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1.
Scand J Clin Lab Invest ; 84(1): 24-29, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38319290

RESUMO

Legumain is known to be regulated in atherosclerotic disease and may have both pro- and anti-atherogenic properties. The study aimed to explore legumain in individuals with familial hypercholesterolemia (FH), a population with increased cardiovascular risk. Plasma legumain was measured in 251 subjects with mostly genetically verified FH, of which 166 were adults (≥18 years) and 85 were children and young adults (<18 years) and compared to 96 normolipidemic healthy controls. Plasma legumain was significantly increased in the total FH population compared to controls (median 4.9 versus 3.3 pg/mL, respectively, p < 0.001), whereof adult subjects with FH using statins had higher levels compared to non-statin users (5.7 versus 3.9 pg/mL, respectively, p < 0.001). Children and young adults with FH (p = 0.67) did not have plasma legumain different from controls at the same age. Further, in FH subjects, legumain showed a positive association with apoB, and markers of inflammation and platelet activation (i.e. fibrinogen, NAP2 and RANTES). In the current study, we show that legumain is increased in adult subjects with FH using statins, whereas there was no difference in legumain among children and young adults with FH compared to controls. Legumain was further associated with cardiovascular risk markers in the FH population. However the role of legumain in regulation of cardiovascular risk in these individuals is still to be determined.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Cisteína Endopeptidases , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Criança , Adulto Jovem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fatores de Risco , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Fatores de Risco de Doenças Cardíacas
2.
BMC Med ; 21(1): 43, 2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36747215

RESUMO

BACKGROUND: Numerous intrauterine factors may affect the offspring's growth during childhood. We aimed to explore if maternal and paternal prenatal lipid, apolipoprotein (apo)B and apoA1 levels are associated with offspring weight, length, and body mass index from 6 weeks to eight years of age. This has previously been studied to a limited extent. METHODS: This parental negative control study is based on the Norwegian Mother, Father and Child Cohort Study and uses data from the Medical Birth Registry of Norway. We included 713 mothers and fathers with or without self-reported hypercholesterolemia and their offspring. Seven parental metabolites were measured by nuclear magnetic resonance spectroscopy, and offspring weight and length were measured at 12 time points. Data were analyzed by linear spline mixed models, and the results are presented as the interaction between parental metabolite levels and offspring spline (age). RESULTS: Higher maternal total cholesterol (TC) level was associated with a larger increase in offspring body weight up to 8 years of age (0.03 ≤ Pinteraction ≤ 0.04). Paternal TC level was not associated with change in offspring body weight (0.17 ≤ Pinteraction ≤ 0.25). Higher maternal high-density lipoprotein cholesterol (HDL-C) and apoA1 levels were associated with a lower increase in offspring body weight up to 8 years of age (0.001 ≤ Pinteraction ≤ 0.005). Higher paternal HDL-C and apoA1 levels were associated with a lower increase in offspring body weight up to 5 years of age but a larger increase in offspring body weight from 5 to 8 years of age (0.01 ≤ Pinteraction ≤ 0.03). Parental metabolites were not associated with change in offspring height or body mass index up to 8 years of age (0.07 ≤ Pinteraction ≤ 0.99). CONCLUSIONS: Maternal compared to paternal TC, HDL-C, and apoA1 levels were more strongly and consistently associated with offspring body weight during childhood, supporting a direct intrauterine effect.


Assuntos
Trajetória do Peso do Corpo , Mães , Masculino , Feminino , Gravidez , Humanos , Criança , Pré-Escolar , Estudos de Coortes , Pai , Índice de Massa Corporal , HDL-Colesterol
3.
Europace ; 25(2): 634-642, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36352512

RESUMO

AIMS: Cardiac disease progression prior to first ventricular arrhythmia (VA) in LMNA genotype-positive patients is not described. METHODS AND RESULTS: We performed a primary prevention cohort study, including consecutive LMNA genotype-positive patients from our centre. Patients underwent repeated clinical, electrocardiographic, and echocardiographic examinations. Electrocardiographic and echocardiographic disease progression as a predictor of first-time VA was evaluated by generalized estimation equation analyses. Threshold values at transition to an arrhythmic phenotype were assessed by threshold regression analyses. We included 94 LMNA genotype-positive patients without previous VA (age 38 ± 15 years, 32% probands, 53% females). Nineteen (20%) patients experienced VA during 4.6 (interquartile range 2.1-7.3) years follow up, at mean age 50 ± 11 years. We analysed 536 echocardiographic and 261 electrocardiogram examinations. Individual patient disease progression was associated with VA [left ventricular ejection fraction (LVEF) odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2-1.6 per 5% reduction, left ventricular end-diastolic volume index (LVEDVi) OR 1.2 (95% CI 1.1-1.3) per 5 mL/m2 increase, PR interval OR 1.2 (95% CI 1.1-1.4) per 10 ms increase]. Threshold values for transition to an arrhythmic phenotype were LVEF 44%, LVEDVi 77 mL/m2, and PR interval 280 ms. CONCLUSIONS: Incidence of first-time VA was 20% during 4.6 years follow up in LMNA genotype-positive patients. Individual patient disease progression by ECG and echocardiography were strong predictors of VA, indicating that disease progression rate may have additional value to absolute measurements when considering primary preventive ICD. Threshold values of LVEF <44%, LVEDVi >77 mL/m2, and PR interval >280 ms indicated transition to a more arrhythmogenic phenotype.


Assuntos
Desfibriladores Implantáveis , Laminopatias , Feminino , Masculino , Humanos , Volume Sistólico , Estudos de Coortes , Função Ventricular Esquerda , Fatores de Risco , Desfibriladores Implantáveis/efeitos adversos , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Laminopatias/complicações , Prevenção Primária , Progressão da Doença
4.
Nutr Metab Cardiovasc Dis ; 32(7): 1651-1660, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35527125

RESUMO

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary heart disease (CHD). Cholesterol-lowering therapy (statins) reduces CHD risk, but have been available only in the last 25 years, thus, elderly FH patients have been exposed to elevated LDL-C levels most of their life. Surprisingly, some of these have never experienced any CHD event, raising the question whether they present CHD resistant characteristics. Identifying possible cardioprotective biomarkers could contribute to future CHD preventive treatment, therefore, we aimed to identify metabolic markers in event-free elderly FH subjects. METHODS AND RESULTS: We used a high-throughput nuclear magnetic resonance (NMR) spectroscopy platform to quantify a large number of metabolites in serum samples from 83 FH patients ≥65 years, and analyze differences between subjects with (n = 39) and without (n = 44) CHD. Mean age was 70 years in both groups (57% and 38% female in the event-free group and CHD group, respectively). The event-free group had significantly higher levels of large and extra-large high-density lipoprotein (HDL) particles, and higher concentration of Apolipoprotein A1 (ApoA1) and cholesterol in HDL and HDL2 particles, compared to the CHD group (p ≤ 0.05 for all). CONCLUSION: CHD resistant elderly FH patients have higher levels of large HDL particles. The mechanisms behind the event-free survival among these patients remain unclear; hence, a deeper understanding of the metabolic profile in event-free elderly FH subjects may lead to development of novel preventive therapies.


Assuntos
Doença das Coronárias , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Idoso , Colesterol/metabolismo , LDL-Colesterol , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Feminino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Masculino
5.
Lipids Health Dis ; 21(1): 145, 2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36577984

RESUMO

BACKGROUND: Limited evidence suggests that surgical and non-surgical obesity treatment differentially influence plasma Lipoprotein (a) [Lp(a)] levels. Further, a novel association between plasma arachidonic acid and Lp(a) has recently been shown, suggesting that fatty acids are a possible target to influence Lp(a). Here, the effects of bariatric surgery and lifestyle interventions on plasma levels of Lp(a) were compared, and it was examined whether the effects were mediated by changes in plasma fatty acid (FA) levels. METHODS: The study includes two independent trials of patients with overweight or obesity. Trial 1: Two-armed intervention study including 82 patients who underwent a 7-week low energy diet (LED), followed by Roux-en-Y gastric bypass and 52-week follow-up (surgery-group), and 77 patients who underwent a 59-week energy restricted diet- and exercise-program (lifestyle-group). Trial 2: A clinical study including 134 patients who underwent a 20-week very-LED/LED (lifestyle-cohort). RESULTS: In the surgery-group, Lp(a) levels [median (interquartile range)] tended to increase in the pre-surgical LED-phase [17(7-68)-21(7-81)nmol/L, P = 0.05], but decreased by 48% after surgery [21(7-81)-11(7-56)nmol/L, P < 0.001]. In the lifestyle-group and lifestyle-cohort, Lp(a) increased by 36%[14(7-77)-19(7-94)nmol/L, P < 0.001] and 14%[50(14-160)-57(19-208)nmol/L, P < 0.001], respectively. Changes in Lp(a) were independent of weight loss. Plasma levels of total saturated FAs remained unchanged after surgery, but decreased after lifestyle interventions. Arachidonic acid and total n-3 FAs decreased after surgery, but increased after lifestyle interventions. Plasma FAs did not mediate the effects on Lp(a). CONCLUSION: Bariatric surgery reduced, whereas lifestyle interventions increased plasma Lp(a), independent of weight loss. The interventions differentially influenced changes in plasma FAs, but these changes did not mediate changes in Lp(a). TRIAL REGISTRATION: Trial 1: Clinicaltrials.gov NCT00626964. Trial 2: Netherlands Trial Register NL2140 (NTR2264).


Assuntos
Cirurgia Bariátrica , Obesidade Mórbida , Humanos , Ácido Araquidônico , Ácidos Graxos , Estilo de Vida , Lipoproteína(a) , Obesidade/cirurgia , Obesidade Mórbida/cirurgia , Resultado do Tratamento , Redução de Peso
6.
BMC Med ; 19(1): 91, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33849542

RESUMO

BACKGROUND: More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring's cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. METHODS: This study is based on 710 mother-father-newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing. RESULTS: Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids. CONCLUSIONS: Maternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring's long-term cardiovascular disease risk.


Assuntos
Pai , Mães , Criança , Estudos de Coortes , Feminino , Sangue Fetal , Humanos , Recém-Nascido , Masculino , Metaboloma , Noruega/epidemiologia , Gravidez
7.
J Intern Med ; 290(5): 1083-1097, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34506681

RESUMO

BACKGROUND: The functional status of lipoprotein particles contributes to atherogenesis. The tendency of plasma low-density lipoprotein (LDL) particles to aggregate and the ability of igh-density lipoprotein (HDL) particles to induce and mediate reverse cholesterol transport associate with high and low risk for cardiovascular disease in adult patients, respectively. However, it is unknown whether children with familial hypercholesterolemia (FH) display lipoprotein function alterations. HYPOTHESIS: We hypothesized that FH children had disrupted lipoprotein functions. METHODS: We analyzed LDL aggregation susceptibility and HDL-apoA-I exchange (HAE), and activity of four proteins that regulate lipoprotein metabolism (cholesteryl ester transfer protein, lecithin-cholesterol acyltransferase, phospholipid transfer protein, and paraoxonase-1) in plasma samples derived from children with FH (n = 47) and from normocholesterolemic children (n = 56). Variation in lipoprotein functions was further explored using an nuclear magnetic resonance-based metabolomics profiling approach. RESULTS: LDL aggregation was higher, and HAE was lower in FH children than in normocholesterolemic children. LDL aggregation associated positively with LDL cholesterol (LDL-C) and negatively with triglycerides, and HAE/apoA-I associated negatively with LDL-C. Generally, the metabolomic profile for LDL aggregation was opposite of that of HAE/apoA-I. CONCLUSIONS: FH children displayed increased atherogenicity of LDL and disrupted HDL function. These newly observed functional alterations in LDL and HDL add further understanding of the risk for atherosclerotic cardiovascular disease in FH children.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Apolipoproteína A-I , Criança , HDL-Colesterol , LDL-Colesterol , Estudos Transversais , Humanos
8.
Europace ; 23(7): 1084-1091, 2021 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-33829244

RESUMO

AIMS: We aimed to assess sex-specific phenotypes and disease progression, and their relation to exercise, in arrhythmogenic cardiomyopathy (AC) patients. METHODS AND RESULTS: In this longitudinal cohort study, we included consecutive patients with AC from a referral centre. We performed echocardiography at baseline and repeatedly during follow-up. Patients' exercise dose at inclusion was expressed as metabolic equivalents of task (MET)-h/week. Ventricular arrhythmia (VA) was defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate therapy by implantable cardioverter-defibrillator. We included 190 AC patients (45% female, 51% probands, age 41 ± 17 years). Ventricular arrhythmia had occurred at inclusion or occurred during follow-up in 85 patients (33% of females vs. 55% of males, P = 0.002). Exercise doses were higher in males compared with females [25 (interquartile range, IQR 14-51) vs. 12 (IQR 7-22) MET-h/week, P < 0.001]. Male sex was a marker of proband status [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-5.0, P = 0.003] and a marker of VA (OR 2.6, 95% CI 1.4-5.0, P = 0.003), but not when adjusted for exercise dose and age (adjusted OR 1.8, 95% CI 0.9-3.6, P = 0.12 and 1.5, 95% CI 0.7-3.1, P = 0.30, by 5 MET-h/week increments). In all, 167 (88%) patients had ≥2 echocardiographic examinations during 6.9 (IQR 4.7-9.8) years of follow-up. We observed no sex differences in deterioration of right or left ventricular dimensions and functions. CONCLUSION: Male AC patients were more often probands and had higher prevalence of VA than female patients, but not when adjusting for exercise dose. Importantly, disease progression was similar between male and female patients.


Assuntos
Displasia Arritmogênica Ventricular Direita , Desfibriladores Implantáveis , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/terapia , Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Displasia Arritmogênica Ventricular Direita/epidemiologia , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Caracteres Sexuais , Adulto Jovem
9.
Acta Paediatr ; 109(1): 115-121, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299108

RESUMO

AIM: Elevated total cholesterol (TC) and glycated haemoglobin (HbA1c) are risk factors for cardiovascular disease; however, little is known about their determinants in infants. We aimed to describe TC and HbA1c concentrations in infants aged 8-14 months and explore the relation between infant TC, HbA1c, breastfeeding, infant diet, and maternal TC and HbA1c. METHODS: In this cross-sectional pilot study, mothers of infants aged 6 and 12 months were invited to complete a food frequency questionnaire and to take home-based dried blood spot samples from themselves and their infants. RESULTS: Among the 143 included infants, the mean (SD, range) concentration was 4.1 (0.8, 2.3-6.6) mmol/L for TC and 4.9 (0.4, 3.7-6.0)% for HbA1c. There was no significant difference between age groups and sexes. There was a positive relation between TC concentrations of all infants and mothers (B = 0.30 unadjusted, B = 0.32 adjusted, P < .001 for both) and a negative relation between infant TC and intake of unsaturated fatty acids in the oldest age group (B = -0.09, P = .03 unadjusted, B = -0.08, P = .06 adjusted). Infant HbA1c was not significantly related to diet or maternal HbA1c. CONCLUSION: TC and HbA1c concentrations varied widely among infants aged 8-14 months. Infant TC was associated with macronutrient intake and maternal TC.


Assuntos
Aleitamento Materno , Colesterol/sangue , Dieta , Hemoglobinas Glicadas/metabolismo , Adulto , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Lactente , Masculino , Projetos Piloto , Valores de Referência
10.
Br J Nutr ; 122(7): 790-799, 2019 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-31262370

RESUMO

Elevated lipoprotein(a) (Lp(a)) is associated with CVD and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FA) in the regulation of Lp(a); however, no studies have investigated the association between plasma Lp(a) concentration and n-6 FA. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary n-6 FA intake and plasma levels of arachidonic acid (AA) in subjects with familial hypercholesterolaemia (FH). We included FH subjects with (n 68) and without (n 77) elevated Lp(a) defined as ≥75 nmol/l and healthy subjects (n 14). Total FA profile was analysed by GC-flame ionisation detector analysis, and the daily intake of macronutrients (including the sum of n-6 FA: 18 : 2n-6, 20 : 2n-6, 20 : 3n-6 and 20 : 4n-6) were computed from completed FFQ. FH subjects with elevated Lp(a) had higher plasma levels of AA compared with FH subjects without elevated Lp(a) (P = 0·03). Furthermore, both FH subjects with and without elevated Lp(a) had higher plasma levels of AA compared with controls (P < 0·001). The multivariable analyses showed associations between dietary n-6 FA intake and plasma levels of AA (P = 0·02) and between plasma levels of Lp(a) and AA (P = 0·006). Our data suggest a novel link between plasma Lp(a) concentration, dietary n-6 FA and plasma AA concentration, which may explain the small diet-induced increase in Lp(a) levels associated with lifestyle changes. Although the increase may not be clinically relevant, this association may be mechanistically interesting in understanding more of the role and regulation of Lp(a).


Assuntos
Ácido Araquidônico/sangue , Hiperlipoproteinemia Tipo II/sangue , Lipoproteína(a)/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Br J Nutr ; 119(10): 1142-1150, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29759104

RESUMO

Postprandial hypertriacylglycerolaemia is associated with an increased risk of developing CVD. How fat quality influences postprandial lipid response is scarcely explored in subjects with familial hypercholesterolaemia (FH). The aim of this study was to investigate the postprandial response of TAG and lipid sub-classes after consumption of high-fat meals with different fat quality in subjects with FH compared with normolipidaemic controls. A randomised controlled double-blind cross-over study with two meals and two groups was performed. A total of thirteen hypercholesterolaemic subjects with FH who discontinued lipid-lowering treatment 4 weeks before and during the study, and fourteen normolipidaemic controls, were included. Subjects were aged 18-30 years and had a BMI of 18·5-30·0 kg/m2. Each meal consisted of a muffin containing 60 g (70 E%) of fat, either mainly SFA (40 E%) or PUFA (40 E%), eaten in a random order with a wash-out period of 3-5 weeks between the meals. Blood samples were collected at baseline (fasting) and 2, 4 and 6 h after intake of the meals. In both FH and control subjects, the level of TAG and the largest VLDL sub-classes peaked at 2 h after intake of PUFA and at 4 h after intake of SFA. No significant differences were found in TAG levels between meals or between groups (0·25≤P≤0·72). The distinct TAG peaks may reflect differences in the postprandial lipid metabolism after intake of fatty acids with different chain lengths and degrees of saturation. The clinical impact of these findings remains to be determined.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos/administração & dosagem , Hiperlipoproteinemia Tipo II/sangue , Período Pós-Prandial/fisiologia , Triglicerídeos/sangue , Adulto , Área Sob a Curva , Índice de Massa Corporal , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Lipoproteínas VLDL/sangue , Masculino , Fatores de Tempo
12.
Curr Opin Lipidol ; 27(4): 382-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27070077

RESUMO

PURPOSE OF REVIEW: There is currently limited information as to whether maternally or paternally inherited familial hypercholesterolemia confers different phenotype risk to offspring. Knowledge about the differences in risk conferred by inheritance could be important with respect to follow-up and more individually targeted treatment of subjects with familial hypercholesterolemia. RECENT FINDINGS: Few studies have, with inconsistent results so far, investigated the significance of familial hypercholesterolemia inheritance on cardiovascular risk markers in offspring. Maternal inheritance of familial hypercholesterolemia includes hypercholesterolemic in-utero conditions for the offspring. How this may influence later risk is briefly discussed in the article. SUMMARY: Current data suggest that the dominating factor of the familial hypercholesterolemia (FH) phenotype is the mutation and not the inheritance, however, maternal inheritance of FH has been reported to adversely affect FH phenotype in terms of increased mortality. More knowledge about how intrauterine hypercholesterolemia during pregnancy influences epigenetic modifications and later cardiovascular disease risk in offspring is needed and this may open up new avenues of treatment of pregnant women with familial hypercholesterolemia.


Assuntos
Hiperlipoproteinemia Tipo II , Fenótipo , Efeitos Tardios da Exposição Pré-Natal , Útero , Animais , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética
14.
Atheroscler Plus ; 57: 13-18, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39027312

RESUMO

Background and aim: Many children with an FH mutation also exhibit elevated lipoprotein(a) levels, which is an independent risk factor for atherosclerotic cardiovascular disease. Studies have reported higher levels of lipoprotein(a) in adult and middle-aged women than men. There is limited knowledge on the concentration and change of lipoprotein(a) levels in children with genetic FH, and therefore we investigated sex-differences in lipoprotein(a) level and change in lipoprotein(a) in girls and boys with genetically confirmed FH. Methods: Medical records were reviewed retrospectively in 438 subjects with heterozygous FH that started follow-up below the age of 19 years at the Lipid Clinic, Oslo University Hospital in Norway, and of these we included 386 subjects with at least one Lp(a) measurement. Results: Mean (SD) age at baseline was 13.8 (7.3) years and the age was similar between sexes. Girls had a higher lipoprotein(a) level than boys at baseline: median (25-75 percentile) 223 (108-487) vs. 154 (78-360) mg/L, respectively (p < 0.01). From baseline to follow-up measurement (mean [SD] 8.9 [6.1] years apart), the mean (95 % CI) absolute and percentage change in Lp(a) level in girls was 151.4 (54.9-247.8) mg/L and 44.8 (16.4-73.1) %, respectively, and in boys it was 66.8 (22.9-110.8) mg/L and 50.5 (8.8-92.3) %, respectively (both p > 0.05). Conclusions: We found an increase in Lp(a) levels in children with genetic FH with age, and higher levels in girls than boys, which could impact risk assessment and future ASCVD. Further research is needed to elucidate whether subjects with FH could benefit from lipoprotein(a)-lowering therapies that are under current investigations.

15.
Atherosclerosis ; 392: 117507, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38663317

RESUMO

BACKGROUND AND AIMS: Elderly familial hypercholesterolemia (FH) patients are at high risk of coronary heart disease (CHD) due to high cholesterol burden and late onset of effective cholesterol-lowering therapies. A subset of these individuals remains free from any CHD event, indicating the potential presence of protective factors. Identifying possible cardioprotective gene expression profiles could contribute to our understanding of CHD prevention and future preventive treatment. Therefore, this study aimed to investigate gene expression profiles in elderly event-free FH patients. METHODS: Expression of 773 genes was analysed using the Nanostring Metabolic Pathways Panel, in peripheral blood mononuclear cells (PBMCs) from FH patients ≥65 years without CHD (FH event-free, n = 44) and with CHD (FH CHD, n = 39), and from healthy controls ≥70 years (n = 39). RESULTS: None of the genes were differentially expressed between FH patients with and without CHD after adjusting for multiple testing. However, at nominal p < 0.05, we found 36 (5%) differentially expressed genes (DEGs) between the two FH groups, mainly related to lipid metabolism (e.g. higher expression of ABCA1 and ABCG1 in FH event-free) and immune responses (e.g. lower expression of STAT1 and STAT3 in FH event-free). When comparing FH patients to controls, the event-free group had fewer DEGs than the CHD group; 147 (19%) and 219 (28%) DEGs, respectively. CONCLUSIONS: Elderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets.


Assuntos
Doença das Coronárias , Perfilação da Expressão Gênica , Hiperlipoproteinemia Tipo II , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/sangue , Masculino , Feminino , Idoso , Doença das Coronárias/genética , Estudos de Casos e Controles , Leucócitos Mononucleares/metabolismo , Fatores Etários , Transcriptoma , Idoso de 80 Anos ou mais
16.
Atherosclerosis ; 389: 117433, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38219649

RESUMO

The scientific evidence supporting the current dietary recommendations for fat quality keeps accumulating; however, a paradoxical distrust has taken root among many researchers, clinicians, and in parts of the general public. One explanation for this distrust may relate to an incomplete overview of the totality of the evidence for the link between fat quality as a dietary exposure, and health outcomes such as atherosclerotic cardiovascular disease (ASCVD). Therefore, the main aim of the present narrative review was to provide a comprehensive overview of the rationale for dietary recommendations for fat intake, limiting our discussion to ASCVD as outcome. Herein, we provide a core framework - a causal model - that can help us understand the evidence that has accumulated to date, and that can help us understand new evidence that may become available in the future. The causal model for fat quality and ASCVD is comprised of three key research questions (RQs), each of which determine which scientific methods are most appropriate to use, and thereby which lines of evidence that should feed into the causal model. First, we discuss the link between low-density lipoprotein (LDL) particles and ASCVD (RQ1); we draw especially on evidence from genetic studies, randomized controlled trials (RCTs), epidemiology, and mechanistic studies. Second, we explain the link between dietary fat quality and LDL particles (RQ2); we draw especially on metabolic ward studies, controlled trials (randomized and non-randomized), and mechanistic studies. Third, we explain the link between dietary fat quality, LDL particles, and ASCVD (RQ3); we draw especially on RCTs in animals and humans, epidemiology, population-based changes, and experiments of nature. Additionally, the distrust over dietary recommendations for fat quality may partly relate to an unclear understanding of the scientific method, especially as applied in nutrition research, including the process of developing dietary guidelines. We therefore also aimed to clarify this process. We discuss how we assess causality in nutrition research, and how we progress from scientific evidence to providing dietary recommendations.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Animais , Humanos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/complicações , Gorduras na Dieta , Lipoproteínas , Lipoproteínas LDL , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Cytokine ; 61(1): 194-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23131422

RESUMO

OBJECTIVE: Matrix degradation within an atherosclerotic plaque is an important pathogenic factor in atherosclerosis, and is largely modulated by the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors (i.e., tissue inhibitor of MMPs [TIMPs]). Familial hypercholesterolemia (FH) is a rare inherited disorder associated with premature coronary heart disease. The aim of the present study was to examine MMP-9 and TIMP-1 on plasma and cellular mRNA levels in homozygous FH patients (n=7) compared with age- and sex-matched heterozygous FH patients (n=6), and with healthy subjects (n=7), and to test whether once-weekly LDL-apheresis (three consecutive sessions) of homozygous FH patients show short-term effects on these variables. RESULTS: The main findings were that (i) Compared to healthy control subjects, homozygous FH patients have significantly higher serum levels of MMP-9 and lower levels of TIMP-1, and consequently significantly higher MMP-9/TIMP-1 ratio, potentially reflecting higher MMP-9 activity. (ii) Peripheral blood mononuclear cells (PBMC) isolated from FH homozygotes have significantly higher mRNA levels of MMP-9 compared to cells from heterozygotes. (iii) TNFα-stimulated PBMC from FH homozygotes released borderline-significantly more MMP-9 than cells from heterozygotes and healthy controls. (iv) LDL-apheresis (one day before treatment versus fifteen days later, on the day after the weekly treatment) had no significant short-term effect on any of the MMP-9 and TIMP-1 variables measured in serum and cells. CONCLUSIONS: The data may suggest that homozygous FH patients have an enhanced matrix degrading potential as compared with heterozygous FH patients and healthy controls, potentially contributing to the increased cardiovascular risk observed in these patients.


Assuntos
Hiperlipoproteinemia Tipo II/sangue , Leucócitos Mononucleares/citologia , Lipoproteínas LDL/sangue , Metaloproteinase 9 da Matriz/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Adolescente , Adulto , Aterosclerose/imunologia , Remoção de Componentes Sanguíneos , Doenças Cardiovasculares/genética , Criança , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Inflamação , Leucócitos Mononucleares/efeitos dos fármacos , Lipoproteínas LDL/genética , Masculino , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , RNA Mensageiro/análise , Fator de Necrose Tumoral alfa/farmacologia , Adulto Jovem
20.
Atherosclerosis ; 368: 25-34, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36522216

RESUMO

BACKGROUND AND AIMS: Statins are becoming more widely used among women of reproductive age; however, nationwide data on statin use across pregnancy is scarce. We therefore aimed to describe the drug utilization patterns for statins and other lipid-modifying agents (LMAs) before, during, and after pregnancy, for all pregnancies in Norway from 2005 to 2018. METHODS: We linked individual-level data from four nationwide electronic health care registries in Norway and characterized the prescription fills of statins and other LMAs across pregnancy. We also examined trends in pregnancy-related LMA use, and characterized women using statins and other LMAs on parameters of health status and co-morbidity. RESULTS: In total, 822,071 pregnancies for 503,723 women were included. The number of statin prescription fills decreased rapidly during the first trimester and returned to pre-pregnancy levels about one year postpartum. Pregnancy-related statin use increased from 2005 (approx. 0.11% of all pregnancies) to 2018 (approx. 0.29% of all pregnancies); however, in total, few statin prescriptions were filled within any trimester of pregnancy (n = 331, 0.04% of all pregnancies). Statin use was more common in women with higher age, higher weight, smoking, and comorbidities such as hypertension and diabetes mellitus; also, statin users often had co-medication pertinent to these conditions. CONCLUSIONS: Although statins and other LMAs were increasingly being used around the time of pregnancy among women in Norway, drug use was mostly discontinued during the first trimester. Our results suggest that pregnancy-related statin use should be monitored, and that drug safety analyses for maternal and offspring health outcomes are needed.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Gravidez , Humanos , Feminino , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Noruega , Uso de Medicamentos , Lipídeos , Prescrições de Medicamentos
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