Asunto(s)

Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Prevención Secundaria , Factores de Riesgo , Medición de Riesgo , Factores de Riesgo de Enfermedad Cardiaca

RESUMEN

OBJECTIVE: To investigate the association between non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), mental symptoms (mood, anxiety disorders and distress) by sex. METHODS: This a cross-sectional study performed in working-age adults from a Health Promotion Center (primary care) in São Paulo, Brazil. Self-reported mental symptoms from rating scales (21-item Beck Anxiety Inventory, Patient Health Questionnaire-9, and K6 distress scale) were evaluated by hepatic steatosis (NAFLD and ALD). Logistic regression models estimated the association between hepatic steatosis subtypes and mental symptoms by Odds ratios (OR) adjusted by confounders in the total sample and sex stratified. RESULTS: Among 7241 participants (70.5% men, median age: 45 years), the frequency of steatosis was of 30.7% (25.1% NAFLD), being higher in men than women (70.5% vs. 29.5%, p < 0.0001), regardless of the steatosis subtype. Metabolic risk factors were similar in both subtypes of steatosis, but not mental symptoms. Overall, NAFLD was inversely associated with anxiety (OR = 0.75, 95%CI 0.63-0.90) and positively associated with depression (OR = 1.17, 95%CI 1.00-1.38). On the other hand, ALD was positively associated with anxiety (OR = 1.51; 95%CI 1.15-2.00). In sex-stratified analyses, only men presented an association of anxiety symptoms with NAFLD (OR = 0.73; 95%CI 0.60-0.89) and ALD (OR = 1.60; 95%CI 1.18-2.16). CONCLUSIONS: The complex association between different types of steatosis (NAFLD and ALD), mood and anxiety disorders indicates the need for a deeper understanding of their common causal pathways.

Asunto(s)

Enfermedad del Hígado Graso no Alcohólico , Adulto , Humanos , Femenino , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/complicaciones , Estudios Transversales , Caracteres Sexuales , Brasil/epidemiología

RESUMEN

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT. METHODS: Hypercholesterolemic individuals ≥60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 × 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75). RESULTS: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497-6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants. CONCLUSIONS: In old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not.

Asunto(s)

Aterosclerosis , Enfermedades Cardiovasculares , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Masculino , Humanos , Adolescente , Anciano , Femenino , Enfermedades Cardiovasculares/epidemiología , Hipercolesterolemia/complicaciones , Hiperlipoproteinemia Tipo II/genética , LDL-Colesterol , Aterosclerosis/genética , Factores de Riesgo

RESUMEN

OBJECTIVE: Neck circumference (NC) is a straightforward method for quantifying upper body adiposity without the limitations that other indices can have. Thus, this study aimed to analyze the relationship between NC, overall (body mass index [BMI]) and central obesity (waist circumference [WC]), and percentage of body fat (BF%) in men and women. METHODS: The associations with NC quartiles (first quartile: reference group), BMI ≥30 kg/m2, WC (>102 cm for men and >88 cm for women), and high BF% (≥21 for men and ≥29 for women) were compared and analyzed by logistic regression models adjusted for demographic characteristics, cardiovascular risk factors, and lean mass. RESULTS: In 4283 adults (mean age: 44 y, 71.8% of men), the mean NC was higher in men (40.5 cm, range: 32-55 cm) than women (34.5 cm, range: 28.5-46 cm). Among men, the fourth quartile of NC (42.5-55 cm) was positively associated with obesity (multivariable odds ratio [OR]: 2.28, 95% confidence interval [CI]: 1.1-4.48). Among women, the fourth quartile of NC (36.5-46 cm) was associated with increased WC (multivariable OR: 2.98; 95% CI: 1.59-5.60). Progressive increases in the ORs were noticed across the associations between NC quartiles (second to fourth) and high BF% in men and women. The highest ORs were observed for the associations between high BF% and the fourth quartiles of NC in men (multivariable OR: 2.42; 95% CI: 1.49-3.93) and in women (multivariable OR: 29.19; 95% CI: 14.01-60.84). CONCLUSIONS: The utility of NC as a measurement of obesity in clinical practice was demonstrated in this large sample of young to middle-aged adults. The highest NC values were positively associated with overall obesity in men and central obesity in women. Moreover, NC was closely associated with high BF% in both sexes, particularly in women.

Asunto(s)

Adiposidad , Obesidad , Adulto , Índice de Masa Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/epidemiología , Factores de Riesgo , Circunferencia de la Cintura

RESUMEN

PURPOSE OF REVIEW: To discuss advances on the RNA-targeted therapies to treat dyslipidemia with the aim of reducing atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: Genetic studies have paved the way for therapies that reduce translation of proteins that play causal roles in dyslipidemia and atherosclerosis like proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B-100 (apoB), apolipoprotein(a) [apo(a)], apolipoprotein C3 (apoC3), and angiopoietin-like 3 (ANGPTL3). Either antisense oligonucleotide (ASO) therapies and small interfering RNA (siRNA) molecules inhibit protein synthesis and consequently improve dyslipidemia. Most of these molecules contain N-acetylgalactosamine (GalNAc) moieties that have high specificity for hepatocytes and therefore reduce concentration in other tissues. Inclisiran, an siRNA for PCSK9, has shown robust LDL-C reductions, with good tolerability, in severe forms of hypercholesterolemia as well as in high cardiovascular disease patients with injections every 3 to 6 months. Pelacarsen is an ASO against apolipoprotein(a) that reduces Lp(a) up to 80% with good tolerability. Either inclisiran or pelacarsen is being tested to show it can prevent ASCVD. AMG 890, an siRNA compound aimed at reducing apo(a) synthesis, is also under investigation. Volanesorsen is an ASO against apoC3 that reduces triglyceride levels up to 70% and is being tested in severe hypertriglyceridemic patients. Vupanorsen is an ASO against ANGPTL3 that reduced triglyceride levels 36-53% among moderate hypertriglyceridemic individuals. Interestingly, it also reduces ApoC3 and non-HDL cholesterol and apoB; however, it lowers HDL cholesterol. RNA-targeted therapies are being extensively tested for dyslipidemia treatment with promising results.

Asunto(s)

Aterosclerosis , Dislipidemias , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , LDL-Colesterol , Dislipidemias/tratamiento farmacológico , Dislipidemias/genética , Humanos , Proproteína Convertasa 9/genética

RESUMEN

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is characterized by high LDL-cholesterol (LDL-C) and early atherosclerotic cardiovascular disease (ASCVD). With a lipid lowering therapy (LLT), most individuals with FH may have a longer ASCVD-free survival. However, there is scant data about older individuals with FH. METHODS: We compared characteristics of genetically defined FH older individuals with age-matched non-FH counterparts. RESULTS: From 4111 genotyped individuals, 462 older than 60 years were included (198 positive and 264 negative for FH variants). There were no differences regarding median age [%25; 75%] 66.0 (62.0; 71.0) and 66.0 (62.2; 71.0) years, p = 0.68 for FH and non-FH, respectively. In both groups, there was a higher frequency of females, however, there were more males in the FH group 37.4% vs. 24.2%, p = 0.002. No differences were seen between FH and non-FH in LLT use: 88.5% vs. 91.5%, p = 0.29. Despite a longer LLT duration in FH patients (with 11.0 (7.0; 20.0) vs. 7.0 (3.0; 13.0) years, p < 0.001), treatment was started late in both groups: at 54.0 (47.0; 61.0) and 59.0 (52.0; 64.0) years, p < 0.001, in FH and non-FH, respectively. FH had greater frequencies of previous and early ASCVD (40.9% vs. 27.3%, p = 0.002, and 22.2% vs. 9.0%, p < 0.001). In FH, male sex [HR (95%CI)] 2.67 (1.50-4.73), p = 0.001, and LLT onset age 0.96 (0.93-0.99), p = 0.009, were independently associated with ASCVD. CONCLUSIONS: Among hypercholesterolemic older individuals participating in a cascade screening program, the genetic diagnosis of FH was associated with higher ASCVD rates, emphasizing the relevance of a monogenic defect as the cause of long-lasting hypercholesterolemia and ASCVD risk, particularly in men.

Asunto(s)

Enfermedades Cardiovasculares , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Anciano , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , LDL-Colesterol , Femenino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Lactante , Masculino , Factores de Riesgo

RESUMEN

AIMS: The objective of this study was to evaluate if vascular age derived from coronary artery calcium (CAC) score improves atherosclerosis cardiovascular disease (ASCVD) risk discrimination in primary prevention asymptomatic heterozygous familial hypercholesterolaemia (FH) patients undergoing standard lipid-lowering therapy. METHODS AND RESULTS: Two hundred and six molecularly confirmed FH individuals (age 45 ± 14 years, 36% males, baseline LDL-cholesterol 6.2 ± 2.2 mmol/L; 239 ± 85mg/dL) were followed by 4.4 ± 2.9 years (median: 3.7 years, interquartile ranges 2.7-6.8). CAC measurement was performed, and lipid-lowering therapy was optimized according to FH guidelines. Vascular age was derived from CAC and calculated according to the Multi Ethnic Study of Atherosclerosis algorithm. Risk estimation based on the Framingham equations was calculated for both biological (bFRS) and vascular (vaFRS) age. During follow-up, 15 ASCVD events (7.2%) were documented. The annualized rate of events for bFRS <10%, 10-20%, and >20% was respectively: 8.45 [95% confidence interval (CI) 3.17-22.52], 23.28 (95% CI 9.69-55.94), and 28.13 (95% CI 12.63-62.61) per 1000 patients. The annualized rate of events for vaFRS <10%, 10-20%, and >20% was respectively: 0, 0, and 50.37 (95% CI 30.37-83.56) per 1000 patients. vaFRS presented a better discrimination for ASCVD events compared to bFRS 0.7058 (95% CI 0.5866-0.8250) vs. vaFRS 0.8820 (95% CI 0.8286-0.9355), P = 0.0005. CONCLUSION: CAC derived vascular age can improve ASCVD risk discrimination in primary prevention FH subjects. This tool may help further stratify risk in FH patients already receiving lipid-lowering medication who might be candidates for further treatment with newer therapies.

Asunto(s)

Enfermedad de la Arteria Coronaria , Hiperlipoproteinemia Tipo II , Calcificación Vascular , Adulto , Calcio , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Humanos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Riesgo , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/epidemiología

RESUMEN

Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (APOB) and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease. Individuals with FH are exposed to elevated LDL-C levels since birth and this explains the high cardiovascular, mainly coronary heart disease, burden of these subjects. However, recent studies show that this risk is heterogenous and depends not only on high LDL-C levels but also on presence of previous cardiovascular disease, a monogenic cause, male sex, smoking, hypertension, diabetes, low HDL-cholesterol, obesity and elevated lipoprotein(a). This heterogeneity in risk can be captured by risk equations like one from the SAFEHEART cohort and by detection of subclinical coronary atherosclerosis. High dose high potency statins are the main stain for LDL-C lowering in FH, however, in most situations these medications are not powered enough to reduce cholesterol to adequate levels. Ezetimibe and PCSK9 inhibitors should also be used in order to better treat LDL-C in FH patients.

Asunto(s)

Anticolesterolemiantes/uso terapéutico , Aterosclerosis/prevención & control , LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Anticolesterolemiantes/efectos adversos , Aterosclerosis/epidemiología , Aterosclerosis/genética , Biomarcadores/sangre , Ezetimiba/uso terapéutico , Predisposición Genética a la Enfermedad , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Inhibidores de PCSK9 , Fenotipo , Proproteína Convertasa 9/metabolismo , Medición de Riesgo , Factores de Riesgo , Inhibidores de Serina Proteinasa/uso terapéutico , Resultado del Tratamiento

RESUMEN

OBJECTIVES: The aim of this study was to evaluate the role of coronary artery calcium (CAC) as a predictor of atherosclerotic cardiovascular disease (ASCVD) (fatal or not myocardial infarction, stroke, unstable angina requiring revascularization, and elective myocardial revascularization) events in asymptomatic primary prevention molecularly proven heterozygous familial hypercholesterolemia (FH) subjects receiving standard lipid-lowering therapy. BACKGROUND: FH is associated with premature ASCVD. However, the clinical course of ASCVD in subjects with FH is heterogeneous. CAC score, a marker of subclinical atherosclerosis burden, may optimize ASCVD risk stratification in FH. METHODS: Subjects with FH underwent CAC measurement and were followed prospectively. The association of CAC with ASCVD was evaluated using multivariate analysis. RESULTS: A total of 206 subjects (mean age 45 ± 14 years, 36.4% men, baseline and on-treatment low-density lipoprotein cholesterol 269 ± 70 mg/dl and 150 ± 56 mg/dl, respectively) were followed for a median of 3.7 years (interquartile range: 2.7 to 6.8 years). CAC was present in 105 (51%), and 15 ASCVD events (7.2%) were documented. Almost one-half of events were hard outcomes, and the others were elective myocardial revascularizations. The annualized rates of events per 1,000 patients for CAC scores of 0 (n = 101 [49%]), 1 to 100 (n = 62 [30%]) and >100 (n = 43 [21%]) were, respectively, 0, 26.4 (95% confidence interval: 12.9 to 51.8), and 44.1 (95% confidence interval, 26.0 to 104.1). In multivariate Cox regression analysis, log(CAC score + 1) was independently associated with incident ASCVD events (hazard ratio: 3.33; 95% CI: 1.635 to 6.790; p = 0.001). CONCLUSIONS: CAC was independently associated with ASCVD events in patients with FH receiving standard lipid-lowering therapy. This may help further stratify near-term risk in patients who might be candidates for further treatment with newer therapies.

Asunto(s)

Anticolesterolemiantes/uso terapéutico , Colesterol/sangre , Enfermedad de la Arteria Coronaria/prevención & control , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Prevención Primaria , Calcificación Vascular/prevención & control , Adulto , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/mortalidad , Regulación hacia Abajo , Femenino , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/mortalidad , Incidencia , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Calcificación Vascular/sangre , Calcificación Vascular/mortalidad

RESUMEN

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder associated with high cardiovascular burden of disease. FH prevalence may vary widely across populations and data in race/ethnically diverse and admixed populations is scarce. ELSA-Brasil epidemiology may be widely generalizable in this regard, and we calculated the ELSA-Brasil FH prevalence and its variation according to age, sex and race/ethnicity. METHODS: In 14,460 individuals aged from 35 to 75 years from the ELSA-Brasil cohort baseline, we classified FH according to the Dutch Lipid Clinic Network criteria score ≥6 (probable and definite FH). LDL-C levels were adjusted for statin use. We calculated the overall ELSA-Brasil FH prevalence and the weighted prevalence for age, sex and race/ethnic categories. We extrapolated those frequencies to the Brazilian population weighting for age-sex-race/ethnicity according to the 2015 Statistics and Geography Brazilian Institute survey. RESULTS: The overall FH prevalence per 1000 individuals in ELSA-Brasil was 3.8 (2.9, 4.9) or 1 in 263. The age/sex/race-ethnicity-weighted FH prevalences were: male, 3.0 (1.7, 4.4) or 1 in 333; female, 4.1 (3.0, 5.2) or 1 in 244 (p<0.001). White race prevalence was 2.4 (1.9, 3.0) or 1 in 417; Brown, 4.9 (4.0, 5.9) or 1 in 204; and Black 6.4 (41.1, 8.7) or 1 in 156 (p<0.001). The weighted extrapolation for the Brazilian population derived similar magnitude frequencies. CONCLUSIONS: FH affects 1 in 263 in ELSA-Brasil and affects disproportionally more Brown (1 in 204), and Black (1 in 156), than White (1 in 417). Weighted extrapolation for the Brazilian population derived similar magnitude frequencies.

Asunto(s)

Población Negra , Hiperlipoproteinemia Tipo II/etnología , Población Blanca , Adulto , Factores de Edad , Anciano , Biomarcadores/sangre , Población Negra/genética , Brasil/epidemiología , LDL-Colesterol/sangre , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Población Blanca/genética

RESUMEN

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder associated with high risk of early major cardiovascular events (MACE) that can impact the health related quality of life (HRQoL), however, this association is unclear. This study evaluated HRQoL in index cases (IC) and first-degree relatives (FDR) of individuals at high risk of FH undergoing genetic cascade screening. METHODS: Data collection was performed before awareness of molecular diagnosis results. Individuals were divided into four groups according to the molecular diagnosis: IC with (IC+) and without (IC-) identified mutations (n = 93 and n = 175, respectively), and affected (FDR+, n = 231) and non-affected (FDR-, n = 159) FDR of IC+. HRQoL measurements, mental (MCS) and physical component (PCS) scores were carried out with SF-12 questionnaire. Associations were tested by generalized linear models. RESULTS: The mean age was 49 ±â€¯15 years, 42.2% were men, MACE had occurred in 30.7%. Overall, both PCS and MCS did not differ between FH and non-FH individuals, however, IC trended to have lower PCS independent of FH presence (p=0.003). Lower PCS were associated with female sex (p=0.018), lower education (p<0.001), professional inactivity (p=0.028), previous MACE occurrence (p<0.001), hypertension (p=0.016), depression (p<0.001) and obesity (p<0.001). Lower MCS were associated with female sex (p=0.009), previous MACE occurrence (p=0.034), depression (p<0.001) and smoking (p=0.009). Neither the presence of FH causing mutations nor pharmacological lipid lowering treatment was associated with HRQoL. CONCLUSIONS: HRQoL is not reduced in both IC and FDR FH individuals in comparison with their non-affected counterparts. Previous MACE and co-morbidities are associated with reduced HRQoL.

Asunto(s)

LDL-Colesterol/sangre , Pruebas Genéticas/métodos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Mutación , Calidad de Vida , Adulto , Anticolesterolemiantes/uso terapéutico , Biomarcadores/sangre , Brasil , Comorbilidad , Estudios Transversales , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Herencia , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Encuestas y Cuestionarios , Resultado del Tratamiento

RESUMEN

BACKGROUND AND AIMS: There is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. METHODS: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. RESULTS: Overall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704-0.784) and 0.730 (95% CI: 0.687-0.774), respectively, p=0.014. CONCLUSIONS: In our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.

Asunto(s)

LDL-Colesterol/sangre , Análisis Mutacional de ADN , Pruebas Genéticas/métodos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Mutación , Adulto , Anciano , Arco Senil/sangre , Arco Senil/genética , Área Bajo la Curva , Biomarcadores/sangre , Brasil , Distribución de Chi-Cuadrado , Toma de Decisiones Clínicas , Estudios de Factibilidad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Selección de Paciente , Fenotipo , Valor Predictivo de las Pruebas , Curva ROC , Reproducibilidad de los Resultados , Factores de Riesgo , Regulación hacia Arriba , Xantomatosis/sangre , Xantomatosis/genética

RESUMEN

BACKGROUND AND AIMS: Achilles tendon xanthomas (ATX) are a sign of long-term exposure to high blood cholesterol in familial hypercholesterolemia (FH) patients, which have been associated with cardiovascular disease. We evaluated the ATX association with the presence and extent of subclinical coronary atherosclerosis in heterozygous FH patients. METHODS: 102 FH patients diagnosed by US-MEDPED criteria (67% with genetically proven FH), with median LDL-C 279 mg/dL (interquartile range: 240; 313), asymptomatic for cardiovascular disease, underwent computed tomography angiography and coronary artery calcium (CAC) quantification. Subclinical coronary atherosclerosis was quantified by CAC, segment-stenosis (SSS) and segment-involvement (SIS) scores. Adjusted Poisson regression was used to assess the association of ATX with subclinical atherosclerosis burden as continuous variables. RESULTS: Patients with ATX (n = 21, 21%) had higher LDL-C and lipoprotein(a) [Lp(a)] concentrations as well as greater CAC scores, SIS and SSS (p < 0.05). After adjusting for age, sex, smoking, hypertension, previous statin use, HDL-C, LDL-C and Lp(a) concentrations, there was an independent positive association of ATX presence with CAC scores (ß = 1.017, p < 0.001), SSS (ß = 0.809, p < 0.001) and SIS (ß = 0.640, p < 0.001). CONCLUSIONS: ATX are independently associated with the extension of subclinical coronary atherosclerosis quantified by tomographic scores in FH patients.

Asunto(s)

Tendón Calcáneo , Apolipoproteína B-100/genética , Enfermedad de la Arteria Coronaria/etiología , Heterocigoto , Hiperlipoproteinemia Tipo II/genética , Mutación , Receptores de LDL/genética , Xantomatosis/etiología , Tendón Calcáneo/diagnóstico por imagen , Adulto , Enfermedades Asintomáticas , Biomarcadores/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Angiografía por Tomografía Computarizada , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/diagnóstico , Lipoproteína(a)/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Proyectos Piloto , Índice de Severidad de la Enfermedad , Xantomatosis/diagnóstico por imagen

RESUMEN

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common genetic disorder characterized by elevated blood cholesterol, increased prevalence of subclinical atherosclerosis and high risk of premature coronary heart disease. However, this risk is not explained solely by elevated LDL-cholesterol concentrations, and other factors may influence atherosclerosis development. There is evidence that increased adiposity may predispose to atherosclerosis in FH. Epicardial fat has been associated with subclinical coronary atherosclerosis in the general population. This study evaluated the association of epicardial fat (EFV) volume with the presence and extent of subclinical coronary atherosclerosis detected by computed tomography angiography in FH patients. METHODS: Ninety-seven FH subjects (35% male, mean age 45 ± 13 years, LDL-C 281 ± 56 mg/dL, 67% with proven molecular defects) underwent computed tomography angiography and coronary artery calcium (CAC) scoring. EFV was measured in non-contrast images using a semi-automated method. Segment-stenosis score (SSS) and segment-involvement score (SIS) were calculated. Multivariate Poisson regression was utilized to assess an independent association of EFV with coronary atherosclerotic burden. RESULTS: EFV was positively associated with age, body mass index, waist circumference, blood glucose, the presence of the metabolic syndrome components, but not with LDL-C. After adjusting for confounders and abdominal circumference, an independent association (shown as ß coefficients and 95% confidence intervals) of EVF with CAC scores [ß = 0.263 (0.234; 0.292), p=0.000], SIS [ß = 0.304 (0.141; 0.465) p=0.000] and SSS [ß = 0.296 (0.121; 0.471), p=0.001] was found. CONCLUSIONS: In FH, EFV was independently associated with coronary atherosclerotic presence and severity.

Asunto(s)

Adiposidad , Enfermedad de la Arteria Coronaria/complicaciones , Hiperlipoproteinemia Tipo II/complicaciones , Pericardio/patología , Tejido Adiposo/patología , Adulto , Aterosclerosis/sangre , Colesterol/sangre , LDL-Colesterol/sangre , Estudios de Cohortes , Femenino , Corazón/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Mutación , Encuestas y Cuestionarios , Tomografía Computarizada por Rayos X

RESUMEN

BACKGROUND: Familial hypercholesterolemia is characterized by elevated plasma cholesterol and early coronary arterial disease onset. However, few studies investigated the association of heterozygous familial hypercholesterolemia with peripheral arterial disease. METHODS: In a cross sectional study 202 heterozygous familial hypercholesterolemia patients (91% confirmed by molecular diagnosis) were compared to 524 normolipidemic controls. Peripheral arterial disease was diagnosed by ankle-brachial index values ≤0.90. RESULTS: Compared with controls, familial hypercholesterolemia patients were older, more often female, with higher rates of hypertension, diabetes, previous coronary disease and higher total cholesterol levels. Smoking (previous and former) was more common among controls. The prevalence of peripheral arterial disease was 17.3 and 2.3% respectively in familial hypercholesterolemia and controls (p < 0.001). Results persisted after matching familial hypercholesterolemia and controls by a propensity score. Regression analyses demonstrated that age (odds ratio- OR = 1.03 95% CI 1.00-1.05, p = 0.033), previous cardiovascular disease (OR = 3.12 CI 95% 1.56-6.25, p = 0.001) and familial hypercholesterolemia diagnosis (OR = 5.55 CI 95% 2.69-11.44, p< 0.001) were independently associated with peripheral arterial disease. Among familial hypercholesterolemia patients, age (OR 1.05, 95% CI 1.02-1.09, p = 0.005), intermittent claudication (OR 6.32, 95% CI 2.60-15.33, p< 0.001) and smoking (OR 2.44, 95% CI 1.08-5.52, p = 0.032) were associated with peripheral arterial disease. CONCLUSIONS: Peripheral arterial disease is more frequent in familial hypercholesterolemia than in normolipidemic subjects and it should routine screened in these individuals even if asymptomatic. However, its role as predictor of cardiovascular events needs to be ascertained prospectively.

Asunto(s)

Heterocigoto , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Enfermedad Arterial Periférica/epidemiología , Adulto , Factores de Edad , Índice Tobillo Braquial , Brasil/epidemiología , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Comorbilidad , Estudios Transversales , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/fisiopatología , Prevalencia , Puntaje de Propensión , Estudios Prospectivos , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Fumar/efectos adversos , Fumar/epidemiología

Asunto(s)

Enfermedad de la Arteria Coronaria/etnología , Inflamación/etnología , Síndrome Metabólico/etnología , Enfermedad del Hígado Graso no Alcohólico/etnología , Obesidad/etnología , Femenino , Humanos , Masculino

RESUMEN

BACKGROUND: There is little knowledge about familial hypercholesterolemia in Brazil. This study presents the first results of genetic cascade screening performed in the city of Sao Paulo. MATERIAL AND METHODS: Two-hundred and forty-eight suspected index cases were initially included. DNA was extracted from peripheral blood and the complete coding sequence of low-density lipoprotein receptor, exon 7 of proprotein convertase subtilisin/kexin type 9 gene and part of exon 26 of apolipoprotein B genes were sequenced. Multiplex Ligation-dependent Probe Amplification was performed on cases where a causal mutation was not identified through sequencing. After the identification of a causal mutation screening in first-degree relatives was pursued. RESULTS: From 248 index cases, a mutation was found in 125 individuals (50.4%). 394 relatives were included in the cascade screening program and a mutation was identified in 59.4%. Seventy different causal mutations in the low-density lipoprotein receptor gene (97.2%) and 2 in the apolipoprotein B gene (2.8%) were found. No mutations were encountered in the proprotein convertase subtilisin/kexin type 9 gene. Mutations in exons 14 and 4 were the most prevalent and, 10 cases of true homozygotes (8 index cases and 2 relatives) and 1 compound heterozygote were identified. The most frequent mutation found was of Lebanese origin, the p.(Cys681*) mutation in exon 14 (8.5%). CONCLUSION: Genetic familial hypercholesterolemia cascade screening is feasible in Brazil and leads to identification of a mutation in approximately half of the index cases with higher rates of success in their relatives.

Asunto(s)

Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Adulto , Anciano , Apolipoproteínas B/sangre , Apolipoproteínas B/genética , Índice de Masa Corporal , Brasil/epidemiología , Exones , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo II/epidemiología , Líbano , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Mutación , Valor Predictivo de las Pruebas , Proproteína Convertasa 9 , Proproteína Convertasas/genética , Serina Endopeptidasas/genética

RESUMEN

To evaluate functional and compositional properties of HDL in subjects from a kindred of genetic apoA-I deficiency, two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2, Q[-2]X, were recruited together with age- and sex-matched healthy controls (n = 11). Homozygotes displayed undetectable plasma levels of apoA-I and reduced levels of HDL-cholesterol (HDL-C) and apoC-III (5.4% and 42.6% of controls, respectively). Heterozygotes displayed low HDL-C (21 ± 9 mg/dl), low apoA-I (79 ± 24 mg/dl), normal LDL-cholesterol (132 ± 25 mg/dl), and elevated TG (130 ± 45 mg/dl) levels. Cholesterol efflux capacity of ultracentrifugally isolated HDL subpopulations was reduced (up to -25%, P < 0.01, on a glycerophospholipid [GP] basis) in heterozygotes versus controls. Small, dense HDL3 and total HDL from heterozygotes exhibited diminished antioxidative activity (up to -48%, P < 0.001 on a total mass basis) versus controls. HDL subpopulations from both homozygotes and heterozygotes displayed altered chemical composition, with depletion in apoA-I, GP, and cholesteryl ester; enrichment in apoA-II, free cholesterol, and TG; and altered phosphosphingolipidome. The defective atheroprotective activities of HDL were correlated with altered lipid and apo composition. These data reveal that atheroprotective activities of HDL particles are impaired in homozygous and heterozygous apoA-I deficiency and are intimately related to marked alterations in protein and lipid composition.

Asunto(s)

Apolipoproteína A-I/deficiencia , Apolipoproteína C-III/sangre , Proteínas de Transferencia de Ésteres de Colesterol/sangre , HDL-Colesterol/sangre , Hipoalfalipoproteinemias/sangre , Lipoproteínas HDL/sangre , Adulto , Apolipoproteína A-I/sangre , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Apolipoproteína C-III/metabolismo , Brasil , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Ésteres del Colesterol/sangre , Ésteres del Colesterol/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/sangre , LDL-Colesterol/metabolismo , Codón sin Sentido , Salud de la Familia , Femenino , Heterocigoto , Homocigoto , Humanos , Hipoalfalipoproteinemias/genética , Hipoalfalipoproteinemias/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL3/sangre , Lipoproteínas HDL3/metabolismo , Masculino , Fosfolípidos/sangre , Fosfolípidos/metabolismo , Esfingolípidos/sangre , Esfingolípidos/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismo

RESUMEN

BACKGROUND: Studies have demonstrated the association of severe anatomical coronary artery disease (CAD) with postprandial triglycerides (TG) concentrations. Nevertheless the relationship between less severe atherosclerosis plaque burden and postprandial TG is less established. OBJECTIVE: to study the relationship between postprandial TG and CAD detected by coronary computed tomographic angiography (CTA). MATERIAL AND METHODS: 130 patients who underwent an oral fat tolerance test were enrolled (85 with CAD detected by CTA and 45 without). Postprandial lipemia was studied by measuring TG from T0h to T6h with 2-h intervals, and analyzed the TG change over time using a longitudinal multivariable linear mixed effects model with the log normal of the TG as the primary outcome. RESULTS: The majority of individuals with CAD had non-obstructive disease (63.3%) Patients with CAD had a slower clearance of postprandial TG change from 4 h to 6 h (p<0.05) compared to patients without CAD. These results remained significant after adjustment for fasting TG and glucose, age, gender, body mass index, and waist circumference. However, those differences did not reach statistical significance after adjustment for fasting HDL-C. CONCLUSION: Patients with mild (<25% lumen obstruction) and moderate CAD (25-50% lumen obstruction) detected by coronary CTA had an impaired postprandial metabolism, with a delayed TG clearance, when compared to individuals with no CAD. This difference was partially explained by the lower HDL-C. Thus, though postprandial TG may contribute to the development of CAD, this association is partially related to low HDL-C.

Asunto(s)

Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Grasas de la Dieta , Periodo Posprandial/fisiología , Triglicéridos/sangre , Adulto , Anciano , Antropometría , Glucemia/análisis , Calcinosis/sangre , Calcinosis/diagnóstico por imagen , HDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/sangre , Estenosis Coronaria/diagnóstico por imagen , Grasas de la Dieta/farmacocinética , Ayuno/sangre , Femenino , Humanos , Hipertensión/sangre , Masculino , Síndrome Metabólico/sangre , Persona de Mediana Edad , Placa Aterosclerótica/sangre , Placa Aterosclerótica/diagnóstico por imagen , Fumar/sangre , Tomografía Computarizada por Rayos X

RESUMEN

OBJECTIVE: In familial hypercholesterolemia (FH), the metabolism and anti-atherogenic functions of HDL can be affected by the continuous interactions with excess LDL amounts. Here, lipid transfers to HDL, an important step for HDL intravascular metabolism and for HDL role in reverse cholesterol transport (RCT) were investigated in FH patients. METHODS: Seventy-one FH patients (39 ± 15 years, LDL-cholesterol=274 ± 101; HDL-cholesterol=50 ± 14 mg/dl) and 66 normolipidemic subjects (NL) (38 ± 11 years, LDL-cholesterol=105 ± 27; HDL-cholesterol=52 ± 12 mg/dl) were studied. In vitro, lipid transfers were evaluated by incubation of plasma samples (37°C, 1h) with a donor lipid nanoemulsion labeled with 3H-triglycerides (TG) and 14C-unesterified cholesterol (UC) or with 3H-cholesteryl ester (EC) and 14C-phospholipids (PL). Radioactivity was counted at the HDL fraction after chemical precipitation of apolipoprotein (apo) B-containing lipoproteins and the nanoemulsion. Data are % of total radioactivity measured in the HDL fraction. RESULTS: Transfer of UC to HDL was lower in FH than in NL (5.6 ± 2.1 vs 6.7 ± 2.0%, p=0.0005) whereas TG (5.5 ± 3.1 vs 3.7 ± 0.9%, p=0.018) and PL (20.9 ± 4.6 vs 18.2 ± 3.7 %, p=0.023) transfers were higher in FH. EC transfer was equal. By multivariate analysis, transfers of all four lipids correlated with HDL-cholesterol and with apo A-I. CONCLUSION: FH elicited marked changes in three of the four tested lipid transfers to HDL. The entry of UC into HDL for subsequent esterification is an important driving force for RCT and reduction of UC transfer to HDL was previously associated to precocious coronary heart disease. Therefore, in FH, HDL functions can be lessened, which can also contribute to atherogenesis.

Asunto(s)

Hiperlipoproteinemia Tipo II/metabolismo , Metabolismo de los Lípidos/genética , Lipoproteínas HDL/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas B/metabolismo , Colesterol/sangre , Colesterol/metabolismo , Ésteres del Colesterol/metabolismo , Femenino , Humanos , Hiperlipoproteinemia Tipo II/genética , Lipoproteínas HDL/genética , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Masculino , Persona de Mediana Edad , Fosfolípidos/metabolismo , Triglicéridos/metabolismo , Adulto Joven