BACKGROUND AND AIMS:Familial hypercholesterolemia (FH), primarily caused by pathogenic LDLR, APOB, or PCSK9 variants, results in elevated LDL-C and increased cardiovascular risk. Genetic testing offers the definitive diagnosis, yet global approaches to FH genetic testing remain unstandardized. We investigate current testing practices worldwide and provide relevant recommendations. METHODS:A survey was distributed to national lead-investigators (NLIs) of 68 countries in the FH-Studies Collaboration, assessing referral criteria, assay methodologies, target genes, and pathogenicity interpretation methods. RESULTS:NLIs from centres in 55/68 countries (81%) responded, spanning Africa (N=2), Americas (N=6), Asia (N=20), Europe (N=26), and Oceania (N=1). DLCN scores were the most common reason for referral to genetic testing (adults:72%; children:57%). Simon Broome and MEDPED criteria were reported only by centres from high-income countries (adults: 7% and 2%; children: 12% and 2%). Methods for testing in index versus non-index cases were significantly different (p <0.001). Next-generation sequencing (NGS) was the predominant assay method for index cases (62%), while Sanger sequencing was favoured for non-index (71%). However, these testing techniques did not differ between centres from high- and non-high-income countries for index cases (p=0.74) and non-index cases (p=0.49). Copy-number variants (CNVs) were assessed by 65% of centres, with most integrating CNV analysis into NGS platforms (86%) and others (14%) using multiplex ligation-dependent probe-amplification (MLPA) or microarrays. Screening encompassed LDLR (100%), APOB (97%), PCSK9 (95%), and other genes. Most centres (96%) incorporated pathogenicity interpretation into their reports, adhering largely to American College of Medical Genetics and Genomics guidelines. CONCLUSIONS:FH genetic testing practices vary widely across countries surveyed, emphasizing the need for global standardization to enhance accuracy and comparability of FH diagnoses worldwide. We suggest that genetic testing should include the three FH-causing genes and ideally the five associated/phenocopy genes.

ObjectiveElevated cholesterol levels are associated with the risk of the most socially significant cardiovascular diseases, such as atherosclerosis, ischemic heart disease, and myocardial infarction.MethodsIn this study, we sought to study the genetic architecture of lipid metabolism by conducting genome-wide association studies of total cholesterol, LDL-C, and HDL-C levels in a sample of the Russian population (n = 8,732) who were not carriers of variants linked to familial hypercholesterolemia and did not take lipid-regulating agents. Based on the detected associations and machine learning methods, several polygenic score models were constructed for each lipid type, and the link between polygenic scores and atherosclerosis, ischemic heart disease, and myocardial infarction was examined in an additional sample of patients diagnosed with either of these diseases (n = 3,954).ResultsA meta-analysis of the results of the conducted genome-wide association studies showed that total cholesterol and LDL-C were largely associated with the same variants located in the HMGCR, CERT1, POLK, ANKDD1B, APOC3, BCL3, CBLC, BCAM, NECTIN2, TOMM40, APOE, APOC1, APOC4, and SMARCA4 genes, while HDL-C was associated with variants located in the LPL, ALDH1A2, LIPC, and CETP genes. Men and women differed in genetic predictors of lipid levels, with variants in the SMARCA4 and LDLR genes associated with cholesterol levels only in women.ConclusionThe models developed in this study consider age and a modifiable factor, BMI. Therefore, the personalized polygenic profiling approach presented in this study enables life-long CVD risk assessment.

The primary analysis of the SELECT randomized clinical trial suggests that semaglutide reduced the rates of cardiovascular (CV) death, myocardial infarction, and stroke in patients with established CV disease (CVD) and overweight or obesity without diabetes. However, the effect of semaglutide on hospitalizations in this population remains unknown. To determine the impact of semaglutide on total hospital admissions and duration of hospital stay. The SELECT trial included patients aged 45 years or older with established CVD and a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 27 or higher without diabetes at 804 clinical settings across North America, South America, Europe, Asia, Africa, and Australia. Patients were randomized from October 2018 to March 2021. This prespecified exploratory analysis was conducted from February 2024 to September 2025. Once-weekly subcutaneous semaglutide, 2.4 mg, or placebo. The total number of hospital admissions and days in hospital between the semaglutide and placebo groups. A total of 17 604 patients (median [IQR] age, 61.0 [55.0-68.0] years; 4872 female patients [27.7%]; median [IQR] BMI, 32.1 [29.7-35.7]) were followed up for a median (IQR) period of 41.8 (33.0-47.0) months. There were 11 287 hospital admissions. The number of total hospitalizations was lower in the semaglutide group vs placebo for any indication (18.3 vs 20.4 admissions per 100 patient-years; mean ratio [MR], 0.90; 95% CI, 0.85-0.95; P < .001) and for serious adverse events (15.2 vs 17.1 admissions per 100 patient-years; MR, 0.89; 95% CI, 0.84-0.94; P < .001). The number of days hospitalized for any indication per 100 patient-years was lower in the semaglutide group vs placebo (157.2 vs 176.2 days; rate ratio [RR], 0.89; 95% CI, 0.82-0.98; P = .01), as well as hospitalizations for serious adverse events (137.6 vs 153.9 days; RR, 0.89; 95% CI, 0.81-0.98; P = .02). No heterogeneity was observed for the reduction of hospital admissions with semaglutide in selected subgroups, including BMI, age, and sex. In this prespecified exploratory analysis of the SELECT randomized clinical trial, the trial cohort had a high rate of hospital admissions. Treatment with once-weekly semaglutide was associated with significant reductions in hospital admissions and overall time spent in hospital, extending its benefits beyond CV risk reduction. ClinicalTrials.gov Identifier: NCT03574597

BackgroundThe purpose of this study was to investigate genetic risk factors associated with ischemic heart disease (IHD) in Russian adults, to develop prognostic PRS models for IHD risk stratification, and to gain a better understanding of molecular mechanisms underlying IHD through a transcriptome analysis.Materials and methodsThe study analyzed data from three independent cohorts: a population sample of 69,500 individuals, a cardiac sample of 5,875 IHD patients, and a sample of 2,870 long-living adults. To identify genomic loci associated with IHD, a GWAS was performed, and its findings were used to develop a PRS model for the IHD phenotype. Additionally, a transcriptome analysis was conducted.ResultsThe GWAS for IHD adjusted for sex, age, and the first ten principal component accounting for population structure identified 75 variants, with 67 located at 9p21.3. Based on the GWAS findings, PRS models were developed and validated for IHD. The risk of IHD adjusted for sex, age, and BMI was the lowest in the sample of long-living adults. The TWAS revealed a significant association between IHD and increased CDKN2B expression in the aorta. According to the DEG results, the CDKN1A gene, a member of the same gene family as CDKN2B, was significantly hypoexpressed in the lower limb veins of patients with IHD.ConclusionPRS models offer great benefits for IHD risk prediction, particularly in individuals at the e tremes of the heritable risk distribution. lncRNAs, such as CDKN2BAS1 and lncRNA-MAP3K4, as well as P2X2 receptors, could be potential therapeutic targets for IHD.

Aims Familial hypercholesterolaemia (FH), primarily caused by pathogenic LDLR, APOB, or PCSK9 variants, results in elevated LDL cholesterol and increased cardiovascular risk. Genetic testing offers the definitive diagnosis, yet global approaches to FH genetic testing remain unstandardized. We investigate current testing practices worldwide and provide relevant recommendations. Methods and results A survey was distributed to national lead investigators of 68 countries in the Familial Hypercholesterolaemia Studies Collaboration, assessing referral criteria, assay methodologies, target genes, and pathogenicity interpretation methods. National lead investigators from centres in 55/68 countries (81%) responded, spanning Africa (n = 2), Americas (n = 6), Asia (n = 20), Europe (n = 26), and Oceania (n = 1). Dutch Lipid Clinic Network (DLCN) scores were the most common reason for referral to genetic testing (adults, 72%; children, 57%). Simon-Broome and Make Early Diagnosis to Prevent Early Death (MEDPED) criteria were reported only by centres from high-income countries (adults, 7% and 2%; children, 12% and 2%). Methods for testing in index vs. non-index cases were significantly different (P < 0.001). Next-generation sequencing (NGS) was the predominant assay method for index cases (62%), while Sanger sequencing was favoured for non-index (71%). However, these testing techniques did not differ between centres from high- and non-high-income countries for index cases (P = 0.74) and non-index cases (P = 0.49). Copy-number variants (CNVs) were assessed by 65% of centres, with most integrating CNV analysis into NGS platforms (86%) and others (14%) using multiplex ligation-dependent probe amplification (MLPA) or microarrays. Screening encompassed LDLR (100%), APOB (97%), PCSK9 (95%), and other genes. Most centres (96%) incorporated pathogenicity interpretation into their reports, adhering largely to American College of Medical Genetics and Genomics guidelines. Conclusion Familial hypercholesterolaemia genetic testing practices vary widely across countries surveyed, emphasizing the need for global standardization to enhance accuracy and comparability of FH diagnoses worldwide. We suggest that genetic testing should include the three FH-causing genes and ideally the five associated/phenocopy genes.

Because one in three of all individuals die from atherosclerotic cardiovascular disease (ASCVD), prevention of ASCVD is key to public health worldwide. Lipid clinics provide specialized diagnostic assessment, lifestyle management, and evidence-based lipid-lowering treatment to prevent ASCVD and acute pancreatitis in high-risk individuals. This includes individuals with familial hypercholesterolemia and/or markedly increased lipoprotein(a), statin intolerance, refractory or difficult-to-control low-density lipoprotein (LDL) cholesterol, severe hypertriglyceridaemia, and other rare or complex lipid disorders. Such specialized care not only benefits the individual patients and their families but facilitates dissemination of best practices in lipid disorder management to healthcare professionals in individual nations. Despite this, there is a lack of guidance on standards and metrics needed to establish a well-harmonized national lipid clinic network in most countries capable of offering comprehensive care. This consensus paper from the European Atherosclerosis Society Lipid Clinic Network aims to meet this unmet clinical need. We provide recommendations to enhance education and training on lipid disorders and to harmonize lipid clinics at both national and international levels. Furthermore, we provide guidance on optimal staffing structures and development of registries to improve diagnosis and management of lipid disorders. Finally, we offer recommendations to national and regional policymakers on funding of lipid clinics, with the long-term goal of reducing the overall societal burden and costs of cardiovascular and other lipid-related diseases.