pediatric FH Guidelines criteria. Among the screened students, 186 (2.2%) exhibited LDL-C levels above 140 mg/dL, including 123 fourth-graders (2.8%) and 63 first-year junior high students (1.5%). The mean LDL-C level across all students was 90.0 mg/dL (standard deviation: 21.3 mg/dL), with the 95th percentile at approximately 125.0 mg/dL. Of the 78 children who visited the hospital, 65 met the FH diagnostic criteria. In children ≥ 10 years old, no significant IMT differences were observed between the Definitive and Probable FH groups and the Possible FH group; however, a significant difference in the FMD percentage was noted between these groups (9.9% [8.1%-11.9%] vs. 14.2% [11.6%-16.3%], P=0.003). Our findings highlight the LDL-C distribution in FH screening and suggest a potential reduction in FMD in pediatric FH patients ≥ 10 years old. These results emphasize the importance of initiating pharmacological interventions in school-aged children to maintain optimal LDL-C levels for lifelong cardiovascular health.

Familial Hypercholesterolemia and Type 2 Diabetes: Diagnostic and Therapeutic Challenges

Familial hypercholesterolemia (FH) is a largely underdiagnosed and undertreated disease. Findings regarding the coexistence and interplay between FH and type 2 diabetes (T2D) are conflicting. Epidemiological data suggest an approximately halved prevalence of T2D in FH and an approximately doubled cardiovascular disease (CVD) risk, dependent on mutation type, age, sex, lifestyle, associated pathologies and therapy.For conference attending physicians involved in hypercholesterolemia management, a FH survey was developed including diagnostic-screening situations, severity assessment, while for hypercholesterolemia patients with premature CVD, a web-based tool was prepared for identification of familial cases. For diagnosis, the Simon Broome, DLCN and MEDPED criteria were used.Physicians showed difficulties in FH identification and risk stratification, overestimating the role of associated metabolic changes and underestimating identified mutations characterized by increased CVD risk at any LDL-C level. In children, neither universal nor early lipid screening in strong family history was recommended, unlike in cases with associated metabolic disturbances. In patients, 21.73% presented definite and/or probable FH diagnosis by at least two scoring systems, 3.84% manifesting also T2D. The case of a 45-year-old patient with gestational diabetes and PCOS, conflicting algorhithms-based FH diagnosis and no means for genetic testing, good cholesterol response to statins but aggravating aorta stenosis exemplifies management challenges.In conclusion, FH identification and individual risk assessment may be assisted by targeting selected patients for diagnosis and physicians for raising awareness, but limited access to mutation analysis and novel non-diabetogenic lipid lowering therapies incumber management of FH and the reduced number of cases with coexisting T2D.

Prevalence of familial hypercholesterolemia in patients with acute coronary syndrome

&amp;lt;p&amp;gt;&amp;lt;strong&amp;gt;Aim &amp;lt;br /&amp;gt;&amp;lt;/strong&amp;gt;To investigate the prevalence of familial hypercholesterolemia in patients with acute coronary syndrome (ACS).&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Methods&amp;lt;/strong&amp;gt; &amp;lt;br /&amp;gt;The study included fifteen patients with first or repeated ACS and treated/nontreated dyslipidaemia admitted to the Department of Cardiovascular Diseases of Clinical Hospital Centre Osijek between 1 January 2020 and 1 January 2021. The cut-off value of low-density lipoprotein (LDL)-C was 4.5mmol/L as a possible cut-off value for familial hypercholesterolemia presence. Data were collected from medical history and during patient&amp;amp;rsquo;s follow-up.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Results&amp;lt;/strong&amp;gt; &amp;lt;br /&amp;gt;Included patients that fulfilled criteria were predominantly male &amp;amp;ndash; 14 (93%), mean age 61 years. The median level of LDL cholesterol at admission because of ACS was 5.14 mmol/L, whereas the follow-up level after one year was 2.27 mmol/L (p=0.001). At first follow-up, 7 (46%) patients were treated with atorvastatin 80 mg or rosuvastatin 40 mg, 3 (20%) atorvastatin 80mg + ezetimibe 10mg, 2 (13%) with rosuvastatin 40 mg+ ezetimibe 10 mg, other patients were treated with a lower dose of statin or ezetimibe. According to LDL-C profile and by calculating the&amp;lt;br /&amp;gt;Dutch Lipid Clinic Network Score, one (of 15) patient was categorized as having definite familial hypercholesterolemia and two (of 15) as having probable familial hypercholesterolemia leading to the use of triple hypolipidemic therapy (statin+ezetimibe+PCSK9 inhibitor) in 2 (13%) patients (one female and one male).&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Conclusion&amp;lt;/strong&amp;gt; &amp;lt;br /&amp;gt;LDL-C level of 4.5 mmol/L and higher represents an indication for screening for familial hypercholesterolemia in patients with ACS. The prevalence of familial hypercholesterolemia in ACS, estimated by the Dutch Lipid Clinic Network Score, could be higher than previously reported.&amp;lt;/p&amp;gt;

Evaluating the prevalence of lipid assessments in children in Alberta, Canada.

Familial hypercholesterolemia is a common, inherited, life-threatening and treatable condition that is characterized by marked elevations of low-density lipoprotein cholesterol (LDL-C), resulting in a high risk of cardiovascular disease, but treatment starting in childhood dramatically reduces this risk. We sought to evaluate the prevalence of pediatric lipid assessments among children in Alberta. We reviewed laboratory and administrative data from Alberta Health between Apr. 1, 2012, and Dec. 31, 2021. We evaluated 2 pediatric cohorts (children aged 2-10 yr and children aged 9-17 yr) to allow for longitudinal assessments throughout the pediatric period. We also reviewed annual frequencies of lipid assessment for all children between 2013 and 2021. Pediatric lipid assessments were performed for 1972 (4.3%) of 46 170 children aged 2-10 years and for 8158 (19.9%) of 40 926 children aged 9-17 years. Female children (aged 2-10 yr) and those living in rural communities were significantly less likely to have a lipid assessment, compared with male children and those in nonrural communities. Among those with lipid assessments, 23 (1.2%) and 86 (1.1%) children aged 2-10 years and 9-17 years, respectively, had an LDL-C level suggestive of probable familial hypercholesterolemia (≥ 4.0 mmol/L). Statin therapy was prescribed in 16 children during the study period. The frequency of lipid assessments was relatively stable, with the exception of a decrease in 2020. Rates of pediatric lipid assessment in Alberta are suboptimal. These findings highlight the need to increase awareness of the benefits of early diagnosis and treatment of familial hypercholesterolemia with regard to long-term health and identify and overcome barriers to diagnosis and treatment.

Genetic testing for familial hypercholesterolemia in Quebec, Canada: a single-centre retrospective cohort study.

Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C) levels. We determined the impact of a full next-generation sequencing (NGS) genetic panel on reclassification of patients with a clinical diagnosis of FH in Quebec compared to the partial genetic panel currently offered by the Quebec Ministère de la Santé et des Services sociaux (Ministry of Health and Social Services) (MSSS), which includes 11 variants that are common in French Canadians. We conducted a retrospective cohort study in a subgroup of patients in the Canadian FH Registry seen at the McGill University Health Centre Preventive Cardiology/Lipid Clinic, Montréal, between September 2017 and September 2021 who were clinically diagnosed with severe hypercholesterolemia, probable FH or definite FH according to the Canadian definition of FH. Next-generation sequencing of the LDLR, APOB and PCSK9 genes, and multiplex ligation-dependent probe amplification of the LDLR gene to detect genetic variants, were performed. Among 335 consecutive patients with heterozygous FH (184 men [54.9%] and 151 women [45.1%]), the baseline LDL-C level was 6.96 (standard deviation 1.79) mmol/L. Patients identified through cascade screening were 11 years younger on average than index patients, and smaller proportions presented to the clinic with cardiovascular risk factors. A pathogenic FH variant was identified in 169 (73.8%) of the 229 patients who underwent genetic testing; the majority had variants in the LDLR (146 [86.4%]) or APOB (24 [14.2%]) gene. The genetic panel offered by the MSSS accounted for only 48% of the variants identified with the full NGS panel. Of the 229 patients, 90 (39.3%, 95% confidence interval 32.9%-46.0%) were reclassified from a clinical diagnosis of probable FH to definite FH after genetic screening with a full FH panel. Genetic testing in patients suspected of having FH provided diagnostic certainty and permitted many patients with a clinical diagnosis of probable FH to be reclassified as having definite FH. Genetic screening allows for increased identification of patients with FH and may therefore help reduce the burden of cardiovascular disease and mortality rates among Canadians with FH. Trial registration: ClinicalTrials.gov, no. NCT02009345.

Yield of Familial Hypercholesterolemia Genetic and Phenotypic Diagnoses After Electronic Health Record and Genomic Data Screening.

Background Data mining of electronic health records to identify patients suspected of familial hypercholesterolemia (FH) has been limited by absence of both phenotypic and genomic data in the same cohort. Methods and Results Using the Geisinger MyCode Community Health Initiative cohort (n=130 257), we ran 2 screening algorithms (Mayo Clinic [Mayo] and flag, identify, network, deliver [FIND] FH) to determine FH genetic and phenotypic diagnostic yields. With 29 243 excluded by Mayo (for secondary causes of hypercholesterolemia, no lipid value in electronic health records), 52 034 excluded by FIND FH (insufficient data to run the model), and 187 excluded for prior FH diagnosis, a final cohort of 59 729 participants was created. Genetic diagnosis was based on presence of a pathogenic or likely pathogenic variant in FH genes. Charts from 180 variant-negative participants (60 controls, 120 identified by FIND FH and Mayo) were reviewed to calculate Dutch Lipid Clinic Network scores; a score ≥5 defined probable phenotypic FH. Mayo flagged 10 415 subjects; 194 (1.9%) had a pathogenic or likely pathogenic FH variant. FIND FH flagged 573; 34 (5.9%) had a pathogenic or likely pathogenic variant, giving a net yield from both of 197 out of 280 (70%). Confirmation of a phenotypic diagnosis was constrained by lack of electronic health record data on physical findings or family history. Phenotypic FH by chart review was present by Mayo and/or FIND FH in 13 out of 120 versus 2 out of 60 not flagged by either (P<0.09). Conclusions Applying 2 recognized FH screening algorithms to the Geisinger MyCode Community Health Initiative identified 70% of those with a pathogenic or likely pathogenic FH variant. Phenotypic diagnosis was rarely achievable due to missing data.

Guidelines for the Diagnosis and Treatment of Pediatric Familial Hypercholesterolemia 2022.

As atherosclerosis begins in childhood, early diagnosis and treatment of familial hypercholesterolemia (FH) is considered necessary. The basic diagnosis of pediatric FH (under 15 years of age) is based on hyper-low-density lipoprotein (LDL) cholesterolemia and a family history of FH; however, in this guideline, to reduce overlooked cases, "probable FH" was established. Once diagnosed with FH or probable FH, efforts should be made to promptly provide lifestyle guidance, including diet. It is also important to conduct an intrafamilial survey, to identify family members with the same condition. If the level of LDL-C remains above 180 mg/dL, drug therapy should be considered at the age of 10. The first-line drug should be statin. Evaluation of atherosclerosis should be started using non-invasive techniques, such as ultrasound. The management target level is an LDL-C level of less than 140 mg/dL. If a homozygous FH is suspected, consult a specialist and determine the response to pharmacotherapy with evaluating atherosclerosis. If the response is inadequate, initiate lipoprotein apheresis as soon as possible.

Genetic testing increases the likelihood of a diagnosis of familial hypercholesterolaemia among people referred to lipid clinics: Danish national study

Background and aimsIt is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. MethodsFrom September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. ResultsA total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. ConclusionsIn a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

Possibilities of lipid clinics in identifying patients with familial hypercholesterolemia

Aim. To assess the detection rate of familial hypercholesterolemia among outpa­tients visiting a lipidologist.Material and methods. We analyzed the causes and nature of lipid metabolism disorders in patients of the Adult Lipidology Center as follows: 1233 people aged 18-84, including 777 women (63,02%) and 456 men (36,98%). Biomaterial samples from 421 patients with the phenotype of definite, possible or probable familial hypercholesterolemia were studied by massive parallel sequencing using a panel of 5 genes associated with familial hypercholesterolemia (LDLR, LDLRAP1, APOB, APOE, PCSK9). For statistical processing, descriptive statistics methods were used.Results. Working-age patients apply 1,56 times more often than patients of the older age group (60,91% vs 39,09%), and the vast majority of them were referred by a primary care physician based on data from periodic health examinations. The mean level of total cholesterol and low-density lipoprotein cholesterol in the lipidology center was 7,58 and 4,8, respectively. Out of 421 samples, 127 patients (10,3% of the total number of patients and 30,16% of the number of biosamples) had previously described variants of the LDLR, APOB and/or PCSK9 genes associated with familial hypercholesterolemia.Conclusion. The detection rate of definite familial hypercholesterolemia ranges from 5,51 to 8,43% of outpatients visiting a lipidologist, while the proportion of verified carriers of gene mutations related to familial hypercholesterolemia is 10,3%. The diagnosis should not be rejected with a formally low probability according to the S. Broom and DLCN criteria, as well as when identifying data suggestive of secondary lipid metabolism disorders.

Familijarna hiperholesterolemija i kaskadni skrining za detekciju novih pacijenata

Familial Hypercholesterolemia (FH) is a metabolic disorder that is inherited in an autosomal dominant manner and is characterized by elevated cholesterol levels and the development of premature atherosclerotic cardiovascular disease (ASCVD). The prevalence of heterozygous FH is 1 in 250-500 individuals, while the prevalence of homozygous FH is 1 in a million. The molecular basis of this condition involves mutations in the genes encoding the LDL receptor (Low-Density Lipoprotein Receptor, LDLR), Apolipoprotein B (ApoB), or Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) enzyme. In patients with FH, laboratory analyses are dominated by elevated levels of low-density lipoprotein cholesterol (LDL-C) above the 95th percentile for age and gender, with most commonly normal values of high-density lipoprotein cholesterol (HDL-C) in very low-density lipoprotein cholesterol (VLDL-C), and triglycerides. The gold standard for diagnosing FH is genetic analysis and mutation detection, but it is often inaccessible due to economic reasons. Today, the diagnosis is made by applying a scoring system within well-validated questionnaires, which assess the probability of FH based on the simultaneous analysis of personal and family history, clinical findings of tendon xanthomas or corneal arcus, as well as biochemical analysis of the lipid profile. Despite clear diagnostic recommendations for FH, there is an extremely low rate of diagnosis of these patients, even in developed healthcare systems, as well as a low rate of treatment. A large number of unrecognized FH patients, along with a significantly increased risk of cardiovascular diseases in untreated young FH patients, have prompted global efforts to diagnose the disease earlier and reduce complications through appropriate treatment. Cascade screening in the detection of new patients involves analyzing the relatives, first-, second-, and third-degree, of patients with known FH (index case, proband). Upon identifying a new case, that individual becomes the new proband, and their relatives are analyzed in subsequent cascades. There are three basic models of cascade screening: clinical, genetic, and hybrid models. Currently, selective clinical cascade screening is most commonly applied. Selective cascade screening detects the disease in individuals at high risk of its manifestation. The expert consensus panel recommends a hybrid model, where genetic testing is performed in all patients with definite or probable FH, and in cascade screening, both cholesterol levels and genetic analysis are continued in their high-risk relatives. Adequate detection of FH patients and timely treatment significantly reduce their cardiovascular morbidity and mortality, justifying the implementation of cascade screening. Conducting screening through routine clinical practice does not yield satisfactory results. Therefore, it is necessary to organize a screening program at the national level, including the establishment of lipidology centers and the provision of genetic screening and genetic counseling services.

The Association of Thyroid-Stimulating Hormone (TSH) Levels and Lipid Profile in Euthyroid Patients with Familial Hypercholesterolemia.

Previous studies reported a relationship between thyroid-stimulating hormone (TSH) and low-density lipoprotein cholesterol (LDL-C) levels. In this study, we aim to evaluate the impact of TSH levels on lipid profile in patients with familial hypercholesterolemia (FH) and euthyroid state. Patients were selected from the Isfahan FH registry. The Dutch Lipid Clinic Network (DLCN) criteria are used to detect FH. Patients were classified into no FH, possible FH, probable FH, and definite FH groups based on the DLCN scores. Patients with any cause of secondary hyperlipidemia, including hypothyroidism, were excluded from this study. The study group consisted of 103 patients with possible FH, 25 patients with definite FH, and 63 individuals with no FH. The mean TSH and LDL-C levels among participants were 2.10 ± 1.22 mU/l and 142.17 ± 62.56 mg/dl, respectively. No positive or negative correlation was found between serum TSH and total cholesterol (P value = 0.438), high-density lipoprotein cholesterol (P = 0.225), triglycerides (P value = 0.863), and LDL-C (P value = 0.203). We found no correlation between serum TSH levels and lipid profiles in euthyroid patients with FH.

Abstract 12665: Using Healthcare Claims Data and Machine Learning to Identify Health Disparities for Individuals With Diagnosed and Undiagnosed Familial Hypercholesterolemia

Introduction: Individuals with Familial Hypercholesterolemia (FH) warrant intensive lipid lowering therapy starting with statins and adding ezetimibe and PCSK9 inhibitors (PCSK9i) as needed to achieve LDL-C treatment targets. Little data exists on whether disparities exist in the US FH population for ezetimibe, PCSK9i or the combination of statins + ezetimibe + PCSK9i. Methods: We queried the Family Heart Database, a healthcare claims database from the Family Heart Foundation, for filled prescriptions for statins, ezetimibe, and PCSK9i in patients with an ICD-10 diagnosis of FH (E.78.01) as well as undiagnosed FH patients (Probable FH) identified by the Family Heart Foundation’s FIND-FH® machine learning algorithm. Data were analyzed in multivariable models including age, education, income, race/ethnicity, and gender. Results: Among 77,671,959 individuals, 280,426 had an ICD-10 diagnosis of FH (51% female, 79.5% White, 11.8% Black, and 8.7% Hispanic) and 899,027 had Probable FH (48% female, 78.7% White, 12.9% Black, and 8.5% Hispanic). Diagnosed and Probable FH males were 46% and 48% more likely, respectively, than females to receive high intensity statins. Individuals in the $100,000+ income bracket - both the diagnosed and Probable FH groups - were 30 to 50% more likely to receive ezetimibe, PCSK9i, or statin + ezetimibe + PCSK9i (Table). The highest education level was associated with 51% higher odds of statin + ezetimibe + PCSK9i use in diagnosed FH patients. Whites were 6-30% more likely to get ezetimibe, PCSK9i, and the combination of statin + ezetimibe + PCSK9i compared to Blacks. Conclusions: Real world patterns of medical care reveal appropriate lipid lowering therapy is more often prescribed for individuals with FH who are White, have high income, or have advanced education. Efforts are warranted to improve equity and provide all individuals with FH an opportunity for cardiovascular risk reduction.

Abstract 9822: Yield of a Familial Hypercholesterolemia Genetic Diagnosis After Electronic Health Record and Genomic Data Screening

Background: Data mining of electronic health records (EHR) has been used as a strategy to identify patients with undiagnosed familial hypercholesterolemia (FH). Most studies have been limited by the absence of both phenotypic and genotypic data in the same cohort. Methods: Using a subset of the Geisinger MyCode Community Health Initiative (MyCode) cohort with both exome sequencing and EHR data (n=130,257), we ran two FH screening algorithms to determine genetic and phenotypic diagnostic yields: the Mayo Clinic algorithm (Mayo), which identifies those with LDL-C levels &gt; 190 mg/dL, and FIND FH®, the Family Heart Foundation’s machine learning model, to identify individuals with phenotypes suggestive of FH. With 29,243 excluded by Mayo (for secondary causes of hypercholesterolemia, no lipid value in EHR), 52,034 excluded by FIND-FH (insufficient data to run the model), and 187 excluded for prior FH diagnosis, a final cohort of 59,729 participants screened by both algorithms was created. Genetic diagnosis was based on the presence of a pathogenic or likely pathogenic (P/LP) variant in 3 genes implicated in FH via genomic screening. Charts from 180 variant negative participants (60 controls; 120 identified by FIND FH and/or Mayo) were reviewed to calculate Dutch Lipid Clinic Network scores; a score &gt; 5 defined probable or definite FH. Results: Mayo flagged 10,415 subjects; 164 (1.6%) had an FH P/LP variant. FIND-FH flagged 573; 28 (4.9%) had an FH P/LP variant giving a net yield from both algorithms of 167/240 (70%). Confirmation of a phenotypic diagnosis was constrained by lack of EHR data on physical findings or family history (high cholesterol, premature atherosclerotic disease) required for score calculation. Phenotypic FH by chart review was present by Mayo and/or FIND-FH in 13/120 vs 2/60 not flagged by either (p&lt; 0.09). Conclusion: After excluding those with a prior FH diagnosis, applying two recognized phenotypic FH screening algorithms to the eligible MyCode cohort identified 70% of those with a P/LP FH variant. Limitations to this approach include participant exclusions for each algorithm, a low yield of positive genomic screening for Mayo, and a low yield of participants for FIND FH. Phenotypic diagnosis was rarely achievable due to missing data.

Low-density lipoprotein cholesterol goal attainment in patients with clinical evidence of familial hypercholesterolemia and elevated Lp(a)

BackgroundAlthough potent lipid-lowering therapies are available, patients commonly fall short of recommended low-density lipoprotein cholesterol (LDL-C) levels. The aim of this study was to examine the relationship between familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] and LDL-C goal attainment, as well as the prevalence and severity of coronary artery disease (CAD). Moreover, we characterized patients failing to meet recommended LDL-C goals.MethodsWe performed a cross-sectional analysis in a cohort of patients undergoing cardiac catheterization. Clinical FH was determined by the Dutch Clinical Lipid Network Score, and Lp(a) ≥ 50 mg/dL (≈ 107 nmol/L) was considered elevated.ResultsA total of 838 participants were included. Overall, the prevalence of CAD was 72%, and 62% received lipid-lowering treatment. The prevalence of clinical FH (probable and definite FH) was 4%, and 19% had elevated Lp(a) levels. With 35%, LDL-C goal attainment was generally poor. Among the participants with clinical FH, none reached their LDL-C target. Among patients with elevated Lp(a), LDL-C target achievement was only 28%. The prevalence and severity of CAD were higher in participants with clinical FH (86% prevalence) and elevated Lp(a) (80% prevalence).ConclusionMost participants failed to meet their individual LDL-C goals according to the ESC 2016 and 2019 guidelines. In particular, high-risk patients with clinical FH or elevated Lp(a) rarely met their target for LDL-C. The identification of these patients and more intense treatment approaches are crucial for the improvement of CAD primary and secondary prevention.

ODP137 Achilles Tendon Size and Characteristics for Diagnosis of Familial Hypercholesterolemia Among Thai Patients

Abstract Background The presence of tendon xanthomas, defined as thickening or nodularities of tendons, is subjective and remains largely undetected in patients with familial hypercholesterolemia (FH) in clinical practice. This study aimed to determine Achilles tendon thickness cutoff values associated with the highest diagnostic accuracy for identifying FH among Thai patients. Methods 63 subjects with possible, probable or definite FH according to the Dutch Lipid Clinic Network criteria, 58 subjects with hypercholesterolemia not compatible with FH and 55 normolipidemia subjects were recruited. Achilles tendon thickness was measured on each side separately at the point of maximum thickness using Lange skinfold calipers, Slim Guide skinfold calipers, plain radiograph of lateral ankles and ultrasonography. Ultrasonographic characteristics of the tendons were also recorded. The diagnostic performance of the maximum Achilles tendon thickness (maximum value of either left or right Achilles tendon of each person) obtained by each method was determined by Receiver-Operating Characteristic curves and optimal cut-points determined by Youden's index. Spearman rank-order correlation coefficient assessed factors associated with Achilles tendon thickness. Results Of all subjects, the mean age was 47 (±13) years, and 45% were male. The study groups were comparable in baseline characteristics except for a higher LDL cholesterol burden, a longer duration of lipid lowering therapy and a higher percentage of subjects receiving high intensity statins and ezetimibe in the FH group. Both types of skinfold calipers demonstrated 61% accuracy for diagnosing FH. An anteroposterior (AP) diameter on plain radiographs ≥7.7 mm had an 80% accuracy with 75% sensitivity and 82% specificity, whereas ultrasonographic thickness ≥6.4 mm. showed a 76% accuracy with 46% sensitivity and 93% specificity. Tendon border irregularities, diffuse hypoechogenicity and calcification were reported in a higher percentage of patients with FH, compared with the other 2 groups. Factors showing a significant correlation with Achilles tendon thickness in the FH group were years since FH diagnosis, a higher Dutch Lipid Clinic Network score and a higher body mass index (BMI). In the overall cohort, factors showing a significant correlation were higher LDL cholesterol burden and higher BMI. Conclusion Achilles tendon thickness measured by calipers showed low accuracy for FH diagnosis. An AP diameter on plain radiographs demonstrated highest sensitivity, whereas ultrasonographic thickness and area of Achilles tendon showed high specificity. Tendon irregularities, diffuse hypoechogenicity and calcification might serve as supportive findings. Presentation: No date and time listed