Dutch Lipid Clinic Network Research Articles

Clinical and angiographic characteristics of patients with familial hypercholesterolemia presenting with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention

Familial hypercholesterolemia (FH) is a world public health problem that enhances the risk of premature coronary artery disease (CAD) with a high incidence of acute coronary syndrome. This study aimed to evaluate the clinical and angiographic characteristics of the patients with and without FH who had ST-elevation myocardial infarction (STEMI). It included 690 patients who presented with the first attack of STEMI and underwent primary percutaneous coronary interventions (PPCI). The patients were analyzed to diagnose FH according to the Dutch Lipid Clinic Network (DLCN) criteria. All angiograms were analyzed for the number of diseased vessels, Syntax score, thrombus burden grade, and final Thrombolysis in Myocardial Infarction (TIMI) flow grade. The majority of patients were male (72.6%) with a mean age of 54 ± 12 years. Based on DLCN criteria, they were classified into unlikely/possible FH (86.1%) and probable/definite FH (13.9%) groups. Probable/definite FH patients were significantly younger, and higher incidence of males < 55 years compared with unlikely/possible FH patients (p < 0.001 for each). Moreover, probable/definite FH patients had a higher frequency of three-vessel disease (p = 0.007) and Syntax score (p < 0.001) with a moderate positive correlation with the DLCN score (r = 0.592, p < 0.001). Furthermore, probable/definite FH patients showed a higher thrombus burden and final TIMI slow/no-reflow when compared to the unlikely/possible FH patients (p = 0.006 and p = 0.027, respectively). Patients with probable/definite FH and LDL-C level were independent predictors of high thrombus burden besides males < 55 years, and the number of diseased vessels. In conclusion, STEMI patients with FH were younger males and associated with severe CAD with frequent multivessel CAD, high anatomical complexity of CAD, and frequent high thrombus burden. Furthermore, FH was one of the predictors of high thrombus burden.

Case detection of familial hypercholesterolemia using various criteria during an annual health examination in the workplace

BackgroundEarly diagnosis and appropriate treatment of subjects with familial hypercholesterolemia (FH) could prevent cardiovascular disease (CAD). ObjectiveWe aimed to identify potential cases of FH during a workplace screening and to explore their clinical data. MethodPersonnel who attended an annual health examination were invited to answer a questionnaire and to provide consent to review their laboratory results. FH was clinically diagnosed using any one of the three standard criteria: Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and Make Early Diagnosis to Prevent Early Deaths (MEDPED). Clinical characteristics were compared between FH and unlikely FH subjects. ResultsAmong 6607 participants, potential cases of FH were identified in 2.5 % by DLCN, 4.0 % by SB, and 0.8 % by MEDPED alone. Premature CAD, hypertension, and current smoking were significantly more common in potential FH subjects than in unlikely FH subjects. Potential FH subjects also had significantly higher body mass index, waist circumference, blood pressure, fasting plasma glucose and triglyceride levels than unlikely FH subjects. Among potential FH subjects, lipid-lowering medication was used in 28.4 %. The achievement of the LDL-C goal (<100 mg/dL) in potential FH subjects was significantly lower than that in unlikely FH subjects (15 % vs. 28 %, respectively, P = 0.005) despite a higher rate of high-intensity statin use (25 % vs. 10 %, respectively, P = 0.002). ConclusionThe workplace screening of FH detected a significant number of potential FH subjects with higher cardiovascular risk. This strategy identified individuals for whom intensification of both lifestyle modifications and pharmacological treatment should be a priority.

Screening for subclinical atherosclerosis in patients clinically diagnosed with familial hypercholesterolemia and determination of imaging-guided patient management strategy

Abstract Introduction Familial hypercholesterolemia (FH) is a monogenic dyslipidemia characterized by elevated plasma LDL-C levels, leading to early cardiovascular disease. The Dutch Lipid Clinic Network (DLCN) score is the most widely used clinical scoring system in current practice. Subclinical atherosclerosis is defined as the detection of atheromatous plaques in arterial territories, such as coronary, carotid or iliofemoral, before a symptom or event occurs. It is an early indicator of atherosclerotic burden. In this study, we investigated the presence of subclinical atherosclerosis in FH patients with a definite or probable clinical diagnosis according to DLCN score. We also tried to identify independent predictors of subclinical atherosclerosis. Methods This study is a single-center, prospective, and cross-sectional investigation involving a cohort of 215 FH patients. These patients are primary prevention patients and among them, 120 patients received a definite clinical diagnosis, while 95 patients received a probable clinical diagnosis based on the DLCN score. Carotid USG and Femoral USG were performed to screen for subclinical atherosclerosis and CAC score was calculated by non-contrast CT. Apo A-I, Apo B and Lp (a) measurements were analyzed by immunonephelometric method. Results The study population consisted of 136 (63%) women and 79 (37%) men. The mean age was 54 years (43-62) and the stigmata rate was 18%. Initially, 17% of patients were on aspirin, and 32% were receiving statin treatment; however, following subclinical atherosclerosis screening, these proportions significantly increased (aspirin usage to %32 and statin usage to %96) within the population. 148 patients (69%) had subclinical atherosclerosis in at least one site. Upon regional analysis, subclinical atherosclerosis rates were 48% in the coronary arteries, 47.5% in the carotid bifurcation region, and 40.5% in the femoral bifurcation region. Additionally, 25% of patients had atherosclerosis at one site, 27% at two sites, and 17% at all three sites. Age, male gender, pretreatment LDL-C level, Apo A-I/Apo B ratio and DM were identified as independent predictors of the presence of subclinical atherosclerosis in the FH patients. Furthermore age, male gender, pretreatment nonHDL-C level, Lp (a) ≥ 30 mg/dl and presence of femoral plaque were identified as independent predictors of coronary atherosclerosis. Conclusion Subclinical atherosclerosis is prevalent among FH patients, and this study has identified independent predictors associated with presence of subclinical atherosclerosis. However, despite this heightened risk, medication utilization among these patients remains below optimal levels and only a small proportion of the population has achieved their treatment goals. Our study highlights the influence of subclinical atherosclerosis on treatment approaches, as demonstrated by the notable rise in statin and aspirin utilization observed after screening.Clinical and biochemical characteristicsSubclinical Atherosclerosis Rates

A retrospective analysis of patients with very HIGH level of LDL-C and the predictors of mortality (HIGH-LDL-PM Registry)

Abstract Introduction Elevated levels of LDL cholesterol (LDL-C) significantly contribute to the development and progression of cardiovascular diseases (CVDs). In HIGH-LDL-PM Registry, we aimed to investigate the demographics and clinical characteristics of patients with very high level of LDL-C and the predictors of mortality, retrospectively. Methods We retrospectively searched the electronic database of Istanbul University-Cerrahpasa Institute of Cardiology and included patients with very high level of LDL-C (&amp;gt;190 mg/dl) in HIGH-LDL-PM registry. The study group were classified as patients with high probability of familial hypercholesterolemia (FH) and low probability of FH according to Dutch Lipid Clinic Network Score (DLCNS). Results The study group were consisted of 1127 patients and almost two thirds (61.5%) were female. The mean age was 56.5 12.2 years. Hypertension, diabetes, chronic kidney disease (CKD) were seen in 55.8%, 23.5% and 3.7%, respectively. One third of study group (31.1%) had coronary artery disease (CAD) and rest of them were primary prevention patients. the main rhythm was sinus in most of the patients (92,2) and 7.8% patients had atrial fibrillation (AF). Only minority of patients (3.9%) had stigmata for elevated cholesterol levels. While 41.8% of patients had high clinical probability for FH, 58.2% of them had low probability according to DLCNS. While 69% of patients were using lipid lowering treatments (LLTs), 42% of them had drug adherence. High dose (HD) statins (atorvastatin 40-80 and rosuvastatin 20-40 mg) were prescribed in more than half (55.2%) of patients with LLTs. Ezetimibe was the preferred agent as combination therapy in 6.9% and PCSK-9is were prescribed only in 2.5% of patients with LLTs. In 38.8% of study population, ASA was prescribed. 50% decrease in LDL-C levels or decreasing LDL-C below 70 or 100 mg/dl as a treatment goal were achieved in 37.1% and 15% of study population. MACE (MI, stroke, PCI or peripheral revascularization) was recorded in 21% of study population and the mortality rate was 10.4% at 12-years FU (6-145 months). Patients with low probability of FH had better survival than patient with high probability (91.4% vs 88.4%). The age, low dose statin use and higher level of LDL-C at FU were predictors of mortality in Cox-regression analysis. Conclusion Our retrospective analysis of patients with very high levels of LDL-C underscores the multifaceted nature of dyslipidemia management and its impact on cardiovascular outcomes. Despite advancements in pharmacotherapy, suboptimal adherence to lipid-lowering treatments remains a significant challenge, contributing to a notable burden of major adverse cardiovascular events and mortality. Identification of predictors of mortality, such as age, statin dosage, and LDL-C levels, highlights the importance of individualized risk assessment and tailored treatment approaches in this high-risk population.

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.

Alterations in serum levels of calcium, vitamin D, phosphorus, and parathyroid hormone in patients with clinically confirmed familial hypercholesterolemia: a cross-sectional study

Background: Familial hypercholesterolemia (FH), an autosomal dominant disease, is associated with increased risk of premature cardiovascular disease (CVD). This study aimed to examine the variations in serum levels of calcium, vitamin D, phosphorus, and parathyroid hormone (PTH) among FH patients, as these factors have been associated with an increased susceptibility to CVD. Materials and Methods: In this cross-sectional study, we used data from Isfahan FH registry. The Dutch Lipid Clinic Network (DLCN) criteria was used for diagnoses of FH patients. Control group included participant with hyperlipidemia and were unlikely FH according to DLCN criteria. All biochemical parameters were measured using standard methods. Results: A total of 131 patients (mean age, 53.1 ± 12.2; male, 51.4%) were included in the analysis. Patients with FH had lower serum vitamin D level compared with control groups in unadjusted model (P= 0.028). The relationship between serum vitamin D and FH was not significant after adjustment for traditional risk factor (P= 0.184). No significant association was observed between FH and serum calcium (P= 0.886), phosphorus (P= 0.463), and PTH (P= 0.849). Besides, there was no significant association between LDL-C or total cholesterol and serum minerals in FH patients. Conclusion: This study found no significant changes in serum calcium, vitamin D, phosphorus, and PTH in patients with FH.

PCSK9 inhibitors on the management of primary and secondary cardiovascular prevention

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

Familial Hypercholesterolaemia Patients with LDLR Mutation Among Asian Population in Southeast Asian Countries: Systematic Review

Familial hypercholesterolaemia (FH) is a genetic disorder associated with premature cardiovascular diseases; however, the majority of patients remain undertreated. This systematic review aimed to determine the prevalence of FH patients with low-density lipoprotein receptor (LDLR) gene pathogenic variants (PV) among the Asian population in Southeast Asian countries. Our search yielded 1,120 citations, with 28 deemed possibly suitable based on title and abstract screening. However, only six studies that utilised the Dutch Lipid Clinic Network (DLCN) or Simon Broome (SB) criteria were eligible to be included. These studies provided prevalence figures for clinically diagnosed FH patients, with a total of 17.1% (n=1,005/5,874); this rate was represented by three Malaysian studies, which estimated that 36–76% of clinically diagnosed FH patients had LDLR PV. Most patients reported having pre-existing cardiovascular disease, a family history of premature coronary artery disease and tendon xanthomata. This study found that the prevalence of LDLR PV among genetically confirmed FH patients in Southeast Asia is 20.5% (n=286/5,874). Genetically confirmed FH patients are at a higher risk of developing premature coronary artery disease, requiring more aggressive lipid-lowering treatment. Therefore, identifying LDLR PV among the population is essential for early FH diagnosis and treatment. KEYWORDS Arterial disease, autosomal dominant, LDL receptor, LDLR prevalence, pathogenic variants, premature CAD, Undertreated

Association Between Patient Sex and Familial Hypercholesterolemia and Long-Term Cardiovascular Risk Factor Management 5 Years After Acute Coronary Syndrome.

Long-term control of cardiovascular risk factors after acute coronary syndrome (ACS) is the cornerstone for preventing recurrence. We investigated the extent of cardiovascular risk factor management in males and females with and without familial hypercholesterolemia (FH) 5 years after ACS. We studied patients hospitalized for ACS between 2009 and 2017 in a Swiss multicenter prospective cohort study. FH was defined based on clinical criteria from the Dutch Lipid Clinic Network and Simon Broome definitions. Five years post-ACS, we assessed low-density lipoprotein-cholesterol (LDL-c) levels, lipid-lowering therapy (LLT), and other cardiovascular risk factors, comparing males to females with and without FH using generalized estimating equations. A total of 3139 patients were included; mean age was 61.4 years (SD, 12.1), 620 (19.8%) were female, and 747 (23.5%) had possible FH. Compared with males at 5-years post-ACS, females were more likely to not use statins (odds ratio, 1.61 [95% CI, 1.28-2.03]) and less likely to have combination LLT (odds ratio, 0.72 [95% CI, 0.55-0.93]), without difference between patients with FH and without FH. Females in both FH and non-FH groups less frequently reached LDL-c values ≤1.8 mmol/L (odds ratio, 0.78 [95% CI, 0.78-0.93]). Overall, patients with FH were more frequently on high-dose statins compared with patients without FH (51.0% versus 42.9%; P=0.001) and presented more frequently with a combination of 2 or more LLT compared with patients without FH (33.8% versus 17.7%; P<0.001), but less frequently reached LDL-c targets of ≤1.8 mmol/L (33.5% versus 44.3%; P<0.001) or ≤2.6 mmol/L (70.2% versus 78.1%; P=0.001). Five years after ACS, females had less intensive LLT and were less likely to reach target LDL-c levels than males, regardless of FH status. Males and females with FH had less optimal control of LDL-c despite more frequently taking high-dose statins or combination LLT compared with patients without FH. Long-term management of patients with ACS and FH, especially females, warrants optimization.

Improving the Detection of Potential Cases of Familial Hypercholesterolemia: Could Machine Learning Be Part of the Solution?

Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations. Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR, APOB, or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227). Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.

LDLR c.89_92dup: a novel frameshift variation in familial hypercholesterolemia

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

LIPID–LOWERING THERAPY WITH PCSK9 INHIBITORS: FAMILIAL HYPERCHOLESTEROLEMIA VS GENERAL POPULATION OUTCOMES

Abstract Background Dyslipidemic patients, particularly those with familial hypercholesterolemia (FH), are at increased risk of cardiovascular events and require beginning a full treatment. This study aims to compare the long–term effects of PCSK9i treatment in FH and non–FH dyslipidemic patients. Methods The study enrolled 381 dyslipidemic patients receiving PCSK9 inhibitors in our dyslipidemia outpatient clinic. FH was defined in accordance with the Dutch Lipid Clinic Network Criteria. The clinical data were collected in both groups and lipid profiles were monitored at 6, 12, and 36 months. Results In patients with FH baseline total cholesterol was significantly higher(260±54.8 mg/dL vs 212±51.3 mg/dL p &amp;lt; 0.001) as well as LDL cholesterol (181.4±51.7 mg/dL vs 137±45.1 mg/dL p &amp;lt; 0.001). A lipid reduction was observed in both groups at 6 months (LDL 69±41 mg/dL vs 62±37 mg/dL p = 0.20) at 12 (LDL 66±41 mg/dL vs 66±40 mg/dL p = 0.96) and 36 months (LDL 73±45 mg/dL vs 72±35 mg/dL p = 0.92). Conclusions PCSK9i treatment is highly effective in reducing LDL–C levels in both FH and non–FH dyslipidemic patients. The Achievement of similar LDL–C levels between these two groups in long–term follow–up could suggest that PCSK9i therapy is equally efficacious in both populations despite different dyslipidemia settings.

Algorithm for detection and screening of familial hypercholesterolemia in Lithuanian population

BackgroundFamilial hypercholesterolemia (FH) is one of the most common autosomal dominant diseases. FH causes a lifelong increase in low-density lipoprotein cholesterol (LDL-C) levels, which in turn leads to atherosclerotic cardiovascular disease. The incidence of FH is widely underestimated and undertreated, despite the availability and effectiveness of lipid-lowering therapy. Patients with FH have an increased cardiovascular risk; therefore, early diagnosis and treatment are vital. To address the burden of FH, several countries have implemented national FH screening programmes. The currently used method for FH detection in Lithuania is mainly based on opportunistic testing with subsequent cascade screening of index cases’ first-degree relatives.MethodsA total of 428 patients were included in this study. Patients with suspected FH are referred to a lipidology center for thorough evaluation. Patients who met the criteria for probable or definite FH according to the Dutch Lipid Clinic Network (DLCN) scoring system and/or had LDL-C > = 6.5 mmol/l were subjected to genetic testing. Laboratory and instrumental tests, vascular marker data of early atherosclerosis, and consultations by other specialists, such as radiologists and ophthalmologists, were also recorded.ResultsA total of 127/428 (30%) patients were genetically tested. FH-related mutations were found in 38.6% (n = 49/127) of the patients. Coronary artery disease (CAD) was diagnosed in 13% (n = 57/428) of the included patients, whereas premature CAD was found in 47/428 (11%) patients. CAD was diagnosed in 19% (n = 9/49) of patients with FH-related mutations, and this diagnosis was premature for all of them.ConclusionsMost patients in this study were classified as probable or possible FH without difference of age and sex. The median age of FH diagnosis was 47 years with significantly older females than males, which refers to the strong interface of this study with the LitHir programme. CAD and premature CAD were more common among patients with probable and definite FH, as well as those with an FH-causing mutation. The algorithm described in this study is the first attempt in Lithuania to implement a specific tool which allows to maximise FH detection rates, establish an accurate diagnosis of FH, excluding secondary causes of dyslipidaemia, and to select patients for cascade screening initiation more precisely.

Simplified Criteria for Identification of Familial Hypercholesterolemia in Children: Application in Real Life.

The diagnosis of familial hypercholesterolemia (FH) in children is primarily based on main criteria including low-density lipoprotein cholesterol (LDL-C) levels, increased in the proband and relatives, and its inheritance. Two other relevant parameters are symptoms, rarely occurring in children, as rare are the FH homozygous patients, and the mutation detection of related genes. The latter allows the final diagnosis, although it is not commonly available. Moreover, the application of diagnostic scores, useful in adults, is poorly applied in children. The aim of this study was to compare the reliability of criteria here applied with different scores, apart from genetic analysis, for FH diagnosis. The latter was then confirmed by genetic analysis. n. 180 hypercholesterolemic children (age 10.2 ± 4.6 years) showing LDL-C levels ≥95th percentile (age- and sex-related), the dominant inheritance pattern of hypercholesterolemia (including LDL-C ≥95th percentile in one parent), were considered potentially affected by FH and included in the study. The molecular analysis of the LDLR, APOB and PCSK9 genes was applied to verify the diagnostic accuracy. Biochemical and family history data were also retrospectively categorized according to European Atherosclerosis Society (EAS), Simon Broome Register (SBR), Pediatric group of the Italian LIPIGEN (LIPIGEN-FH-PED) and Dutch Lipid Clinic Network (DLCN) criteria. Detailed kindred biochemical and clinical assessments were extended to three generations. The lipid profile was detected by standard laboratory kits, and gene analysis was performed by traditional sequencing or Next-Generation Sequencing (NGS). Among 180 hypercholesterolemic subjects, FH suspected based on the above criteria, 164/180 had the diagnosis confirmed, showing causative mutations. The mutation detection rate (MDR) was 91.1%. The scoring criteria proposed by the EAS, SBR and LIPIGEN-FH-PED (resulting in high probable, possible-defined and probable-defined, respectively) showed high sensitivity (~90%), low specificity (~6%) and high MDR (~91%). It is noteworthy that their application, as a discriminant for the execution of the molecular investigation, would lead to a loss of 9.1%, 9.8% and 9.1%, respectively, of FH-affected patients, as confirmed by the genetic analysis. DLCN criteria, for which LDL-C cut-offs are not specific for childhood, would lead to a loss of 53% of patients with mutations. In the pediatric population, the combination of LDL-C ≥95th percentile in the proband and the dominant inheritance pattern of hypercholesterolemia, with LDL-C ≥95th percentile in one parent, is a simple, useful and effective diagnostic criterion, showing high MDR. This pattern is crucial for early FH diagnosis. EAS, SBR and LIPIGEN-FH-PED criteria can underestimate the real number of patients with gene mutations and cannot be considered strictly discriminant for the execution of molecular analysis.

Screening for familial hypercholesterolemia in Sri Lanka: A laboratory-based multicenter study

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

LDLR c.415G > A causes familial hypercholesterolemia by weakening LDLR binding to LDL

BackgroundFamilial hypercholesterolemia (FH) is a prevalent hereditary disease that can cause aberrant cholesterol metabolism. In this study, we confirmed that c.415G > A in low-density lipoprotein receptor (LDLR), an FH-related gene, is a pathogenic variant in FH by in silico analysis and functional experiments.MethodsThe proband and his family were evaluated using the diagnostic criteria of the Dutch Lipid Clinic Network. Whole-exome and Sanger sequencing were used to explore and validate FH-related variants. In silico analyses were used to evaluate the pathogenicity of the candidate variant and its impact on protein stability. Molecular and biochemical methods were performed to examine the effects of the LDLR c.415G > A variant in vitro.ResultsFour of six participants had a diagnosis of FH. It was estimated that the LDLR c.415G > A variant in this family was likely pathogenic. Western blotting and qPCR suggested that LDLR c.415G > A does not affect protein expression. Functional studies showed that this variant may lead to dyslipidemia by impairing the binding and absorption of LDLR to low-density lipoprotein ( LDL).ConclusionLDLR c.415G > A is a pathogenic variant in FH; it causes a significant reduction in LDLR’s capacity to bind LDL, resulting in impaired LDL uptake. These findings expand the spectrum of variants associated with FH.

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.

Prevalence, clinical features and prognosis of familial hypercholesterolemia in Chinese Han patients with acute coronary syndrome after a coronary event: a retrospective observational study

BackgroundFamilial hypercholesterolemia (FH) is an autosomal semi-dominant disease, characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-c) from conception and accelerated atherosclerotic cardiovascular disease, often resulting in early death. The aim of this study was to evaluate the prevalence of clinically defined FH in Chinese Han patients with acute coronary syndrome (ACS) and compare the long-term prognosis of ACS patients with and without FH receiving lipid-lowering therapy containing statins after a coronary event.MethodsAll ACS patients were screened at the Second Affiliated Hospital of Xi’an Jiaotong University between Jan 2019 and Sep 2020, and 531 participants were enrolled. All were examined for FH under the Dutch Lipid Clinical Network (DLCN) criteria, and those patients were divided into definite/probable FH, possible FH and unlikely FH. The severity of coronary artery disease was evaluated by the Gensini scoring system. Plasma levels of total cholesterol (TC), triacylglycerol (TG), HDL-cholesterol (HDL-c), LDL-cholesterol (LDL-c), very low-density lipoproteins-cholesterol (VLDL-c), apolipoprotein A1 (apoA1), apolipoprotein B (apoB) and lipoprotein (a) (Lp(a)) were determined centrally at baseline and the last follow-up visit in the fasting state. The non-high-density lipoprotein cholesterol (non-HDL-c) concentration, the TC/HDL-c and apoB/apoA1 ratios were calculated. After FH patients received lipid-lowering treatment containing statin, the target LDL-c levels recommended by the guidelines (LDL-c < 1.8 mmol/L or < 1.4 mmol/L and a reduction > 50% from baseline) were evaluated, and the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) during the 12-month follow-up was recorded.ResultsThe prevalence of clinically definite or probable FH was 4.3%, and the prevalence of possible FH was 10.6%. Compared with the unlikely FH patients with ACS, the FH patients had higher levels of TC, LDL-c, apoB, Lp(a), non-HDL-c, TC/HDL-c and apoB/apoA1 ratio, more severe coronary artery diseases and greater prevalence of left main and triple or multiple vessel lesions. After lipid-lowering therapy containing statins, a minority of FH patients reached the target LDL-c levels defined by the guidelines (χ2 = 33.527, P < 0.001). During the 12-month follow-up, a total of 72 patients experienced MACCE. The survival curve in patients in the FH group was significantly lower than that in the unlikely FH group (HR = 1.530, log-rank test: P < 0.05). Furthermore, the survival curve in patients with high LDL-c (≥ 1.8 mmol/L) was significantly lower than that in patients with low LDL-c (< 1.8 mmol/L) at the 12-month follow-up visit (HR = 1.394, log-rank test: P < 0.05). No significant difference was observed between patients with LDL-c levels ≥ 1.4 mmol/L and with < 1.4 mmol/L at the 12-month follow-up visit by using Kaplan–Meier survival analysis (HR = 1.282, log-rank test: P > 0.05).ConclusionsFH was an independent risk factor for MACCE in adult patients after a coronary event during long-term follow-up. However, there was inadequate high-intensity statins prescriptions for high-risk patients in this current study. It is important for FH patients to optimize lipid-lowering treatment strategies to reach the target LDL-c level to improve the long-term prognosis of clinical outcomes.

Hypercholesterolemia Familial: Early Cardiovascular Complications, Treatment Challenges, and the Fatal Consequences of Delayed Diagnosis: an in-Depth Case Study

Familial Hypercholesterolemia (FH) is among the most common genetic disorders, present from birth. The transmission is mainly autosomal dominant. It is characterized by a exclusive increase in low-density lipoproteins (LDL). It is associated with a high risk of premature cardiovascular complications. The diagnosis of FH is generally based on the clinical presentation or genetic tests. The commonly used criteria are those of the Dutch Lipid Clinic Network. FH is a hereditary condition still largely underdiagnosed and undertreated. The prognosis of the disease is related to atheromatous cardiovascular complications, which, in the absence of treatment, lead to the patient's death in the first three decades, often due to myocardial infarction or sudden death. The management of familial hypercholesterolemia systematically involves two categories of measures: so-called hygienic-dietary measures associated with the treatment of other risk factors when they exist, and drug treatments. Familial hypercholesterolemia is still poorly detected. It is necessary to develop systematic approaches to identify patients with FH, conduct cascade screening of their relatives, and increase awareness and control of FH.

Knowledge, attitude, and practice of physicians towards familial hypercholesterolaemia in north regions of Saudi Arabia.

To assess knowledge, attitude and practice of physicians regarding familial hypercholesterolaemia. The cross-sectional study was conducted from October to December 2022 in Aljouf, Tabouk, Hail and northern border regions of Saudi Arabia after approval from the ethics review committee of Qurayyat Health Affairs. Those included were physicians specialising in familial hypercholesterolaemia and having experience in family medicine, endocrinology, paediatrics, cardiology, internal medicine and obstetrics and gynaecology. Their knowledge, attitude and practice were assessed using a predesigned questionnaire. Data were analysed using SPSS 20. Of the 430 subjects, 220(51.2%) were males, 89(20.7%) were aged 36-40 years, 169(39.3%) were residents, and 146(34%) had experience >15 years. Overall, 270(62.8%), 286(66.5%) and 287(66.7%) subjects did not know about the clinical diagnostic algorithms of Simon Broom, Dutch Lipid Clinic Network and United States MedPed programme investigated criteria, respectively. There were, 149(34.7%) subjects with high awareness level, and the level of awareness was significantly affected by gender, level of training, medical specialty, and familiarity with familial hypercholesteremia (p<0.05). There were 343(79.8%) subjects who said they had never diagnosed familial hypercholesterolaemia. There were knowledge gaps, low awareness, and inappropriate practices related to familial hypercholesterolemia, indicating the need for targetted programmes.