Laboratory diagnosis of severe hypertriglyceridaemia. Cases from the dyslipidaemia regristy of the spanish atherosclerosis society

Background and Aims Severe hypertriglyceridaemia (sHTG) increases the risk of cardiovascular disease and acute pancreatitis episodes. Patients with sHTG fit mainly into two clinical entities: Familial or Multifactorial Chylomicronemia Syndromes (FCS and MCS, respectively). FCS and MCS exhibit clinical differences but also separate genetic and biochemical characteristics that can be assessed in the laboratory. The aim of this work has been to implement a laboratory workflow to help diagnose sHTG patients with either FCS or MCS. Methods Patients with two fasting triglycerides >1000mg/dL determinations were sequenced with a capture probe panel of 24 triglycerides-related genes using massive parallel sequencing (n=200). Two-step sequential ultracentrifugation was performed (n= 159) to diagnose Type I hyperlipoproteinemia (HLP I) and post heparin lipoprotein lipase activity was measured to discard or confirm its deficiency (n=60). Results Most patients had MCS as they: (i) did not exhibit HLPI and/or (ii) their genetic profile was not compatible with FCS and (iii) were not deficient in LPL activity. FCS cases were identified as they had: (i) HLPI, and/or (ii) biallelic pathogenic variants in LPL (n=5), GPIHBP1 (n=3), or LMF1 (n=2) genes and/or (iii) LPL activity deficiency. We identified 4 FCS patients with HLPI, biallelic pathogenic variants in APOA5 but a rescued LPL activity. An additional study of Apo-AV functionality was designed to confirm the FCS diagnosis in these cases. Conclusions Laboratory studies, in patients with severe hypertriglyceridaemia, provide with information of clinical utility to distinguish between Familial and Multifactorial Chylomicronemia Syndromes.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Efecto de las variantes genéticas en apoa5 en la activación de la lipoproteina lipasa y su asociación al síndrome de quilomicronemia familiar

La lipoproteína Lipasa (LPL) tiene entre sus activadores a la APO-AV, aunque existe controversia sobre si esta resulta esencial en la activación de la enzima. Nuestro objetivo fue estudiar el efecto de determinadas variantes genéticas en APOA5 presentes en 4 pacientes con historia de Hipertrigliceridemia Grave (HTG) sobre la actividad de la Lipoproteína Lipasa post-heparina in vitro y su asociación con las manifestaciones clínicas del Síndrome de Quilomicronemia Familiar (SQF). Material y métodos: Para estudiar la capacidad de activación del suero cada paciente sobre la actividad Lipoproteína Lipasa, se añadieron cantidades crecientes del suero pre-heparina de cada paciente, como fuente de APO-AV, a la mezcla de reacción (10, 20 y 40 µL; pre-calentados a 56 °C durante 60 minutos con PMSF al 0.1% (m/v)). En cada ensayo enzimático a punto final se empleó LPL de un plasma post-heparina (100 U/Kg) procedente de un individuo sano. Por otro lado, se estableció el perfil apolipoproteico mediante turbidimetría, ELISA y ultracentrifugación secuencial, se estableció la presencia de HPLI mediante el cálculo del cociente de triglicéridos en quilomicrones entre triglicéridos en VLDL y se recogieron datos clínicos y antropométricos. Resultados: PACIENTE RESUMEN DE VARIANTES GENÉTICAS EN APOA5 1 Hom c.758T>C 2 het c.758T>C & c.326_327insC 3 Het c.990_993delAACA & c.289C>T 4 het c.289C>T & c.50-2ª>G Los pacientes 1, 2 y 3, presentaron HPLI, y hospitalizaciones por episodios de pancreatitis. Además, los sueros pre-heparina de estos pacientes no activaron significativamente la actividad LPL (p<0.05). En cambio, el paciente 4 no presentó HPLI, no tuvo episodios de pancreatitis y su plasma pre-heparina sí activó significativamente la actividad LPL (p<0.05). Conclusiones: En pacientes con historia clínica de HTG, determinadas variantes genéticas en APOA5 no activan a la LPL, asociándose además a la presencia de HPLI y a una clínica compatible con SQF.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Long-term effect of 2 intensive statin regimens on treatment and incidence of cardiovascular events in familial hypercholesterolemia : The SAFEHEART study

Funding: This study was supported by Fundación Hipercolesterolemia Familiar; Grant G03/181 Grant 08-2008 Centro Nacional de Investigaci?n Cardiovascular (CNIC).Background: Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH. Objectives: The objectives of the study were to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (ACVEs) and changes in the cardiovascular risk. Methods: SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs. Results: A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5-10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67-3.39) and 1.22 (0.54-2.93) at enrollment for ATV and RV, respectively (P <.001). There were no significant differences at the follow-up: 1.29 (0.54-2.82) and 1.22 (0.54-2.76) in the ATV and RV groups, respectively (P =.51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C <100 mg/dL and 4% in secondary prevention with ATV and 5% with RV achieved an LDL-C <70 mg/dL. The use of ezetimibe was marginally greater in the RV group. One hundred sixty ACVEs occurred during follow-up, being its incidence rate 1.1 events/100 patient-years in the ATV group and 1.2 in the RV group (P =.58). Conclusion: ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated

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

Background 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. Methods 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. Findings 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. Interpretation 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. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

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

Background: 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. Methods: 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. Findings: 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. Interpretation: 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

Potential utility of the SAFEHEART risk equation for rationalising the use of PCSK9 monoclonal antibodies in adults with heterozygous familial hypercholesterolemia

BACKGROUND AND AIMS: Patients with familial hypercholesterolaemia (FH) may require proprotein convertase subtilisin/kexin-type 9 (PCSK9) mAb as add-on therapy to achieve LDL-cholesterol (LDL-C) goals. However, the current cost of these therapies means that choosing suitable patients is based on consensus or clinical judgement rather than a quantitative risk assessment. We used the SAFEHEART Risk Equation (RE) to estimate the number needed to treat (NNT) at different risk thresholds and baseline LDL-C to identify those FH patients more likely to derive the greatest benefit from PCSK9 mAb. METHODS: Five-year event rates were calculated using the SAFEHEART-RE for every patient, overall and across LDL-C strata. A 60% reduction of LDL-C after theoretical treatment with PCSK9 mAb was assumed. Individual absolute risk simulating the effects of PCSK9 inhibition was calculated using the SAFEHEART-RE and, in a similar way, by using the Cholesterol Treatment Trialists' (CTT) Collaboration criteria. Absolute risk reduction and NNTs were calculated. RESULTS: Of the total SAFEHEART population, 2,153 were FH cases aged 18 years or older, on maximum tolerated lipid lowering treatment. NNTs were dependent of both baseline predicted risk and baseline LDL-C level ranging from 44 to 17 for those with 5-year risk of ≥1 to ≥5. The smallest NNT (12) was observed among those with 5-year risk of ≥5% and LDL-C ≥160 mg/dl. Using the CTT criteria produced similar results. CONCLUSIONS: The SAFEHEART-RE may provide a useful quantitative tool for rationalising the selection of FH patients who might derive greater absolute benefits from PCSK9 mAb

Estándares SEA 2022 para el control global del riesgo cardiovascular

One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to better knowledge of vascular disease, its prevention and treatment. It is well known that cardiovascular diseases are the leading cause of death in our country and entail a high degree of disability and health care costs. Arteriosclerosis is a multifactorial disease and therefore its prevention requires a global approach that takes into account the different risk factors with which it is associated. Therefore, this document summarizes the current level of knowledge and includes recommendations and procedures to be followed in patients with established cardiovascular disease or at high vascular risk. Specifically, this document reviews the main symptoms and signs to be evaluated during the clinical visit, the laboratory and imaging procedures to be routinely requested or requested for those in special situations. It also includes vascular risk estimation, the diagnostic criteria of the different entities that are cardiovascular risk factors, and makes general and specific recommendations for the treatment of the different cardiovascular risk factors and their final objectives. Finally, the document includes aspects that are not usually referenced in the literature, such as the organization of a vascular risk consultation. (c) 2021 The Authors. Published by Elsevier Espana, S.L.U. on behalf of Sociedad Espanola de Arteriosclerosis. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/)

Long-term effect of 2 intensive statin regimens on treatment and incidence of cardiovascular events in familial hypercholesterolemia : The SAFEHEART study

Funding: This study was supported by Fundación Hipercolesterolemia Familiar; Grant G03/181 Grant 08-2008 Centro Nacional de Investigaci?n Cardiovascular (CNIC).Background: Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH. Objectives: The objectives of the study were to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (ACVEs) and changes in the cardiovascular risk. Methods: SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs. Results: A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5-10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67-3.39) and 1.22 (0.54-2.93) at enrollment for ATV and RV, respectively (P <.001). There were no significant differences at the follow-up: 1.29 (0.54-2.82) and 1.22 (0.54-2.76) in the ATV and RV groups, respectively (P =.51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C <100 mg/dL and 4% in secondary prevention with ATV and 5% with RV achieved an LDL-C <70 mg/dL. The use of ezetimibe was marginally greater in the RV group. One hundred sixty ACVEs occurred during follow-up, being its incidence rate 1.1 events/100 patient-years in the ATV group and 1.2 in the RV group (P =.58). Conclusion: ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated