Diagnosis Of Familial Hypercholesterolemia Research Articles

A Case Report of Giant Tuberous Xanthoma with Type IIa Familial Hypercholesterolemia

Abstract Tuberous xanthomas are nontender, yellow to red papules to nodules that occur on the extensor surface, and trauma-prone areas such as the elbows, knees, Achilles tendon, and buttocks. A 10-year-old female child born out of second-degree consanguineous marriage presented with multiple skin-colored nodular lesions on axillary folds, both elbows, cubital fossa, medial side of the wrist, interphalangeal joints, buttocks, knees, popliteal fossa, and Achilles tendons. After complete evaluation, diagnosis of familial hypercholesterolemia type IIa with tuberous xanthoma was made. Tuberous xanthoma usually presents in combined type III dyslipidemias, but in our case, it is presented in type IIa familial hypercholesterolemia. Early diagnosis and treatment of familial hypercholesterolemia are important for preventing complications.

Applicability of Artificial Intelligence in the Field of Clinical Lipidology: A Narrative Review.

The development of advanced technologies in artificial intelligence (AI) has expanded its applications across various fields. Machine learning (ML), a subcategory of AI, enables computers to recognize patterns within extensive datasets. Furthermore, deep learning, a specialized form of ML, processes inputs through neural network architectures inspired by biological processes. The field of clinical lipidology has experienced significant growth over the past few years, and recently, it has begun to intersect with AI. Consequently, the purpose of this narrative review is to examine the applications of AI in clinical lipidology. This review evaluates various publications concerning the diagnosis of familial hypercholesterolemia, estimation of low-density lipoprotein cholesterol (LDL-C) levels, prediction of lipid goal attainment, challenges associated with statin use, and the influence of cardiometabolic and dietary factors on the discordance between apolipoprotein B and LDL-C. Given the concerns surrounding AI techniques, such as ethical dilemmas, opacity, limited reproducibility, and methodological constraints, it is prudent to establish a framework that enables the medical community to accurately interpret and utilize these emerging technological tools.

Diagnosis of Familial Hypercholesterolemia in Children and Young Adults.

The early detection and treatment of familial hypercholesterolemia (FH) in childhood and adolescence are critical for increasing life expectancy. The purpose of our study was to investigate blood lipid parameters, features of physical signs of cholesterol accumulation, and a personal and family history of premature cardiovascular diseases in children and young adults when FH is diagnosed. The analysis included patients under 18 years of age (n = 17) and young adults (18-44 years of age; n = 43) who received a diagnosis of FH according to clinical criteria. Targeted high-throughput sequencing was performed using a custom panel of 43 genes. A family history of cardiovascular diseases was more often noted in the group under 18 years of age than in young adults (p < 0.001). Among young adults, there was a high prevalence of typical signs of the disease such as tendon xanthomas and the early development of arterial atherosclerosis (p < 0.001). By molecular genetic testing, "pathogenic" and "probably pathogenic" variants were identified in the genes of 73.3% of patients under 18 years of age and 51.4% of patients 18-44 years of age. Thus, blood lipid screening tests combined with an accurate assessment of the family history is a highly relevant and inexpensive option for diagnosing FH in childhood. Molecular genetic testing allows us to make an accurate diagnosis and to improve adherence to treatment.

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway.

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron.

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.

Assessment of ethnic inequalities in diagnostic coding of familial hypercholesterolaemia (FH): A cross-sectional database study in Lambeth, South London

Background and aimsDifferences in the perceived prevalence of familial hypercholesterolemia (FH) by ethnicity are unclear. In this study, we aimed to assess the prevalence, determinants and management of diagnostically-coded FH in an ethnically diverse population in South London. MethodsA cross-sectional analysis of 40 practices in 332,357 adult patients in Lambeth was undertaken. Factors affecting a (clinically coded) diagnosis of FH were investigated by multi-level logistic regression adjusted for socio-demographic and lifestyle factors, co-morbidities, and medications. ResultsThe age-adjusted FH % prevalence rate (OR, 95%CI) ranged from 0.10 to 1.11, 0.00–1.31. Lower rates of FH coding were associated with age (0.96, 0.96–0.97) and male gender (0.75, 0.65–0.87), p < 0.001. Compared to a White British reference group, a higher likelihood of coded FH was noted in Other Asians (1.33, 1.01–1.76), p = 0.05, with lower rates in Black Africans (0.50, 0.37–0.68), p < 0.001, Indians (0.55, 0.34–0.89) p = 0.02, and in Black Caribbeans (0.60, 0.44–0.81), p = 0.001. The overall prevalence using Simon Broome criteria was 0.1%; we were unable to provide ethnic specific estimates due to low numbers.Lower likelihoods of FH coding (OR, 95%CI) were seen in non-native English speakers (0.66, 0.53–0.81), most deprived income quintile (0.68, 0.52–0.88), smokers (0.68,0.55–0.85), hypertension (0.62, 0.52–0.74), chronic kidney disease (0.64, 0.41–0.99), obesity (0.80, 0.67–0.95), diabetes (0.31, 0.25–0.39) and CVD (0.47, 0.36–0.63). 20% of FH coded patients were not prescribed lipid-lowering medications, p < 0.001. ConclusionsInequalities in diagnostic coding of FH patients exist. Lower likelihoods of diagnosed FH were seen in Black African, Black Caribbean and Indian ethnic groups, in contrast to higher diagnoses in White and Other Asian ethnic groups. Hypercholesterolaemia requiring statin therapy was associated with FH diagnosis, however, the presence of cardiovascular disease (CVD) risk factors lowered the diagnosis rate for FH.

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.

Plasma proteomics identify fibroblast growth factor 5 as a biomarker for genetically proven Familial Hypercholesterolemia

Abstract Background Subjects affected by genetically proven heterozygous Familial Hypercholesterolemia (FH) present lifelong exposure to high Low Density Lipoprotein Cholesterol ("LDL-C burden") causing premature ACVD. Nevertheless, the diagnosis of FH is still far from being optimal due to shortcomings of the clinical algorithms in detecting this form of severe ACVD since early decades of life (1) and because a significant proportion of FH present comparable LDL-C levels to that of subjects who are hypercholesterolemic but are not diagnosed as FH ("non-FH") (2). Purpose We previously demonstrated that targeted proteomics identify subjects at high Atherosclerotic Cardiovascular Diseases (ACVD) risk in the general populations beyond the known risk factors (3). Hence, we now tested whether targeted proteomics may differentiate FH subjects from the general population and from "non-FH". Methods We compared the plasma relative abundance of 264 proteins (Proximity Extension Assay; Olink) in 133 genetically proven FH with that of 586 normocholesterolemic subjects ("controls") and that of 55 non-FH (LDL-C between 190-220 mg/dL, not on statins). We trained and validated a Machine Learning (ML) boosting prediction model (4) in these cohorts to identify the protein markers representative of FH (Random Forest classifiers). Results Fibroblast Growth Factor 5 (FGF-5) resulted as the most powerful plasma protein in differentiating FH subjects from the controls, with an excellent performance (Area Under the Curve (AUC)=0.995 (0.985-1.000); sensitivity=100%; specificity=99.54%; P&amp;lt;0.0001). FGF-5 also emerged as the top protein in differentiating the FH subjects from non-FH (AUC= 1.000 (0.914-1.000; sensitivity=100%, specificity=100% and P&amp;lt;0.001). Finally, when the two groups were matched for LDL-C, FGF-5 still differentiated the FH from the non-FH subjects, (AUC=1.000 (0.914-1.000), sensitivity=100%, specificity=100%, p&amp;lt;0.001). Conclusions FGF-5 allows a clear-cut identification of FH versus controls and, of even more importance, from non-FH with the same LDL-C. The LDL-C burden might be responsible for our findings.

Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments.

Familial hypercholesterolemia (FH) is the most common monogenic disorder in humans. It affects millions of people globally, increasing the risk of developing cardiovascular disease (CVD) at a younger age due to elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth. While effective traditional and novel treatments are available, the most significant challenge with FH is the lack of timely diagnosis. As a result, many patients remain undertreated leading to an increased risk of CVD. To mitigate risk, initiating early and aggressive LDL-C-lowering therapies is recommended. Moreover, given its autosomal dominant inheritance patterns, it is also recommended to perform cascade lipid and/or genetic testing of all first-degree relatives. This review highlights the importance of early FH diagnosis and available treatment options. Greater awareness and improved screening efforts can help diagnose and treat more individuals, ultimately reducing the CVD risk associated with FH.

Abstract 13186: Factors Associated With Dysglycemia and Type 2 Diabetes Mellitus Onset in Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by high blood LDL-C and cardiovascular disease (CVD). Type 2 diabetes mellitus (T2DM) is an independent cause of CVD and there is evidence that FH is associated with a lower frequency of its development. On the other hand, lipid lowering therapy (LLT) may increase T2DM risk. Goals: Evaluate the risk of dysglycemia and T2DM development in a cohort of molecularly proven FH individuals. Methods: This is a prospective analysis of a population enrolled on a genetic cascade screening program evaluated from March 2011 to January 2022. FH diagnosis was confirmed by molecular testing of variants in LDLR, APOB and PCSK9. Dysglycemia and T2DM diagnoses were done according to the ADA Criteria or use of any antidiabetic drugs. Results: 790 FH patients were included (age 45.5±15.0 years, 56.8% female, baseline LDL-C 198±74 mg/dL), 96.6% had LDLR variants. The prevalence of T2DM was 13.3% and 67.4% were taking LLT at baseline . There were 206 (26%) new cases of T2DM or dysglycemia after a median 51-month follow-up . In multivariate Cox regression analysis age (HR:1.026, CI95%: 1.014-1.038, p=0.000) , body mass index (HR: 1.062, CI95%: 1.035-1.090, p=0.000) and current smoking (HR: 2.005, HR: 1.337-3.008, p=0.001) were independently associated with T2DM and dysglycemia, while metformin use was associated with a lower risk (HR: 0.147, CI95%: 0.076-0.284, p=0.000). History of previous CVD, use of lipid lowering therapy at baseline, high intensity LLT , or type of molecular defect were not associated with higher T2DM/dysglycemia risk. Conclusions: In this cohort of molecularly proven FH subjects, T2DM affected more than 1 in 10 people at baseline. Previous CVD and classical risk factors but neither molecular defects nor lipid lowering therapy were associated with T2DM/dysglycemia onset.

Abstract 11930: Using Implementation Science to Develop a Familial Hypercholesterolemia Screening Program in Primary Care: The CARE-FH Study

Introduction: Cholesterol screening in primary care is necessary to identify children and young adults with familial hypercholesterolemia (FH). Research question: What is the current state of FH screening and what barriers exist to screening? What implementation strategies informed by human centered design can be utilized to improve FH screening in primary care? Aim: We partnered with key stakeholders to sequentially define the current state of FH screening, assess acceptability, feasibility, and appropriateness of implementing an FH screening program, and select clinically usable strategies to be deployed as a package in the CARE-FH clinical trial. Methods: Data on the perspectives of primary care clinicians to implement an FH screening program were collected. Methods informed by implementation science and human centered design for data collections included: contextual inquiries, surveys, and deliberative engagement sessions. Results: Current screening for FH occurred rarely, and then only after a cardiovascular event or sometimes in primary care due to a family history of high cholesterol or early heart attack. Surveys of primary care clinicians suggested FH screening in primary care was acceptable, appropriate, and feasible. Reported and observed barriers and facilitators to screening identified where improvement in FH screening and diagnosis could occur. Data from the current state and perspectives on FH screening were used to identify multilevel implementation strategies that were presented to and modified by clinician and healthcare stakeholders. This package of strategies was pilot tested in one primary care clinic and further refined to a final implementation strategy package to be tested in a geographical cluster randomized stepped wedge trial. Conclusion: We created an implementation strategy package to be deployed and evaluated in the CARE-FH clinical trial to improve FH awareness, identification, and initiate guideline-based care.

Abstract 13051: Profiling CD8+ T Cell Activation in Experimental Models With LDL-R Deficiency and in Patients With Familial Hypercholesteroleamia

Introduction and Hypothesis: Familial Hypercholesterolaemia (FH) is a rare genetic disease characterized by elevated plasma cholesterol levels, xanthomas, overt atherosclerosis and premature cardiovascular death. HoFH and severe HeFH present an elevated inflammatory burden and poorly responsive to therapeutics such as anti-PCSK9 monoclonal antibodies. Therefore, innovative approaches to diagnose the severity of the disease and control the over-activation of the immune-inflammatory response in the arterial wall of FH patients should be studied to improve the management of this genetic disease. Here we profiled the activation of CD8+ T lymphocytes from experimental models and with patients with clinical diagnosis of FH. Methods: Immunophenotypic characterization of T cells from WT and LDLR KO mice was performed in vitro and in vivo coupled to proteomics and WB analysis on isolated T cells. CD8 T cell response in FH patients, carrying mutations in the LDLR gene, was profiled. Results: LDLR mRNA expression increased after in vitro activation of CD8, but not CD4 T cells, suggesting a different regulation of cholesterol homeostasis between T cell subsets. LDLR deficiency mainly affected CD8 T cell activation as demonstrated by reduced in vitro and in vivo proliferation and cytokine production after ovalbumin vaccination of LDL-R KO T cells compared to their wild type counterpart. The addition of LDL to serum free media increased CD8 proliferation in WT but not in KO CD8 T cells. Proteomic and WB analysis showed that this phenotype is the consequence of reduced mTORC1 activation and impaired lysosomal organization. The proliferation of CD8 T cells from FH patients was less pronounced compared to sex- and age-matched controls. In addition, CD8 T cells from FH vaccinated for seasonal influenza were tested in vitro with virus-derived peptides, showing a decreased granzyme production compared to CD8 from vaccinated controls. Conclusions: LDLR plays a critical role in regulating the immunometabolic reprogramming of activated CD8 T cells by fuelling the cholesterol-lysosome-mTORC1 axis. Acknowledgments: This study is supported by a Grant from the Italian Ministry of Health: RF-2019-12370896

Long-term treatment persistence and maintained reduction of LDL-cholesterol levels with evolocumab over 30 months: Results from the Spanish cohort of the European prospective HEYMANS study

AimsLimited data exist on low-density lipoprotein-cholesterol (LDL-C) level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. HEYMANS (NCT02770131) is the first multi-country, multicenter, observational study of European patients initiating evolocumab as part of their routine clinical management, based on local reimbursement criteria (overall data recently published). The aim of this analysis is to describe clinical characteristics, baseline and changes in LDL-C levels, treatment patterns and persistence to evolocumab over 30 months in the Spanish cohort using data from the HEYMANS Registry. MethodsHEYMANS was a prospective study of adult patients (≥18 years) who received at least one dose of evolocumab. A total of 1951 patients were enrolled from 12 countries and were followed up for 30 months after evolocumab initiation. Data were collected for 6 months before evolocumab initiation and up to 30 months thereafter. The Spanish cohort included patients who started evolocumab in routine clinical practice from March 2016 to September 2019. Demographic and clinical characteristics, lipid-lowering therapies (LLT), and lipid levels were collected. ResultsIn total, 201 patients were included in the Spanish cohort. Median follow-up (Q1–Q3) was 30.0 (12–30) months. A total of 61.7% of patients were men and the mean (standard deviation) age was 59.5 (10.8) years. Most patients (68.7%) had experienced a prior cardiovascular event, 45.3% had coronary artery disease or stable angina, and 60.2% had a diagnosis of familial hypercholesterolemia. Overall, 57.7% of patients were receiving treatment with statins, most of them with high-intensity statins (85.3%); 45.8% of patients were intolerant to statins, and 26.4% of patients did not receive any LLT. At baseline, median (Q1–Q3) LDL-C levels were 151 (123–197) mg/dL. After 3 months of treatment, baseline LDL-C decreased by 66% to a median of 50 (30–83) mg/dL and these levels were maintained over time, with a median LDL-C of 55 (40–99) mg/dL at 30 months. At months 10–12 of treatment, LDL-C levels<55mg/dL were achieved by 56.3% of patients. LDL-C levels<70mg/dL were achieved by 70.1% of patients, and a lowering of LDL-C levels ≥50% was achieved by 76.8% of patients. The percentage of patients on evolocumab treatment was 95% at 12 months and 93% at 30 months. ConclusionsIn the Spanish cohort in routine clinical practice, evolocumab therapy provided a reduction in LDL-C levels consistent with that reported in previous clinical trials, which was sustained during 30 months of follow-up. Treatment with evolocumab was started at LDL-C levels 50% higher than those recommended by The Spanish Society of Arteriosclerosis and the Therapeutic Positioning Report. The probability of achieving the 2019 ESC/EAS LDL-C goals would improve with combination therapy and also with a lower LDL-C threshold when starting evolocumab. Persistence to evolocumab remained high during follow-up, with a very low percentage of discontinuation (5% at 12 months; 7% at 30 months).

High Lipoprotein(a) May Explain One-Quarter of Clinical Familial Hypercholesterolemia Diagnoses in Danish Lipid Clinics.

Cholesterol carried in lipoprotein(a) adds to measured low-density lipoprotein cholesterol (LDL-C) and may therefore drive some diagnoses of clinical familial hypercholesterolemia (FH). We investigated plasma lipoprotein(a) in individuals referred to Danish lipid clinics and evaluated the effect of plasma lipoprotein(a) on a diagnosis of FH. Individuals referred to 15 Danish lipid clinics who were suspected of having FH according to nationwide referral criteria were recruited between September 1, 2020 and November 30, 2021. All individuals were classified according to the Dutch Lipid Clinical Network criteria for FH before and after LDL-C was adjusted for 30% cholesterol content in lipoprotein(a). We calculated the fraction of individuals fulfilling a clinical diagnosis of FH partly due to elevated lipoprotein(a). We included a total of 1166 individuals for analysis, of whom 206 fulfilled a clinical diagnosis of FH. Median lipoprotein(a) was 15 mg/dL (29 nmol/L) in those referred and 28% had lipoprotein(a) greater than or equal to 50 mg/dL (105 nmol/L), while 2% had levels greater than or equal to 180 mg/dL (389 nmol/L). We found that in 27% (55/206) of those fulfilling a clinical diagnosis of FH, this was partly due to high lipoprotein(a). Elevated lipoprotein(a) was common in individuals referred to Danish lipid clinics and in one-quarter of individuals who fulfilled a clinical diagnosis of FH, this was partly due to elevated lipoprotein(a). These findings support the notion that the LPA gene should be considered an important causative gene in patients with clinical FH and further support the importance of measuring lipoprotein(a) when diagnosing FH as well as for stratification of cardiovascular risk.

A retrospective study of people with familial hypercholesterolaemia in a Belgian lipid clinic

Background Familial hypercholesterolaemia (FH) is a genetic disease characterised by hypercholesterolaemia and premature cardiovascular events. Early diagnosis and treatment can reduce the cardiovascular burden. We describe the characteristics of patients with heterozygous FH followed in a tertiary hospital in Belgium. Methods We retrospectively studied a population of 321 patients with definite heterozygous FH who visited the UZ Leuven lipid clinic at least once between 1 January 2016 and 31 December 2020. Data are represented as mean ± SD. Results The age at time of diagnosis of FH was 39 ± 18 years. Patients with atherosclerotic disease (secondary prevention) were older (p < .001), more often male (p < .001), had a higher body mass index (p < .001), prevalence of (pre)diabetes (p < .001) and hypertension (p < .001) and had lower levels of low-density lipoprotein-cholesterol (LDL-C) (p < .001) than individuals without atherosclerotic disease (primary prevention). The average LDL-C in both primary (109 ± 53 mg/dL) and secondary (81 ± 63 mg/dL) prevention did not meet the targets of LDL-C as proposed by the 2019 ESC/EAS guidelines for the management of dyslipidaemias. However, LDL-C levels in the subgroup of patients treated with PCSK9 inhibition therapy, and especially in the triple therapy group (combination of statin, ezetimibe and PCSK9 inhibitor), were markedly lower (p < .001). Conclusions In this Belgian population, people with heterozygous FH remain undertreated. Reaching treatment targets in FH seems possible, although this requires combination treatment (with PCSK9-targeted therapy) in most patients. Earlier diagnosis of FH, more extensive lipid-lowering treatment and reimbursement options and a more holistic approach are needed to lower LDL-C and cardiovascular risk in patients with FH.

Genetic backgrounds and diagnosis of familial hypercholesterolemia.

Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These disorders are responsible for a significant number of deaths in many adult populations worldwide. Familial hypercholesterolemia (FH) is a genetic disorder that causes extremely high levels of LDL cholesterol. The most common mutations occur in genes responsible for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). While genetic testing is a dependable method for diagnosing the disease, it may not detect primary mutations in 20%-40% of FH cases.

Reporting LDL cholesterol results by clinical biochemistry laboratories in Czechia and Slovakia to improve the detection rate of familial hypercholesterolemia.

This survey aims to assess the implementation of recommendations from the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) by clinical biochemistry laboratories in Czechia and Slovakia in their policies for reporting low-density lipoprotein cholesterol (LDL-C) concentrations. The web-based survey was distributed to all 383 Czech and Slovak clinical biochemistry laboratories that measure lipids by external quality assessment provider SEKK. A total of 17 single-answer questions were included. The questionnaire was focused on the detection and decision points in familial hypercholesterolemia (FH). All survey answers were taken into account. The laboratories followed the EFLM and EAS guidelines when they reported an interpretative comment considering FH diagnosis in adults. A total of 203 (53%) laboratories answered. Only 5% of laboratories added interpretative comments considering FH diagnosis when LDL-C concentrations are above 5.0 mmol/L in adults, and 3% of laboratories added interpretative comments considering FH diagnosis when LDL-C concentrations are above 4.0 mmol/L in children. Only 7% of laboratories reported goals for all cardiovascular risk categories (low, moderate, high, very high). Non-HDL cholesterol concentrations were calculated by 74% of responders. A significant number (51%) of participants did not measure apolipoprotein B, and 59% of laboratories did not measure lipoprotein(a). Only a small portion of laboratories from Czechia and Slovakia reported high LDL-C results with interpretative comments considering FH diagnosis in adults, the laboratories did not follow the guidelines.

LDLR and PCSK9 3´UTR variants and their putative effects on microRNA molecular interactions in familial hypercholesterolemia: a computational approach.

Familial hypercholesterolemia (FH) is caused by pathogenic variants in low-density lipoprotein (LDL) receptor (LDLR) or its associated genes, including apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDLR adaptor protein 1 (LDLRAP1). However, approximately 40% of the FH patients clinically diagnosed (based on FH phenotypes) may not carry a causal variant in a FH-related gene. Variants located at 3' untranslated region (UTR) of FH-related genes could elucidate mechanisms involved in FH pathogenesis. This study used a computational approach to assess the effects of 3'UTR variants in FH-related genes on miRNAs molecular interactions and to explore the association of these variants with molecular diagnosis of FH. Exons and regulatory regions of FH-related genes were sequenced in 83 FH patients using an exon-target gene sequencing strategy. In silico prediction tools were used to study the effects of 3´UTR variants on interactions between miRNAs and target mRNAs. Pathogenic variants in FH-related genes (molecular diagnosis) were detected in 44.6% FH patients. Among 59 3'UTR variants identified, LDLR rs5742911 and PCSK9 rs17111557 were associated with molecular diagnosis of FH, whereas LDLR rs7258146 and rs7254521 and LDLRAP1 rs397860393 had an opposite effect (p < 0.05). 3´UTR variants in LDLR (rs5742911, rs7258146, rs7254521) and PCSK9 (rs17111557) disrupt interactions with several miRNAs, and more stable bindings were found with LDLR (miR-4435, miR-509-3 and miR-502) and PCSK9 (miR-4796). LDLR and PCSK9 3´UTR variants disturb miRNA:mRNA interactions that could affect gene expression and are potentially associated with molecular diagnosis of FH.

Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults

Background and aimsThe early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy. MethodsThe area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics. ResultsAUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p < 0.01), Swedish (p < 0.01), and Italian testing sets (p < 0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets. ConclusionsCompared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.