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1.
Arch. argent. pediatr ; 122(2): e202310094, abr. 2024. tab, fig
Artigo em Inglês, Espanhol | LILACS, BINACIS | ID: biblio-1532934

RESUMO

Introducción. La asociación entre los marcadores lipídicos en la infancia/adolescencia y la incidencia de eventos clínicos cardiovasculares en la adultez está poco explorada en la literatura. El objetivo de esta revisión sistemática fue analizar la evidencia disponible sobre este tema. Población y métodos. Esta revisión sistemática se realizó de acuerdo con las guías PRISMA. Se realizó una búsqueda bibliográfica para detectar los estudios que evaluaron la asociación entre los niveles lipídicos en la edad pediátrica y la incidencia de eventos cardiovasculares en la edad adulta. No hubo restricciones idiomáticas ni geográficas en la búsqueda. Resultados. En total, cinco estudios observacionales (todas cohortes prospectivas) que incluyeron 43 540 pacientes fueron identificados y considerados elegibles para este estudio. Cuatro estudios evaluaron el nivel de triglicéridos; todos reportaron una asociación significativa entre este marcador en la edad pediátrica y los eventos cardiovasculares en la adultez. Un estudio reportó la misma asociación con el nivel de colesterol total, mientras que otro evidenció el valor predictivo de la lipoproteína (a) para el mismo desenlace clínico. Un solo estudio evaluó el colesterol asociado a lipoproteínas de alta densidad (C-HDL), sin encontrar una relación con el punto final de interés. El análisis del colesterol asociado a lipoproteínas de baja densidad (C-LDL) arrojó resultados contradictorios, aunque la asociación fue significativa en los estudios con un tamaño muestral más grande y con un mayor número de eventos durante el seguimiento. Conclusión. Los datos de esta revisión sugieren que las alteraciones de los marcadores lipídicos en la infancia y la adolescencia se asocian con un mayor riesgo cardiovascular en la adultez temprana y media.


Introduction. The association between lipid markers in childhood/adolescence and the incidence of clinical cardiovascular events in adulthood has been little explored in the bibliography. The objective of this systematic review was to analyze available evidence on this topic. Population and methods. This systematic review was conducted in accordance with the PRISMA guidelines. A comprehensive bibliographic search was done to find studies assessing the association between lipid levels in childhood and the incidence of cardiovascular events in adulthood. There were no language or geographic restrictions. Results. A total of 5 observational studies (all prospective cohorts) including 43 540 patients were identified and considered eligible for this study. Four studies assessed triglyceride levels; all reported a significant association between this lipid marker in childhood and cardiovascular events in adulthood. A study reported the same association with total cholesterol level, while another showed the predictive value of lipoprotein (a) for the same clinical outcome. Only one study assessed high-density lipoprotein cholesterol (HDL-C), but it did not find an association with the endpoint of interest. The analysis of lowdensity lipoprotein cholesterol (LDL-C) showed contradictory results, although the association was significant in the studies with a larger sample size and a higher number of events during follow-up. Conclusion. According to this review, alterations in lipid markers in childhood and adolescence are associated with a higher cardiovascular risk in early and middle adulthood.


Assuntos
Humanos , Pré-Escolar , Criança , Adolescente , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Colesterol , Triglicerídeos , Estudos Prospectivos , Fatores de Risco , Estudos Observacionais como Assunto , HDL-Colesterol , LDL-Colesterol
2.
Curr Atheroscler Rep ; 25(12): 899-909, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37921916

RESUMO

PURPOSE OF REVIEW: Heterozygous familial hypercholesterolemia (HeFH) is the most common monogenic autosomal dominant disorder. However, the condition is often underdiagnosed and undertreated. The objective of this review is to provide an update on the risk stratification in patients with HeFH, incorporating new cardiovascular imaging techniques, various biomarkers, and genetic studies. RECENT FINDINGS: The diagnosis of HeFH places patients in a high cardiovascular risk category due to the increased incidence of premature atherosclerotic cardiovascular disease. However, the level of risk varies significantly among different individuals with HeFH. Achieving an optimal stratification of cardiovascular risk is crucial for establishing appropriate and accurate treatment and management strategies. Different new tools such as risk scores have emerged in recent years, aiding physicians in assessing the risk stratification for HeFH using imaging, biomarkers, and genetics. This review emphasizes that not all patients with HeFH face the same cardiovascular risk. By utilizing different assessment tools, we can identify those who require more intensive monitoring, follow-up, and treatment.


Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Testes Genéticos , Biomarcadores , Fatores de Risco
3.
High Blood Press Cardiovasc Prev ; 30(4): 305-317, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37284910

RESUMO

INTRODUCTION: The polycystic ovary syndrome (PCOS) may represent an important model of lipid alterations. Lipoprotein(a) [Lp(a)] has emerged as a new marker of cardiovascular risk. AIM: The main objective of this meta-analysis was to analyze the available evidence on Lp(a) levels in patients with PCOS compared to a control group. METHODS: This meta-analysis was performed according to PRISMA guidelines. A literature search was performed to detect studies that have quantified Lp(a) levels in women with PCOS compared to a control group. The primary outcome was Lp(a) levels expressed in mg/dL. Random effects models were used. RESULTS: Twenty-three observational studies including 2,337 patients were identified and considered eligible for this meta-analysis. In the overall analysis, the quantitative analysis showed that patients with PCOS have a higher Lp(a) levels (SMD: 1.1 [95% CI: 0.7 to 1.4]; I2=93%) compared to the control group. The results were similar in the analysis of the subgroups of patients according to body mass index (normal weight group: SMD: 1.2 [95% CI: 0.5 to 1.9], I2=95%; overweight group: SMD: 1.2 [95% CI: 0.5 to 1.8], I2=89%). Sensitivity analysis showed that the results were robust. CONCLUSIONS: This meta-analysis shows that women with PCOS had higher levels of Lp(a) compared to healthy women used as a control group. These findings were observed in both overweight and non-overweight women.


Assuntos
Síndrome do Ovário Policístico , Feminino , Humanos , Síndrome do Ovário Policístico/diagnóstico , Sobrepeso , Lipoproteína(a) , Estudos Observacionais como Assunto
4.
Rev. argent. cardiol ; 91(2): 149-152, jun. 2023. graf
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1529593

RESUMO

RESUMEN Introducción : La hipertrigliceridemia grave (HTGG) es un desorden metabólico con múltiples causas e implicancias tera péuticas. Se desconocen hasta la fecha las características clínicas, la prevalencia y sus posibles causas en nuestra población. Objetivo : estimar la prevalencia, describir las características clínicas y causas subyacentes de la HTGG en un hospital de tercer nivel del municipio de General Pueyrredón. Materia y métodos : Estudio descriptivo y observacional realizado con pacientes ambulatorios e internados de un hospital provincial. Se incluyeron pacientes adultos con triglicéridos (TG) mayores que 885 mg/dL (10 mmol/L) evaluados desde enero de 2018 a diciembre de 2021. Se extrajeron sus historias clínicas y, luego, se los contactó para obtener medidas antro pométricas, variables sociodemográficas, antecedentes personales y familiares, causas secundarias de hipertrigliceridemia y el tratamiento recibido. Resultados : Se analizaron 16 029 muestras; 46 presentaron HTGG, lo que representa una prevalencia total del 0,28% (IC 95% 0,20-0,40%) (IC 95% 0,20-0,40%); se incluyeron 19 participantes en el análisis. La edad media fue de 48,47 años (DE ±16); el 84,2% de ellos eran hombres. La mediana de triglicéridos fue 1821 mg/dL (rango intercuartílico 917-7000 mg/dL); 17 participantes (84,97%) presentaban hipercolesterolemia (colesterol total mayor que 200 mg/dL). Casi el 50% refirió consumo de alcohol, el 55% presentaba obesidad y el 68% diabetes tipo II. Solo 9 participantes se encontraban en tratamiento, 4 con fibratos y 5 con estatinas. Conclusión : se encontró una prevalencia del 0,28%, más alta que la esperada y reportada en series previas. Por otro lado, se destaca la subutilización de medicación para el tratamiento de esta dislipidemia grave.


ABSTRACT Background : Severe hypertriglyceridemia (SHTG) is a metabolic disorder with multiple origins and management implications. Prevalence, clinical characteristics, and its possible causes are unknown in Argentina. Objective : The aim of this study was to estimate the prevalence and describe the clinical characteristics and underlying SHTG causes in a third level hospital in the municipality of General Pueyrredón. Methods : An observational, descriptive study was performed using an electronic database from a provincial Hospital. It included adult patients with triglyceride (TG) levels above 885 mg/dL (10 mmol/L) evaluated from January 2018 to December 2021. Medical records were collected, and patients were then contacted to obtain anthropometric measurements, sociodemographic variables, personal and family history, secondary causes of hypertriglyceridemia, and treatment received. Results : Among 16 029 patients analyzed, 46 presented SHTG, representing a total prevalence of 0.28% (95% CI 0.20-0.40%). Finally, 19 participants with mean age 48.47±16 years and 84.2% men were included in the analysis. Median TG level was 1821 mg/dL (interquartile range 917-7000 mg/dL), and 17 participants (84.97%) had hypercholesterolemia (total cholesterol >200 mg/dL). Almost 50% reported alcohol consumption, 55% were obese and 68% had type II diabetes. Nine participants were under pharmacological treatment, 4 with fibrates and 5 with statins. Conclusion : A prevalence of 0.28% SHTG was found, higher than that reported in other series. Another finding was the underuse of medication for this severe dyslipidemia.

5.
J Clin Lipidol ; 16(5): 562-573, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35918256

RESUMO

BACKGROUND: Lipid-lowering medication is effective in reducing the risk of cardiovascular disease in several clinical scenarios. However, the evidence in patients with familial hypercholesterolemia (FH) and severe primary hypercholesterolemia is less robust. OBJECTIVES: The main objective of the present systematic review was to analyze the association between lipid-lowering medication and cardiovascular risk reduction in patients with FH or severe primary hypercholesterolemia. METHODS: This systematic review was performed according to PRISMA guidelines. A literature search was performed to detect studies that evaluated the association between lipid-lowering medication and cardiovascular events in FH patients. The diagnosis of FH varied in the studies analyzed. Genetic and clinical criteria or a combination of both were used. Likewise, we considered patients with severe primary hypercholesterolemia. RESULTS: Fourteen studies including 21059 patients were considered eligible for this research. This systematic review showed that the vast majority of the studies with statins reported a significant cardiovascular risk reduction. Statin use was associated with a lower risk of major adverse cardiovascular events (3 studies), coronary heart disease (2 studies), cardiovascular death (4 studies), all-cause mortality (4 studies) and combined endpoint of coronary heart disease and mortality (1 study). When analyzing the association between non-statin lipid-lowering medications and the incidence of cardiovascular events, the results were conflicting. CONCLUSION: Despite the low level of evidence, this systematic review showed that statins reduce cardiovascular events in patients with HeFH. Evidence for other lipid-lowering drugs is not conclusive.


Assuntos
Doenças Cardiovasculares , Doença das Coronárias , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , LDL-Colesterol , Hipercolesterolemia/tratamento farmacológico , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/complicações , Doença das Coronárias/complicações
6.
J Clin Endocrinol Metab ; 107(5): 1216-1224, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-34888679

RESUMO

Primary hyperlipidemias include a heterogeneous set of monogenic and polygenic conditions characterized by a strong family aggregation, severe forms of hypercholesterolemia and/or hypertriglyceridemia, appearance early on life, and a high risk of cardiovascular events and/or recurrent pancreatitis. In real life, a small proportion of the primary hyperlipidemia cases is recognized and treated properly. Our goal is to present an update of current and upcoming therapies for patients with primary hyperlipidemia. Recently, new lipid-lowering medications have obtained authorization from the U.S. Food and Drug Administration and the European Medicines Agency. These drugs target metabolic pathways, including (adenosine 5'-triphosphates)-citrate lyase (bempedoic acid), proprotein convertase subtilisin/kexin 9 (inclisiran), apolipoprotein CIII (volanesorsen), and angiopoietin-like 3 (volanesorsen), that have additive effects with the actions of the currently available therapies (i.e., statins, ezetimibe or fibrates). We discuss the potential clinical indications for the novel medications. To conclude, the addition of these new medications to the therapeutic options for primary hyperlipidemia patients may increase the likelihood of achieving the treatment targets. Also, it could be a safer alternative for patients with side effects for the currently available drugs.


Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Hiperlipidemias , Hipertrigliceridemia , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Pró-Proteína Convertase 9
7.
Clin Investig Arterioscler ; 33(6): 308-313, 2021.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-34656372

RESUMO

INTRODUCTION: Statins are the first line of treatment in patients with severe hypercholesterolemia (SH). However, despite the knowledge regarding its effectiveness and security for preventing cardiovascular diseases, treatment is a major challenge. MATERIAL AND METHODS: A prospective observational study was conducted by telephone survey to determine cardiovascular risk factors, annual monitoring, statins use and persistence and new-onset cardiovascular events (CVE) after 5 years in patients with SH including in a program for detection of familial hypercholesterolemia. RESULTS: 115 participants were analysed, the median age was 56 ±10 being 74% females. 63.4% of women and 43% of men had been correctly controlled in the last year. Patients on lipid lowering drugs stratified by sex was 38.8% in women and 26.7% in men, however, only 22 participants (31.8%) were persistence with statins since 2015.Overall, 48% of the patients presented a CVE and 3.4% died. Multivariate analysis did not reveal predictors for CVE. CONCLUSIONS: In our population with SH we found a high risk to present a CVE and a dramatic low use and persistence with the treatment.


Assuntos
Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
8.
Arch Cardiol Mex ; 90(2): 130-136, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32897268

RESUMO

Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.


Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.


Assuntos
Apolipoproteína B-100/genética , Hiperlipoproteinemia Tipo II/genética , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Adulto , Idoso , Apolipoproteínas E/genética , Argentina , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único
9.
Arterioscler Thromb Vasc Biol ; 40(10): 2508-2515, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32757650

RESUMO

OBJECTIVE: Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3±15.8 years, 38.0% males), and 63 children (age 8.8±4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in the LDLR. True HoFH due to LDLR variants had higher total (P=0.015) and LDL (low-density lipoprotein)-cholesterol (P=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (P=0.051) and had a greater frequency of xanthomas (P=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults with LDLR variants. Children who are true HoFH had higher frequency of major cardiovascular events (P=0.02), coronary heart (P=0.013), and aortic/supra-aortic valve diseases (P=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type of LDLR variant. From 118 subjects with LDLR variants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2 LDLR variants, those with at least one null allele were younger (P=0.003) and had a greater frequency of major cardiovascular events (P=0.038) occurring at an earlier age (P=0.001). CONCLUSIONS: There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.


Assuntos
Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Homozigoto , Hiperlipoproteinemia Tipo II/genética , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Fatores Etários , Apolipoproteína B-100/genética , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Criança , Pré-Escolar , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Estudos Retrospectivos , Fatores de Risco , América do Sul/epidemiologia , Adulto Jovem
10.
Arch. cardiol. Méx ; 90(2): 130-136, Apr.-Jun. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1131021

RESUMO

Abstract Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.


Resumen Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Receptores de LDL/genética , Apolipoproteína B-100/genética , Pró-Proteína Convertase 9/genética , Hiperlipoproteinemia Tipo II/genética , Apolipoproteínas E/genética , Fenótipo , Argentina , Variação Genética , Polimorfismo de Nucleotídeo Único , Mutação
11.
Arch Cardiol Mex ; 90(2): 151-157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32459195

RESUMO

Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.


Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.


Assuntos
Variação Genética , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , Adulto , Idoso , Apolipoproteína B-100/genética , Argentina , Feminino , Humanos , Lipase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico
12.
JAMA Cardiol ; 5(2): 217-229, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31895433

RESUMO

Importance: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. Observations: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. Conclusions and Relevance: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.


Assuntos
Hiperlipoproteinemia Tipo II/prevenção & controle , Efeitos Psicossociais da Doença , Saúde Global , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Guias de Prática Clínica como Assunto , Saúde Pública
13.
Lancet ; 394(10199): 697-708, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31448741

RESUMO

Atherosclerosis and its clinical manifestation as ischaemic heart disease remains a considerable health burden. Given that many factors contribute to ischaemic heart disease, a multifactorial approach to prevention is recommended, starting with lifestyle advice, smoking cessation, and control of known cardiovascular risk factors, such as blood pressure and lipids. Within the lipid profile, the principal target is lowering LDL cholesterol, firstly with lifestyle interventions and subsequently with pharmacological therapy. Statins are the recommended first-line pharmacological treatment. Some individuals might require further lowering of LDL cholesterol or be unable to tolerate statins. Additional therapies targeting different pathways in cholesterol metabolism are now available, ranging from small molecules taken orally, to injectable therapies. Examples include ezetimibe, which targets Niemann-Pick C1-like protein, and monoclonal antibodies that target PCSK9. Phase 3 trials have also been completed for bempedoic acid (targeting ATP-citrate lyase) and inclisiran (an interference RNA-based therapeutic targeting hepatic PCSK9 synthesis). In addition to LDL cholesterol, mendelian randomisation studies support a causal role for lipoprotein(a) and triglycerides in ischaemic heart disease. In this Series paper, we appraise currently available and emerging therapies for lowering LDL cholesterol, lipoprotein(a), and triglycerides for prevention of ischaemic heart disease.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/farmacologia , LDL-Colesterol/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas/efeitos dos fármacos , Isquemia Miocárdica/prevenção & controle , LDL-Colesterol/sangue , Humanos , Lipoproteínas/sangue , Isquemia Miocárdica/tratamento farmacológico , Pró-Proteína Convertase 9 , Fatores de Risco , Triglicerídeos/sangue
14.
Atherosclerosis ; 277: 256-261, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30270055

RESUMO

BACKGROUND AND AIMS: Marked hypercholesterolemia, defined as low density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL, may be due to LDLR, APOB, and PCSK9 variants. In a recent analysis, only 1.7% of cases had such variants. Our goal was to identify other potential genetic causes of hypercholesterolemia. METHODS: In a total of 51,253 subjects with lipid testing, 3.8% had elevated total cholesterol >300 mg/dL and/or LDL-C≥190 mg/dL. Of these, 246 were further studied, and 69 without kidney, liver, or thyroid disease and who met Dutch Lipid Clinic Network criteria of ≥6 points had DNA sequencing done at the LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1, ABCG5, ABCG8, CYP27A1, LIPA, LIPC, LIPG, LPL, and SCARB1 gene loci and also had 10 SNP analysis for a weighted high LDL-C genetic risk score. RESULTS: In the 69 subjects with genetic analyses, the following variants were observed in 37 subjects (53.6%): LDLR (n = 20, 2 novel), ABCG5/8 (n = 7, 2 novel), APOB (n = 3, 1 novel), CYP27A1 (n = 3, 1 novel), LIPA (n = 2, 1 novel), APOE (n = 2), LIPC (n = 1, novel), LIPG (n = 1, novel), and SCARB1 (n = 1); 14 subjects (20.3%) had a high polygenic score, with 4 (5.8%) having no variants. CONCLUSIONS: Our data indicate that in addition to variants in LDLR, APOB, PCSK9, APOE, LDLRAP1, and STAP1, variants in ABCG5/8, CYP27A1, LIPA, LIPC, and LIPG may be associated with hypercholesterolemia and such information should be used to optimize therapy.


Assuntos
LDL-Colesterol/sangue , Variação Genética , Hiperlipoproteinemia Tipo II/genética , Argentina/epidemiologia , Biomarcadores/sangue , Bases de Dados Factuais , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco
15.
Atherosclerosis ; 277: 234-255, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30270054

RESUMO

BACKGROUND AND AIMS: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. METHODS: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. RESULTS: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. CONCLUSIONS: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.


Assuntos
Anticolesterolemiantes/uso terapêutico , Remoção de Componentes Sanguíneos , Saúde Global , Hiperlipoproteinemia Tipo II/terapia , Cooperação Internacional , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Remoção de Componentes Sanguíneos/efeitos adversos , LDL-Colesterol/sangue , Comportamento Cooperativo , Predisposição Genética para Doença , Pesquisas sobre Atenção à Saúde , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Prevalência , Fatores de Risco , Resultado do Tratamento
16.
J Clin Lipidol ; 11(2): 524-531, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28502510

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. OBJECTIVE: The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. METHODS: Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. RESULTS: Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics' analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. CONCLUSION: This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina.


Assuntos
Variação Genética , Hiperlipoproteinemia Tipo II/genética , Adolescente , Adulto , Idoso , Argentina , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Conformação Proteica , Receptores de LDL/química , Receptores de LDL/genética , Receptores de LDL/metabolismo , Adulto Jovem
17.
J Clin Lipidol ; 11(1): 160-166, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28391882

RESUMO

BACKGROUND: There is little information about familial hypercholesterolemia (FH) epidemiology and care in Ibero-American countries. The Ibero-American FH network aims at reducing the gap on diagnosis and treatment of this disease in the region. OBJECTIVE: To describe clinical, molecular, and organizational characteristics of FH diagnosis in Argentina, Brazil, Chile, Colombia, Mexico, Portugal, Spain, and Uruguay. METHODS: Descriptive analysis of country data related to FH cascade screening, molecular diagnosis, clinical practice guidelines, and patient organization presence in Ibero-America. RESULTS: From a conservative estimation of an FH prevalence of 1 of 500 individuals, there should be 1.2 million heterozygous FH individuals in Ibero-America and roughly 27,400 were diagnosed so far. Only Spain, Brazil, Portugal, and Uruguay have active cascade screening programs. The prevalence of cardiovascular disease ranged from 10% to 42% in member countries, and the highest molecular identification rates are seen in Spain, 8.3%, followed by Portugal, 3.8%, and Uruguay with 2.5%. In the 3 countries with more FH patients identified (Spain, Portugal, and Brazil) between 10 and 15 mutations are responsible for 30% to 47% of all FH cases. Spain and Portugal share 5 of the 10 most common mutations (4 in low density lipoprotein receptor [LDLR] and the APOB3527). Spain and Spanish-speaking Latin American countries share 6 of the most common LDLR mutations and the APOB3527. LDL apheresis is available only in Spain and Portugal and not all countries have specific FH diagnostic and treatment guidelines as well as patient organizations. CONCLUSIONS: Ibero-American countries share similar mutations and gaps in FH care.


Assuntos
Hiperlipoproteinemia Tipo II/epidemiologia , Doenças Cardiovasculares/complicações , Humanos , Hiperlipoproteinemia Tipo II/complicações , Portugal/epidemiologia , América do Sul/epidemiologia , Espanha/epidemiologia
18.
Atheroscler Suppl ; 22: 1-32, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27939304

RESUMO

BACKGROUND: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. METHODS: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients.


Assuntos
Prestação Integrada de Cuidados de Saúde , Hiperlipoproteinemia Tipo II/terapia , Cooperação Internacional , Lacunas da Prática Profissional , Sistema de Registros , Projetos de Pesquisa , Acesso à Informação , Comportamento Cooperativo , Mineração de Dados , Prestação Integrada de Cuidados de Saúde/organização & administração , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/mortalidade , Armazenamento e Recuperação da Informação , Objetivos Organizacionais , Resultado do Tratamento
20.
Opt Lett ; 39(12): 3634-7, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24978555

RESUMO

A method for retrieving low-coherence interferograms, based on the use of a microwave photonics filter, is proposed and demonstrated. The method is equivalent to the double-interferometer technique, with the scanning interferometer replaced by an analog fiber-optics link and the visibility recorded as the amplitude of its radio-frequency (RF) response. As a low-coherence interferometry system, it shows a decrease of resolution induced by the fiber's third-order dispersion (ß3). As a displacement sensor, it provides highly linear and slope-scalable readouts of the interferometer's optical path difference in terms of RF, even in the presence of third-order dispersion. In a proof-of-concept experiment, we demonstrate 20-µm displacement readouts using C-band EDFA sources and standard single-mode fiber.


Assuntos
Interferometria/métodos , Interferometria/instrumentação , Interferometria/estatística & dados numéricos , Micro-Ondas , Modelos Teóricos , Fibras Ópticas , Fenômenos Ópticos , Ondas de Rádio
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