Dutch Lipid Clinic Network Score Research Articles

Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. Adult patients ( n = 2156, mean age 50 ± 15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study.

Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection. We identified 213 subjects with FH gene panel reports (LDLR, APOB, PCSK9, and APOE) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded. A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald. Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.

Clinical characteristics of carriers of pathogenic LDLR and АРОВ mutations

Aim. To analyze the clinical characteristics of carriers of pathogenic LDLR and АРОВ mutations, as well as the prognostic value of Dutch Lipid Clinic Network Score (DLCNS) as applied to carriage of АРОВ or LDLR.Material and methods. The study included 1233 outpatient lipid clinic patients. Biomaterial samples from 421 patients with the hereditary dyslipidemia were studied using Next Generation Sequencing (NGS) to identify carriage of familial hypercholesterolemia (FH)-associated genes (LDLR, АРОВ, PCSK9, LDLRAP1), as well as polymorphism of the APOE gene. Statistical processing was performed using descriptive statistics methods.Results. According to the data obtained, the most significant predictors of pathogenic LDLR mutations are the levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), family history of coronary artery disease (CAD), and previous coronary artery bypass grafting. The level of LDL-C, family history of cerebrovascular accident or CAD, and arcus senilis were more significant for verifying the carriage of pathogenic АРОВ mutations. Using screening potential carriers of FH using the DLCN or Simon-Broome diagnostic criteria, the probability of FH may be underestimated due to the discrepancy between the scale criteria and the prognostic contribution of clinical or anamnestic data. These scales do not take into account the estrogen status of potential female carriers of FH.Conclusion. Thus, diagnostic criteria for identifying potential FH vary among different patient groups. Their diagnostic significance depends on sex, and in women, on reproductive status. Only part of DLCN and Simon-Broome criteria can be applied to assess the FH likelihood, and to a greater extent for carriage of LDLR, but not АРОВ.

Achilles tendon ultrasonography in the clinical screening of familial hypercholesterolaemia - a cross-sectional analysis.

People with familial hypercholesterolaemia are 13 times more likely to develop cardiovascular disease than the general population. However, familial hypercholesterolaemia remains largely underdiagnosed. Tendon xanthoma is a specific clinical feature of familial hypercholesterolaemia and its presence alone implies a probable diagnosis of familial hypercholesterolaemia according to the Dutch Lipid Clinic Network Score (DLCNS). The aim of the study was to determine whether ultrasound detects more Achilles tendon xanthomas (ATX) than clinical examination. We recruited 100 consecutive patients with LDL-C ≥4 mmol/l. Achilles tendons were evaluated through clinical examination by trained physicians and sonographic examination by another physician blind to the results of clinical examination. Blind second readings of ultrasound images were performed by an expert in musculoskeletal ultrasound. We compared the proportion of patients with ATX detected by either clinical examination or ultrasound and the proportion of patients with a probable/definite familial hypercholesterolaemia diagnosis on the DLCNS before and after ultrasound. Mean (SD) age was 47 (12) years; mean highest LDL-C was 6.57 mmol/l (2.2). ATX were detected in 23% of patients by clinical examination and in 60% by ultrasound. In consequence, 43% had a probable/definite diagnosis of familial hypercholesterolaemia on the DLCNS using clinical examination compared with 72% when ultrasound was used. Compared to clinical examination, ultrasound examination of the Achilles tendon substantially improves the detection of ATX and may help to better identify patients with familial hypercholesterolaemia who are at high risk for premature cardiovascular disease.

Analysis of routine molecular genetic diagnostics of familial hypercholesterolemia at tertiary care lipid clinics

Abstract Background Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease, causing dyslipidemia and premature atherosclerotic cardiovascular disease (ASCVD), with currently ∼2,000,000 unidentified adult cases as well as ∼500,000 children cases in Europe. Purpose Aim of this study is to analyse the current yield of routine molecular genetic diagnostics for FH and the spectrum of mutations in two specialist lipid clinics. Methods We investigated all genetic tests performed for FH in our clinics over a 4-year period. Reports of causative mutations in the main FH-causing genes including LDLR, APOB, PCSK9 were collected. Variants were classified based on HGVS nomenclature using the mutation database ClinVar. For clinical classification, the Dutch Lipid Clinic Network Score (DLCNS) was used, which is based on off-treatment low-density lipoprotein cholesterol (LDL-C) ranges, family and patient history as well as pathognomonic signs. Results Of 473 patients tested, 102 (21.6%) had a causative mutation (LDLR=84%, APOB=9%, PCSK9=5%), three of which were novel. 14 further, previously unreported variants of unknown significance were identified. The detection rate was 64% in patients with clinically definite FH i.e. DLCNS >8 (10.7% of the cohort), 30% in those with a DLCNS between 6 and 8 (20.6%), 16% in those with a DLCNS between 3 and 5 (47.2%) and 4% in DLCNS <3 (21.5%). The detection rate among those with an off-treatment LDL-C ≥190 mg/dL was 30.5%, and 7.5% in those <190 mg/dL. Median DLCNS at testing was 4, in positively tested 6. Mean off-treatment LDL-C levels were significantly higher in positively compared to negatively tested (266±67 mg/dl vs 198±61 mg/dl; p<0.001), and in those with DLCNS ≥6 compared to <6 (284±67 mg/dl vs 190±53 mg/dl p<0.001). The currently established LDL-C cut-off of 190 mg/dL showed a sensitivity of 90.6% [80.1 - 96.1] and a specificity of 35.9% [29.5 - 42.9], while a DLCNS cut-off of ≥6 shows a sensitivity of 60.3% [48.1 – 71.3], a specificity of 76.7% [71.0 – 81.6]. Both performed well in ROC analyses with an AUC of 0.632 for the LDL-C cut-off of 190 mg/dL vs 0.707 for DLCNS≥6, with an insignificant difference in AUC between the two (-0.075; p=0.053). Conclusions Practically, a simple off-treatment LDL-C cut-off of 190 mg/dL, performing comparably to the more time-consuming DLCNS might enhance the identification of suspected cases especially by non-specialists and in primary care, allowing for a much needed surge in referrals to specialist centers for diagnostic workup, thereby possibly improving diagnosis rates in this severely underdiagnosed disease.Mutation detection within DLCNS groupsOff-treatment LDL-C by mutation status

Detection of hidden cases of familial hypercholesterolemia in the Netherlands: a central laboratory data-driven strategy

Abstract Introduction Familial hypercholesterolemia (FH) is a common genetic disorder in which patients are at high risk for premature coronary artery disease (CAD) due to lifelong exposure to low-density lipoprotein cholesterol (LDL-C). Although early diagnosis and lipid lowering therapy (LLT) are essential to prevent adverse cardiovascular outcomes, FH patients remain globally underdiagnosed and undertreated, warranting novel screening methods to identify these patients. In the present study we aimed to evaluate whether existing central laboratory data can be utilized as a new method to detect undiagnosed FH patients. Additionally, we investigated the extent of underdiagnosis and undertreatment among patients with severe hypercholesterolemia in the Netherlands. Methods In this single-center, cross-sectional study, we selected individuals with at least one previously measured LDL-C plasma level ≥99.5th percentile for age and sex, from a central laboratory database containing lipid profiles of approximately 600.000 primary care patients. First, a blood sample was obtained to get more recent lipid values. Participating patients were subsequently asked to fill out a detailed questionnaire on medical and family history. Using these data, we calculated the Dutch Lipid Clinic Network (DLCN) criteria for each patient for the clinical diagnosis of FH. Results We identified a total of 5,100 patients with severe hypercholesterolemia (at least one LDL-C ≥99.5th percentile for age and sex) from the central laboratory database. Out of these, 1,206 patients (24%) participated in this study. Mean ± SD LDL-C corrected for LLT was 5.72 ± 1.83 mmol/L, 785 patients (65.1%) used LLT, and 150 patients (12.4%) had CVD in their medical history. In total, 131 patients (11%) had a persistent LDL-C ≥99.5th percentile for age and sex. DLCN criteria for phenotypic FH (DLCN score ≥6) were met by 302 patients (25%) of whom 39 patients (12.9%) had undergone prior genetic testing according to clinical guidelines. Of the 302 clinically diagnosed FH patients only 1 (0.3%) met the European Society of Cardiology (ESC) guideline recommending LDL-C targets <1.8 mmol/L in FH patients. Conclusion These data highlight the significant underdiagnosis and undertreatment of FH in the Netherlands, despite the fact that this country has a relatively high FH identification rate. We demonstrate that the use of central laboratory data is an effective strategy for identifying previously undetected cases of FH and eagerly await the genetic confirmation of the newly identified FH patients in this study, which will provide valuable insights into the genetic basis of this disorder and help further improve patient care.

Prevalence of familial hypercholesterolemia in patients with acute coronary syndrome

<p><strong>Aim <br /></strong>To investigate the prevalence of familial hypercholesterolemia in patients with acute coronary syndrome (ACS).<br /><strong>Methods</strong> <br />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’s follow-up.<br /><strong>Results</strong> <br />Included patients that fulfilled criteria were predominantly male – 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<br />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).<br /><strong>Conclusion</strong> <br />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.</p>

Incidence of familial hypercholesterolemia in patients with early manifestations of coronary artery disease: data from a Russian multicenter study and meta-analysis

Aim. To assess the possibility of familial hypercholesterolemia (FH) detection among patients with early coronary artery disease (CAD) in practice in comparison with data from different populations. Patients with early manifestations of CAD are a promising group for identifying a proband with FH and subsequent cascade screening. The question remains open about the sufficiency of clinical criteria for diagnosing this disease.Material and methods. We examined 651 patients with CAD manifestations aged £55 years in men and £60 years in women. FH was diagnosed according to the Dutch Lipid Clinic Network (DLCN) criteria, and cardiovascular risk was assessed using the Montreal-FH-SCOR E. In 35 phenotype-positive patients with FH, as well as 5 with lowdensity lipoprotein cholesterol levels ³5,5 mmol/l and 23 with age of manifestation of coronary artery disease £35 years, the coding sequence of the genes for apolipoprotein B (APOB), low-density lipoprotein receptor (LDLR), low-density lipoprotein receptor adapter protein 1 (LDLRAP1), proprotein convertase subtilisin/kexin type 9 (PCSK9).Results. Definite FH was in 8 (1,2%), probable in 27 (4.2%), possible in 339 (52,1%) patients, while 277 (42,5%) patients had DLCN score of <3 points; 31 (88,6%), of 35 phenotype-positive patients had a high Montreal-FH-SCORE risk. Six carriers of pathogenic variants were identified, 2 of which were among phenotype-negative patients. A meta-analysis of 16 studies with 13065 patients (2012-2023) showed that the incidence of FH is 5,22 (4,848-5,619)% (fixed model) and 5,93 (4,528-7,515)% (random model).Conclusion. The use of existing diagnostic scales does not provide guaranteed detection of FH among patients with early CAD. It is likely that DLCN modification by additional gradation of the criterion for the age of CAD manifestation will help increase its diagnostic value.

Effect of causative genetic variants on atherosclerotic cardiovascular disease in heterozygous familial hypercholesterolemia patients.

Heterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment. A retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study's participants for the occurrence of ASCVD. A causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305-4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017-1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899-3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups (p = 0.523). In this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.

Referral rate, profile and degree of control of patients with familial hypercholesterolemia: data from a single lipid unit from a Mediterranean area

BackgroundThe challenging rigorous management of hypercholesterolemia promotes referral to specialized units. This study explored the need, based on referral rate and cardiovascular (CV) risk factor control in patients evaluated for familial hypercholesterolemia (FH), for a lipid unit (LU).MethodsOver a four-year period, 340 referrals to our unit were analyzed to establish the lipid disorder referral rate. Moreover, 118 patients referred for potential FH during the period 2010–2018 (52.4 ± 13.9 years, 47.5% male, Caucasian, 26.3% obese, 33.1% smokers and 51.7% with some glycaemic alteration) were investigated. The Dutch Lipid Clinic Network (DLCN) score, type and dose of lipid-lowering drugs, lipid profile including lipoprotein (a) (Lp(a)) and the presence of plaques with carotid ultrasound (CU) were recorded.ResultsLipids represented 6.2% of referrals (38 patient-years) requiring a 2–3 h weekly monographic outpatient consultation. The potential FH sample displayed a DLCN score ≥ 6 in 78% and modifiable CV risk factors in 51%. Only 22% achieved tight disease control despite intensive treatment. The statin-ezetimibe combination treatment group achieved better goals (73.0% vs. 45.5%, P = 0.003), and the rosuvastatin group had a higher proportion of prediabetes (60.9% vs. 39.1%, P = 0.037). Neither CU plaque presence nor Lp(a) > 50 mg/dL was linked with established CV disease patients, but higher Lp(a) concentrations were detected between them (102.5 (26.3–145.8) vs. 25.0 (13.0–52.0) mg/dL, P = 0.012).ConclusionsThe referral rate, degree of control, and proportion of modifiable CV risk factors in FH patients demonstrate the need for LU in our area as well as optimize control and treatment.

Genetic Identification of Homozygous Familial Hypercholesterolemia by Long-Read Sequencing Among Patients With Clinically Diagnosed Heterozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma LDL-C (low-density lipoprotein cholesterol) and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. We hypothesized that a subset of patients with clinically diagnosed heterozygous FH (HeFH) may in fact have HoFH, and this could be identified by genetic diagnosis. We recruited patients with a clinical diagnosis of HeFH based on a Dutch Lipid Clinic Network score ≥6 and no secondary cause of hypercholesterolemia. We performed targeted next-generation sequencing of the LDLR, APOB, PCSK9, and LDLRAP1 genes, followed by long-read sequencing of the LDLR gene in patients with >1 pathogenic LDLR variant. We examined lipid levels and cardiovascular events. Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) and >1 pathogenic variant in the LDLR gene in 11 patients (1.6%). We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygotes and 3 compound heterozygotes). The mean baseline LDL-C and prevalence of premature cardiovascular disease of patients with genetically identified HoFH was significantly higher than patients with HeFH. In a cohort of patients with clinically diagnosed HeFH, genetic testing including long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe clinical phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.

Correlation of the Dutch Lipid Clinic Network score as a diagnostic tool and lipid parameters in patients with familial hypercholesterolemia

Introduction. Familial hypercholesterolemia is a congenital disorder of lipid metabolism. The Dutch Lipid Clinic Network score is used for early diagnosis of familial hypercholesterolemia. The aim of the study was to examine correlation between the above score and the first measured lipid values in patients who had not used lipid-lowering therapy. Material and Methods. 390 patients identified as familial hypercholesterolemia+ (n=247) and familial hypercholesterolemia-(n=143) according to the Dutch Lipid Clinic Network score. Family and personal history, physical examination, demographic and anthropometric characteristics and lipid status were analyzed. Results. The familial hypercholesterolemia+group had all Dutch Lipid Clinic Network score components significantly higher than the familial hyper?cholesterolemia-group. The highest average number of points in familial hypercholesterolemia+ group carries low-density lipoprotein level and family history data. Significantly higher levels of total cholesterol, low-density lipoprotein and apolipoprotein B were found in the familial hypercholesterolemia+ group, while high-density lipo?protein was lower in the familial hypercholesterolemia-group. The Dutch Lipid Clinic Network score correlates best with level of low-density lipoprotein and apolipoprotein B (p<0.001). The cut-off point for low-density lipoprotein is 4.9 mmol/L (sensitivity 56%; specificity 8%), while the cut-off point for apolipoprotein B is 1.52 g/L (sensitivity 42%; specificity 12.5%) for diagnosis of familial hypercholesterolemia. Conclusion. Low-density lipoprotein and apolipoprotein B values significantly correlate with Dutch Lipid Clinic Network score values. Elevated values of low-density lipoprotein (>4.9 mmol/L) significantly affect the total value of the Dutch Lipid Clinic Network score and are considered components that carry large number of points for the diagnosis of familial hypercholesterolemia.

Abstract 13821: Genetic Identification of Homozygous Familial Hypercholesterolemia by Long-Read Sequencing Among Patients With Clinically Diagnosed Heterozygous Familial Hypercholesterolemia

Background: Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. The objective of this study was to identify and characterize patients with HoFH among patients with clinically diagnosed heterozygous FH (HeFH). Methods: We studied patients from the British Columbia FH Registry with a Dutch Lipid Clinic Network score ≥6 and no secondary cause of hypercholesterolemia. We performed targeted next-generation sequencing of the LDLR , APOB , PCSK9 and LDLRAP1 genes. Long-read sequencing of the LDLR gene was subsequently done for patients with >1 pathogenic LDLR variant to determine haplotypes. We examined lipid levels and cardiovascular events (unstable angina, myocardial infarction and coronary revascularization). Results: Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) patients and >1 pathogenic variant in the LDLR gene in 11 (1.6%) patients. We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygous and 3 compound heterozygous in trans). The mean baseline LDL-C of genetically identified HoFH patients was significantly higher than those with 1 variant. The prevalence of premature cardiovascular disease was numerically greater in the genetically identified HoFH group (29.4% vs 18.0%, p=0.2). Conclusions: In a cohort of patients with clinically diagnosed HeFH, genetic testing by long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.

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

Comparison of severe hypercholesterolemia patients with and without pathogenic variants

Abstract Introduction A pathogenic variant causally related to familial hypercholesterolemia (FH) is found in less than half of adults with severe hypercholesterolemia. The characteristics of adults with severe hypercholesterolemia without pathogenic variant have been poorly described, and it remains unclear whether intensive preventive strategies should be recommended. In this study we compared the characteristics of adults with severe hypercholesterolemia with and without pathogenic variant for FH. Methods Between November 2020 and February 2022, we recruited individuals older than 16 years with a Dutch Lipid Clinic Network (DLCN) score ≥6 and genotyped LDLR, APOB and PCSK9. Participants were part of the multicenter CATCH study, testing the implementation of genetic cascade screening for FH in Switzerland. All genetic analyses were performed in a single central laboratory. Variants classified as likely pathogenic or pathogenic were interpreted as FH-causing. We also assessed socio-economic status, cardiovascular risk factors, lifestyle behavior, and use of lipid-lowering drugs. Results In total, 150 non-related adults with a DLCN score of ≥6 were included, out of whom 62 (41.3%) had genetically confirmed FH. Most variants were found in the LDLR gene (77%). Overall, 70% were using a lipid-lowering drug and 20% were current smokers. Compared to adults with genetically confirmed FH, those without pathogenic variants were older (57.6 vs 50.4 years old), had lower untreated LDL-cholesterol levels (p<0.001), higher triglyceride levels (p=0.032), higher BMI (p=0.014), and had more frequently hypertension (62.5% vs 36.1%). No socio-economic differences were observed. Although adherence to Mediterranean diet was higher among adults without pathogenic variant, they reached less frequently the recommended level of physical activity than adults with genetically confirmed FH (66.2% vs 82.1%). Xanthomas or xanthelasmas, but not corneal arcus, were more frequent among genetically confirmed FH (5.7% vs 20.3%). Conclusions Adults with severe hypercholesterolemia and without a pathogenic FH variant had less optimal control of cardiovascular risk factors than genetically confirmed FH. One fifth were smokers and one third of all patients included in this study were not taking any lipid-lowering drugs, regardless of the presence of a pathogenic variant. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swiss Heart Foundation

The burden of severe hypercholesterolemia and familial hypercholesterolemia in a population-based setting in the US

BackgroundContemporary prevalence, awareness, and control of severe hypercholesterolemia (SH) and familial hypercholesterolemia (FH) and the associated atherosclerotic cardiovascular disease risk in the US are unknown. MethodUsing electronic health records, we assessed the burden of SH and FH in Olmsted County, Minnesota, US, between 2004 and 2015. We defined SH as low-density lipoprotein cholesterol (LDL-C) level ≥190 mg/dl without secondary causes of hypercholesterolemia and FH as a Dutch Lipid Clinic Network score ≥6. Controls were age- and sex-matched individuals with LDL-C level <190 mg/dl. ResultsThe age- and sex-adjusted point and period prevalence (age-recursive method) of SH was 4.44% and 8.95%, respectively; 1 in 21 had FH (∼1:233 adults), and 46.2% had a recorded diagnosis. Guideline recommended targets (LDL-C <100 mg/dl and <70 mg/dl in the primary and secondary prevention settings, respectively) were achieved in 33.1% and 21.2% of SH cases, with less women overall achieving the target than men (18.6% vs. 23.7%, p=0.022). After adjustment for conventional risk factors, the hazard ratio for incident coronary heart disease (CHD) in those with SH was 1.21 (1.05-1.39; p=0.010), in those with SH and a family history of CHD was 2.16 (1.57-2.96; p<0.001) and in those with FH was 4.61 (2.66-7.97; p<0.001). The association of SH with CHD was modified by age (p-interaction = 0.015), such that the risk was greater at younger ages. ConclusionsSH was prevalent and an independent risk factor for incident CHD. Awareness and control were low, highlighting a treatment gap (more prominent in women) that needs to be addressed.

Implementation of a biochemical, clinical, and genetic screening programme for familial hypercholesterolemia in 26 centres in Spain: The ARIAN study.

Background: Familial hypercholesterolemia (FH) is clearly underdiagnosed and undertreated. The aim of this present study is to assess the benefits of FH screening through a joint national program implemented between clinical laboratories and lipid units. Methods: All clinical laboratory tests from 1 January 2017 to 31 December 2018 were reviewed, and those with LDL cholesterol (LDL-C) levels >250 mg/dl were identified in subjects >18 years of age of both sexes. Once secondary causes had been ruled out, the treating physician was contacted and advised to refer the patient to an LU to perform the Dutch Lipid Clinic Network score and to request genetic testing if the score was ≥6 points. Next Generation Sequencing was used to analyse the promoter and coding DNA sequences of four genes associated with FH (LDLR, APOB, PCSK9, APOE) and two genes that have a clinical overlap with FH characteristics (LDLRAP1 and LIPA). A polygenic risk score based on 12 variants was also obtained. Results: Of the 3,827,513 patients analyzed in 26 centers, 6,765 had LDL-C levels >250 mg/dl. Having ruled out secondary causes and known cases of FH, 3,015 subjects were included, although only 1,205 treating physicians could be contacted. 635 patients were referred to an LU and genetic testing was requested for 153 of them. This resulted in a finding of sixty-seven pathogenic variants for FH, 66 in the LDLR gene and one in APOB. The polygenic risk score was found higher in those who had no pathogenic variant compared to those with a pathogenic variant. Conclusion: Despite its limitations, systematic collaboration between clinical laboratories and lipid units allows for the identification of large numbers of patients with a phenotypic or genetic diagnosis of FH, which will reduce their vascular risk. This activity should be part of the clinical routine.

Burden of cardiovascular disease in a large contemporary cohort of patients with heterozygous familial hypercholesterolemia

Background and aimsHeterozygous familial hypercholesterolemia (HeFH) is increasingly better diagnosed and treatments can improve the cardiovascular prognosis. We evaluated the long-term cardiovascular risk of HeFH using the French REgistry of Familial hypERCHOLesterolemia (REFERCHOL). MethodsWe studied HeFH patients diagnosed genetically and clinically by the Dutch Lipid Clinic Network (DLCN) criteria in all lipid clinics across the country and their 5-year risk of cardiovascular events (all fatal and non-fatal acute coronary, cerebral and peripheral arterial disease events, aortic valve replacement surgery) using the French national health data system. ResultsThe database comprised 3202 individuals, 2010 (62.8%) with genetically verified HeFH and 1192 (37.2%) a DLCN score ≥6. Of these individuals, 2485 (77.6%) were in primary prevention and 717 (22.4%) in secondary prevention. The incidence of cardiovascular events was 24.58 per 1000 person-years for the overall sample, 19.15 in primary prevention and 43.40 in secondary prevention. The incidence of myocardial infarction, cerebral infarction and death was 16.32 per 1000 person-years for the overall sample, 12.93 in primary prevention and 28.08 in secondary prevention. The incidence of aortic valve replacement was 1.78 per 1000 person-years. In the overall sample, at inclusion, 41% were not treated for LDL cholesterol, 48% of these in primary prevention and 20% in secondary prevention and high-dose statins were used by only 24% of individuals, 15% of these in primary prevention and 45% in secondary prevention. ConclusionsThe incidence of cardiovascular events in HeFH is high and lipid-lowering treatment is far from optimal. The cardiovascular risk of HeFH is underestimated and patients are inadequately treated.

A Danish nationwide study of individuals suspected of FH referred from general practice to lipid clinics: Clinical characteristics, plasma lipoprotein(a) and final diagnosis

Background and Aims : Familial hypercholesterolemia (FH) is an inherited condition characterized by severely elevated plasma levels of low-density lipoprotein (LDL) cholesterol believed to occur in approximately 1:250 subjects. FH is associated with a very high risk of premature atherosclerotic cardiovascular disease. Unfortunately, less than 20% of the affected are currently diagnosed in Denmark, which represents a health challenge here and in most other (Western) countries. The aims of the study were to describe important clinical characteristics and examine the proportion of verified FH diagnoses among adult subjects referred from General Practice to Danish Lipid Clinics on suspicion of FH. Also we aimed to investigate the importance of plasma lipoprotein(a) levels for a diagnosis of FH.Methods: All subjects referred from General Practice to one of the 15 Danish Lipid Clinics between September 2020 and November 2021 will be included. More than 1.200 individuals are expected to be recruited into the study and informed consent will be obtained from the subjects. Referrals for suspicion of FH were based on pre-specified criteria including LDL cholesterol levels > 5.0 mmol/l (> 4.0 mmol/l in subjects < 40 years) or premature cardiovascular disease. Secondary dyslipidaemias were excluded before admittance. Individuals were interviewed for personal and familial cardiovascular disease, diet, lifestyle, treatment and examined for cholesterol deposits. Individuals were classified according to the Dutch Lipid Clinic Network Score for FH.Results: Main results will be available in April 2022 and will be presented at the Congress.Conclusions: Will be presented when the results are available. Background and Aims : Familial hypercholesterolemia (FH) is an inherited condition characterized by severely elevated plasma levels of low-density lipoprotein (LDL) cholesterol believed to occur in approximately 1:250 subjects. FH is associated with a very high risk of premature atherosclerotic cardiovascular disease. Unfortunately, less than 20% of the affected are currently diagnosed in Denmark, which represents a health challenge here and in most other (Western) countries. The aims of the study were to describe important clinical characteristics and examine the proportion of verified FH diagnoses among adult subjects referred from General Practice to Danish Lipid Clinics on suspicion of FH. Also we aimed to investigate the importance of plasma lipoprotein(a) levels for a diagnosis of FH. Methods: All subjects referred from General Practice to one of the 15 Danish Lipid Clinics between September 2020 and November 2021 will be included. More than 1.200 individuals are expected to be recruited into the study and informed consent will be obtained from the subjects. Referrals for suspicion of FH were based on pre-specified criteria including LDL cholesterol levels > 5.0 mmol/l (> 4.0 mmol/l in subjects < 40 years) or premature cardiovascular disease. Secondary dyslipidaemias were excluded before admittance. Individuals were interviewed for personal and familial cardiovascular disease, diet, lifestyle, treatment and examined for cholesterol deposits. Individuals were classified according to the Dutch Lipid Clinic Network Score for FH. Results: Main results will be available in April 2022 and will be presented at the Congress. Conclusions: Will be presented when the results are available.

Effectiveness of Dutch lipid score (modified for Italy) in a cohort of subjects aged &gt; 18 years and comparison with the subpopulation between 18-45 years

Background and Aims : Familial hypercholesterolemia (FH) is the most frequent genetic disorder among dyslipidemias. Our aim is to evaluate the performance of Dutch Lipid Clinic Network Score (DLCNS) modified for Italy (DLCNS-I) in identifying patients with genetically defined FH, particularly in those ones <45 years.