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OBJECTIVE: Lipoprotein(a)-hyperlipoproteinemia (Lp(a)-HLP) along with progressive cardiovascular disease has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. We aimed to study the long-term preventive effect of LA and to assess hypothetical clinical correlations of apolipoprotein(a) (apo(a)) by analyzing genotypes and phenotypes. APPROACH AND RESULTS: This prospective observational multicenter study included 170 patients with Lp(a)-HLP and progressive cardiovascular disease (48.9 years median age at diagnosis) despite other cardiovascular risk factors, including low-density lipoprotein cholesterol had maximally been treated (mean baseline low-density lipoprotein cholesterol: measured, 2.56 mmol/L [98.9 mg/dL] and corrected, 1.72 mmol/L [66.3 mg/dL]). Patients were prospectively investigated during a 5-year period about annual incidence rates of cardiovascular events. In addition, apo(a) isoforms and polymorphisms at the apo(a) gene (LPA) were characterized. One hundred fifty-four patients (90.6%) completed 5 years of follow-up. Mean Lp(a) concentration before commencing regular LA was 108.1 mg/dL. This was reduced by a single LA treatment by 68.1% on average. Significant decline of the mean annual cardiovascular event rate was observed from 0.58±0.53 2 years before regular LA to 0.11±0.15 thereafter (P<0.0001); 95.3% of patients expressed at least 1 small apo(a) isoform. Small apo(a) isoform (35.2%) carrying phenotypes were not tagged by single-nucleotide polymorphisms rs10455872 or rs3798220. CONCLUSIONS: Results of 5 years of prospective follow-up confirm that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP. Patients clinically selected by progressive cardiovascular disease were characterized by a highly frequent expression of small apo(a) isoforms. Only Lp(a) concentration seemed to comprehensively reflect Lp(a)-associated cardiovascular risk, however.
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Apoproteína(a)/sangue , Remoção de Componentes Sanguíneos/métodos , Doenças Cardiovasculares/prevenção & controle , Hiperlipoproteinemias/terapia , Lipoproteína(a)/sangue , Idoso , Biomarcadores/sangue , Remoção de Componentes Sanguíneos/efeitos adversos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Alemanha , Humanos , Hiperlipoproteinemias/sangue , Hiperlipoproteinemias/epidemiologia , Hiperlipoproteinemias/genética , Incidência , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Lipoprotein(a) (Lp(a)) hyperlipoproteinemia is a major risk factor for cardiovascular disease, which is not affected by treatment of other cardiovascular risk factors. This study sought to assess the effect of chronic lipoprotein apheresis (LA) on the incidence of cardiovascular events in patients with progressive cardiovascular disease receiving maximally tolerated lipid-lowering treatment. METHODS AND RESULTS: In a prospective observational multicenter study, 170 patients were investigated who commenced LA because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. Patients were characterized regarding plasma lipid status, lipid-lowering drug treatment, and variants at the LPA gene locus. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (y+1, y+2) were compared. The mean age of patients was 51 years at the first cardiovascular event and 57 years at the first LA. Before LA, mean low-density lipoprotein cholesterol and Lp(a) were 2.56±1.04 mmol·L(-1) (99.0±40.1 mg·dL(-1)) and Lp(a) 3.74±1.63 µmol·L(-1) (104.9±45.7 mg·dL(-1)), respectively. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA (P<0.0001). Event rates including all vascular beds declined from 0.61 to 0.16 (P<0.0001). Analysis of single years revealed increasing major adverse coronary event rates from 0.30 to 0.54 (P=0.001) for y-2 to y-1 before LA, decline to 0.14 from y-1 to y+1 (P<0.0001) and to 0.05 from y+1 to y+2 (P=0.014). CONCLUSIONS: In patients with Lp(a)-hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events. CLINICAL TRIAL REGISTRATION URL: https://drks-neu.uniklinik-freiburg.de. Unique identifier: DRKS00003119.
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Remoção de Componentes Sanguíneos/métodos , Doenças Cardiovasculares/epidemiologia , Progressão da Doença , Hiperlipoproteinemias/terapia , Hipolipemiantes/uso terapêutico , Lipoproteína(a)/sangue , Idoso , LDL-Colesterol/sangue , Feminino , Seguimentos , Alemanha , Humanos , Hiperlipoproteinemias/sangue , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Soluble suppression of tumorigenicity 2 (sST2) has emerged as a strong prognostic biomarker in patients with heart failure and myocardial infarction. The aim of this study was to evaluate the long-term prognostic value of sST2 in patients with stable coronary artery disease (CAD). METHODS: sST2 plasma concentrations were measured in 1345 patients with stable CAD referred for coronary angiography at a single tertiary care center. The primary endpoint was all-cause mortality. RESULTS: During a median follow-up time of 9.8 years, 477 (36%) patients died. The median sST2 plasma concentration at baseline was significantly higher among decedents than survivors (21.4 vs 18.5 ng/mL; P < 0.001). In multivariate Cox proportional hazards regression analysis, sST2 was an independent predictor of all-cause mortality (risk ratio 1.16 per 1-SD increase in log-transformed values; 95% CI 1.05-1.29; P = 0.004). In the same multivariate analysis, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were also independent predictors, whereas galectin-3 was not. Patients with sST2 in the highest quartile (>24.6 ng/mL) displayed a 2-fold increased risk of death in univariate analysis, which was attenuated but remained significant in a fully adjusted model (risk ratio 1.39; 95% CI 1.10-1.76; P = 0.006). Further analysis showed that the prognostic impact of sST2 was additive to NT-proBNP and hs-cTnT. Using a multibiomarker approach combining these 3 complementary makers, we demonstrated that patients with all 3 biomarkers in the highest quartiles had the poorest outcome. CONCLUSIONS: In this cohort of patients with stable CAD, increased sST2 was an independent predictor of long-term all-cause mortality and provided complementary prognostic information to hs-cTnT and NT-proBNP.
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Doença da Artéria Coronariana/mortalidade , Receptores de Superfície Celular/sangue , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Isoformas de Proteínas/sangue , Troponina T/sangueRESUMO
OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors. METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors. RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (ß = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects. CONCLUSION: This study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.
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Aterosclerose , Diabetes Mellitus Tipo 2 , Hipertensão , Infarto do Miocárdio , Humanos , Estudo de Associação Genômica Ampla , Diabetes Mellitus Tipo 2/genética , Análise da Randomização Mendeliana , Aterosclerose/genética , Aterosclerose/complicações , Infarto do Miocárdio/etiologia , Fatores de Risco , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Romosozumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase 3 trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (ß 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (ß -0.20; CI -0.38, -0.02), HDL cholesterol (ß -0.05; CI -0.10, -0.01), and apolipoprotein A-I (ß -0.05; CI -0.08, -0.02) (difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow-up (hazard ratio [HR] = 1.13; 1.03, 1.23) and with severity of coronary artery disease on angiogram as reflected by Friesinger score (0.05; 0.01, 0.09). Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR, and apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Doenças Cardiovasculares , Doença da Artéria Coronariana , HDL-Colesterol , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Red blood cell (RBC) fatty acid (FA) patterns are becoming recognized as long-term biomarkers of tissue FA composition, but different analytical methods have complicated inter-study and international comparisons. Here we report RBC FA data, with a focus on the Omega-3 Index (EPA + DHA in% of total FAs in RBC), from samples of seven countries (USA, Canada, Italy, Spain, Germany, South Korea, and Japan) including 167,347 individuals (93% of all samples were from the US). FA data were generated by a uniform methodology from a variety of interventional and observational studies and from clinical laboratories. The cohorts differed in size, demographics, health status, and year of collection. Only the Canadian cohort was a formal, representative population-based survey. The mean Omega-3 Index of each country was categorized as desirable (>8%), moderate (>6% to 8%), low (>4% to 6%), or very low (≤4%). Only cohorts from Alaska (treated separately from the US), South Korea and Japan showed a desirable Omega-3 Index. The Spanish cohort had a moderate Omega-3 Index, while cohorts from the US, Canada, Italy, and Germany were all classified as low. This study is limited by the use of cohorts of convenience and small sample sizes in some countries. Countries undertaking national health status studies should utilize a uniform method to measure Omega-3 FA levels.
Assuntos
Ácidos Docosa-Hexaenoicos , Ácidos Graxos Ômega-3 , Canadá , Ácido Eicosapentaenoico , Eritrócitos , Ácidos Graxos , HumanosRESUMO
BACKGROUND: Several studies have investigated the role of Lipoprotein (a) as a risk factor for cardiovascular disease (CVD) and have produced controversial results. DATA SOURCES: We conducted a systematic literature review in the databases MEDLINE, EMBASE, and COCHRANE aimed at retrieving prospective studies that investigated the prognostic value of Lipoprotein (a) concentrations on cardiovascular risk and mortality. METHODS: From each study we extracted estimates of risk ratios (RR) with respect to the risk of CVD (endpoints: all coronary heart disease (CHD) events pooled, major coronary events, myocardial infarction, stroke) and all cause mortality. Study specific risk ratios were standardised to contrast the top third with the bottom third of the study specific Lipoprotein (a) distribution. Pooled summary estimates were calculated by using fixed and random effects meta analysis techniques, in total and stratified by study design and study population. RESULTS: For the present meta analysis we selected 67 prospective studies including 181,683 individuals. Synthesising data from 37 studies that reported estimates for the endpoint 'CHD events' resulted in a RR of 1.57 (95% CI: 1.41 to 1.75, p < 0.001). For this endpoint subgroup analyses by design and population showed significant estimates: population based cohort studies: n = 15 studies, RR = 1.48 (95% CI: 1.26 to 1.74, p < 0.001), cohort studies including patients with previous disease: total: n = 11 studies, RR = 1.67 (95% CI: 1.28 to 2.17, p < 0.001), with CHD: n = 6 studies, RR = 2.37 (95% CI: 1.41 to 3.97, p = 0.001), nested case control studies: n = 11 studies, RR = 1.64 (95% CI: 1.47 to 1.83, p < 0.001). We did not find any significant effect on risk of stroke (n = 16 studies, RR = 1.10 (95% CI: 0.97 to 1.25, p = 0.137)) and mortality (n = 9 studies, RR = 1.12 (95% CI: 0.94 to 1.33, p = 0.200)). CONCLUSIONS: This meta analysis of prospective studies shows a clear association between elevated Lipoprotein (a) levels and increased risk of CHD. This effect is substantially higher in individuals with previous CHD. Our systematic review showed no evidence of an effect on stroke and all cause mortality.
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Doenças Cardiovasculares/fisiopatologia , Lipoproteína(a)/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Humanos , Estudos Prospectivos , Fatores de Risco , Estados UnidosRESUMO
AIMS: Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients. METHODS AND RESULTS: Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1ß (IL-1ß) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1ß-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated ß cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro. CONCLUSIONS: Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.
Assuntos
Transdiferenciação Celular , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/sangue , Uromodulina/sangue , Calcificação Vascular/prevenção & controle , Adulto , Idoso , Animais , Aorta/imunologia , Aorta/metabolismo , Transdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Condrogênese , Citocinas/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/imunologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Osteogênese , Fenótipo , Carbamilação de Proteínas , Insuficiência Renal Crônica/imunologia , Transdução de Sinais , Uromodulina/genética , Uromodulina/farmacologia , Calcificação Vascular/sangue , Calcificação Vascular/imunologia , Adulto JovemRESUMO
PURPOSE: Organic cation transporters (Octs) use cations like endogenous compounds, toxins, and drugs, such as metformin, as substrates. Therefore, these proteins determine the pharmacokinetics and -dynamics of metformin and thus its efficacy. Of note, metformin is today the most commonly used pharmaceutical in the treatment of type 2 diabetes (T2DM) with nevertheless a great variability in clinical response, which attributes to genetic variances. The aim of this study was to determine the influence of intronic OCT1 SNPs on prevalence of all-cause and cardiovascular death. PATIENTS AND METHODS: Genotypes of 27 intronic SNPs in OCT1 were investigated in the LURIC study, a prospective cohort of 3316 participants scheduled for coronary angiography. We investigated whether these variants were associated with all-cause and cardiovascular death in 73 individuals with T2DM under metformin therapy, in individuals without diabetes, individuals with T2DM and individuals with T2DM without metformin therapy. RESULTS: In a multivariate Cox regression analysis adjusted for classical cardiovascular risk factors, 4 intronic OCT1 SNPs were significantly associated with all-cause and cardiovascular mortality in individuals with T2DM on metformin therapy. CONCLUSION: According to their OCT1 genotype, some individuals with T2DM on metformin therapy might be prone to an increased risk of cardiovascular death.
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Phenome-wide association studies (PheWAS) allow agnostic investigation of common genetic variants in relation to a variety of phenotypes but preserving the power of PheWAS requires careful phenotypic quality control (QC) procedures. While QC of genetic data is well-defined, no established QC practices exist for multi-phenotypic data. Manually imposing sample size restrictions, identifying variable types/distributions, and locating problems such as missing data or outliers is arduous in large, multivariate datasets. In this paper, we perform two PheWAS on epidemiological data and, utilizing the novel software CLARITE (CLeaning to Analysis: Reproducibility-based Interface for Traits and Exposures), showcase a transparent and replicable phenome QC pipeline which we believe is a necessity for the field. Using data from the Ludwigshafen Risk and Cardiovascular (LURIC) Health Study we ran two PheWAS, one on cardiac-related diseases and the other on polyunsaturated fatty acids levels. These phenotypes underwent a stringent quality control screen and were regressed on a genome-wide sample of single nucleotide polymorphisms (SNPs). Seven SNPs were significant in association with dihomo-γ-linolenic acid, of which five were within fatty acid desaturases FADS1 and FADS2. PheWAS is a useful tool to elucidate the genetic architecture of complex disease phenotypes within a single experimental framework. However, to reduce computational and multiple-comparisons burden, careful assessment of phenotype quality and removal of low-quality data is prudent. Herein we perform two PheWAS while applying a detailed phenotype QC process, for which we provide a replicable pipeline that is modifiable for application to other large datasets with heterogenous phenotypes. As investigation of complex traits continues beyond traditional genome wide association studies (GWAS), such QC considerations and tools such as CLARITE are crucial to the in the analysis of non-genetic big data such as clinical measurements, lifestyle habits, and polygenic traits.
Assuntos
Doenças Cardiovasculares , Biologia Computacional , Ácidos Graxos , Estudo de Associação Genômica Ampla , Fenótipo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Biologia Computacional/métodos , Dessaturase de Ácido Graxo Delta-5 , Estudos Epidemiológicos , Estudos de Associação Genética , Nível de Saúde , Humanos , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos TestesRESUMO
Epistasis analysis elucidates the effects of gene-gene interactions (G×G) between multiple loci for complex traits. However, the large computational demands and the high multiple testing burden impede their discoveries. Here, we illustrate the utilization of two methods, main effect filtering based on individual GWAS results and biological knowledge-based modeling through Biofilter software, to reduce the number of interactions tested among single nucleotide polymorphisms (SNPs) for 15 cardiac-related traits and 14 fatty acids. We performed interaction analyses using the two filtering methods, adjusting for age, sex, body mass index (BMI), waist-hip ratio, and the first three principal components from genetic data, among 2,824 samples from the Ludwigshafen Risk and Cardiovascular (LURIC) Health Study. Using Biofilter, one interaction nearly met Bonferroni significance: an interaction between rs7735781 in XRCC4 and rs10804247 in XRCC5 was identified for venous thrombosis with a Bonferroni-adjusted likelihood ratio test (LRT) p: 0.0627. A total of 57 interactions were identified from main effect filtering for the cardiac traits G×G (10) and fatty acids G×G (47) at Bonferroni-adjusted LRT p < 0.05. For cardiac traits, the top interaction involved SNPs rs1383819 in SNTG1 and rs1493939 (138kb from 5' of SAMD12) with Bonferroni-adjusted LRT p: 0.0228 which was significantly associated with history of arterial hypertension. For fatty acids, the top interaction between rs4839193 in KCND3 and rs10829717 in LOC107984002 with Bonferroni-adjusted LRT p: 2.28×10-5 was associated with 9-trans 12-trans octadecanoic acid, an omega-6 trans fatty acid. The model inflation factor for the interactions under different filtering methods was evaluated from the standard median and the linear regression approach. Here, we applied filtering approaches to identify numerous genetic interactions related to cardiac-related outcomes as potential targets for therapy. The approaches described offer ways to detect epistasis in the complex traits and to improve precision medicine capability.
Assuntos
Doenças Cardiovasculares/epidemiologia , Biologia Computacional/métodos , Epistasia Genética , Ácidos Graxos/sangue , Marcadores Genéticos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Neopterin is produced upon activation of the cell-mediated immune response, and may be a novel risk marker for adverse outcomes resulting from coronary artery disease. METHODS: We measured neopterin in 1801 study participants with and 511 without angiographic coronary artery disease. Rates of death were determined after a median follow-up of 8.0 years. RESULTS: Estimated glomerular filtration rate and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were the strongest predictors of neopterin. Neopterin was positively related to age and inversely related to LDL cholesterol, HDL cholesterol, and triglycerides. Use of lipid-lowering drugs lowered neopterin. Sex, body mass index, diabetes mellitus, hypertension, smoking status, Friesinger coronary score, and clinical instability at presentation were not associated with neopterin. Unlike C-reactive protein, neopterin was not increased in unstable angina pectoris, non-ST-elevation myocardial infarction, or ST-elevation myocardial infarction. In the third and fourth quartiles of neopterin, unadjusted hazard ratios for death from any cause were 1.94 (95% CI 1.44-2.61) and 3.32 (95% CI 2.53-4.30) compared to individuals in the first quartile, whereas hazard ratios for death from cardiovascular causes were 2.14 (95% CI 1.44-3.18) and 3.84 (95% CI 2.67-5.52), respectively. Neopterin remained predictive of total and cardiovascular mortality after adjusting for sex, age, body mass index, type 2 diabetes, hypertension, smoking status, LDL cholesterol, HDL cholesterol, triglycerides, estimated glomerular filtration rate, NT-proBNP, and clinical status at presentation, but NT-proBNP substantially weakened this association. CONCLUSIONS: Neopterin is an independent predictor of all-cause and cardiovascular mortality in individuals with or without stable coronary artery disease.
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Doenças Cardiovasculares/mortalidade , Angiografia Coronária , Neopterina/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Feminino , Alemanha , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (ß = 0.20, p = 4.6 × 10-49 ) and GALNT1 (ß = 0.11 per G allele, p = 4.4 × 10-11 ). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (ß = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (ß = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (ß = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
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Proteínas Adaptadoras de Transdução de Sinal/sangue , Densidade Óssea/genética , Fraturas Ósseas/sangue , Fraturas Ósseas/genética , Análise da Randomização Mendeliana , Idoso , Animais , Osso e Ossos/patologia , Criança , Metilação de DNA , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Metanálise como Assunto , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Fenótipo , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = -0.142/-0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
Assuntos
Biomarcadores/sangue , Dor no Peito/diagnóstico , Técnicas de Diagnóstico Cardiovascular , Infarto do Miocárdio/diagnóstico , Troponina I/sangue , Adulto , Fatores Etários , Idoso , Biomarcadores/análise , Dor no Peito/sangue , Dor no Peito/epidemiologia , Dor no Peito/fisiopatologia , Estudos de Coortes , Técnicas de Diagnóstico Cardiovascular/normas , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/fisiopatologia , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Fatores Sexuais , Troponina I/análiseRESUMO
BACKGROUND: Homoarginine (hArg) has been shown to be of prognostic value in patients with chronic left heart failure. The present study aims to assess the clinical utility and prognostic value of hArg levels in patients with complex congenital heart disease (CHD). METHODS: Plasma hArg levels were measured in 143 patients with complex CHD and compared to clinical status, echocardiographic and laboratory parameters as well as the occurrence of adverse cardiac events. RESULTS: Median hArg levels were 1.5 µmol/l in CHD patients as compared to 1.70 µmol/l in healthy controls (p = 0.051). Median hArg levels were lowest in patients with Fontan palliation (1.27 µmol/l) and Eisenmenger physiology (0.99 µmol/l) and decreased with the severity of adverse cardiac events with lowest values found in patients prior to death or overt heart failure (0.89 µmol/l). According to ROC analysis, the most important predictors of adverse cardiac events were hArg levels (AUC 0.837, p<0.001, CI 0.726-0.947), NYHA class (AUC 0.800, p<0.001, CI 0.672-0.928) and NT-proBNP levels (AUC 0.780, p<0.001, CI 0.669-0.891). The occurrence of overt heart failure or death due to progressive heart failure were best predicted by NYHA class (AUC 0.945, p<0.001, CI 0.898-0.992), hArg levels (AUC 0.911, p<0.001, CI 0.850-0.971) and NT-proBNP levels (AUC 0.877, p<0.001, CI 0.791-0.962), respectively. CONCLUSION: In patients with complex CHD, hArg levels can predict adverse cardiac events as reliably as or even better than NT-proBNP levels and thus might be of prognostic value in this subset of patients.
Assuntos
Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/diagnóstico , Homoarginina/sangue , Adolescente , Adulto , Biomarcadores , Ecocardiografia , Feminino , Cardiopatias Congênitas/mortalidade , Humanos , Masculino , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prognóstico , Curva ROCRESUMO
Hepatic lipase (HL) functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Plasma HL activity is known to be regulated by hormonal and metabolic factors, but HL responsiveness to insulin as well as its role in modulating atherosclerotic risk is still controversial. We investigated on the influence of a known polymorphism in the neurotransmitter neuropeptide Y (NPY) on HL activity in two different cohorts consisting of diabetic and nondiabetic patients. HL activity was 24% and 34% higher on nondiabetic and diabetic subjects in the presence of the 7Pro allele in NPY, respectively. The presence of the 7Pro allele was an independent predictor of HL activity in multivariate analyses in both cohorts. These data suggest a regulatory effect of NPY on HL activity. Among carriers of the 7Pro allele, we also found a statistically significant lower absolute number of infarctions compared to noncarriers (p < 0.05) and a nonsignificant trend towards less myocardial infarction in the 7Pro allele diabetic carriers (p = 0.085). In conclusion, the common 7Pro allele in NPY was associated with higher HL activity in nondiabetic and diabetic subjects and its presence seems to coincide with a lower frequency of certain cardiovascular events.
RESUMO
BACKGROUND AND AIMS: Galectin-3 binding protein (Gal-3BP) has been associated with inflammation and cancer, however, its role in coronary artery disease (CAD) and cardiovascular outcome remains unclear. METHODS: Gal-3BP plasma levels were measured by ELISA in 2922 individuals from the LURIC study (62.7 ± 10.6 years, 62.7% male). All-cause and cardiovascular mortality was assessed by Kaplan-Meier analysis and Cox proportional hazards regression. Causal involvement of Gal-3BP was tested for by Mendelian randomization. Gal-3BP effects on human monocyte-derived macrophages were assessed in vitro. RESULTS: During 8.8 ± 3.0 years, 866 individuals died, 654 of cardiovascular causes. There was a significant increase in all-cause and cardiovascular mortality with increasing Gal-3BP quintiles. After thorough adjustment, all-cause mortality remained significantly increased in the fifth Gal-3BP quintile (HRQ5 1.292 (1.030-1.620), p = 0.027); cardiovascular mortality remained increased in Gal-3BP quintiles two to five (HRQ51.433 (1.061-1.935, p = 0.019). Gal-3BP levels were not associated with diagnosis and extent of coronary artery disease. In addition, Mendelian randomization did not show a direct causal relationship between Gal-3BP levels and mortality. Gal-3BP levels were, however, independently associated with markers of metabolic and inflammatory distress. In vitro, Gal-3BP induced a pro-inflammatory response in human monocyte-derived macrophages. Adding Gal-3BP levels to the ESC score improved risk assessment in patients with ESC SCORE-based risk >5% (p = 0.010). CONCLUSIONS: In a large clinical cohort of CAD patients, Gal-3BP levels are independently associated with all-cause and cardiovascular mortality. The underlying mechanisms may likely involve metabolic and inflammatory distress. To further evaluate the potential clinical value of Gal-3BP, prospective studies are needed.
Assuntos
Doença da Artéria Coronariana/sangue , Galactosefosfatos/sangue , Medição de Risco , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/mortalidade , Causas de Morte/tendências , Células Cultivadas , Angiografia Coronária , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/mortalidade , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Seguimentos , Galactosefosfatos/genética , Regulação da Expressão Gênica , Alemanha/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , RNA Mensageiro/genética , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
Risk stratification is crucial in prevention. Circulating microRNAs have been proposed as biomarkers in cardiovascular disease. Here a miR panel consisting of miRs related to different cardiovascular pathophysiologies, was evaluated to predict outcome in the context of prevention. MiR-34a, miR-223, miR-378, miR-499 and miR-133 were determined from peripheral blood by qPCR and combined to a risk panel. As derivation cohort, 178 individuals of the DETECT study, and as validation cohort, 129 individuals of the SHIP study were used in a case-control approach. Overall mortality and cardiovascular events were outcome measures. The Framingham Risk Score(FRS) and the SCORE system were applied as risk classification systems. The identified miR panel was significantly associated with mortality given by a hazard ratio(HR) of 3.0 (95% (CI): 1.09-8.43; p = 0.034) and of 2.9 (95% CI: 1.32-6.33; p = 0.008) after adjusting for the FRS in the derivation cohort. In a validation cohort the miR-panel had a HR of 1.31 (95% CI: 1.03-1.66; p = 0.03) and of 1.29 (95% CI: 1.02-1.64; p = 0.03) in a FRS/SCORE adjusted-model. A FRS/SCORE risk model was significantly improved to predict mortality by the miR panel with continuous net reclassification index of 0.42/0.49 (p = 0.014/0.005). The present miR panel of 5 circulating miRs is able to improve risk stratification in prevention with respect to mortality beyond the FRS or SCORE.
Assuntos
Doenças Cardiovasculares/genética , MicroRNA Circulante , Estudos de Associação Genética , Predisposição Genética para Doença , MicroRNAs/genética , Adulto , Idoso , Biomarcadores , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Adiponectin, the most abundant adipocytokine of adipose tissue cells, has recently been found to be decreased in coronary artery disease (CAD). Data concerning adiponectin in different stages of CAD are rare, and it was not investigated if adiponectin levels are influenced by the severity of angina pectoris. METHODS: Thus, we measured adiponectin serum levels by means of ELISA in 1626 male probands, including 273 control subjects, 367 subjects with silent CAD, 608 patients with stable, and 378 patients with unstable angina. RESULTS: As compared to controls (8.56; 5.85 to 12.85 microg/ml) and subjects with silent CAD (8.60; 5.99 to 12.64 microg/ml), adiponectin was significantly decreased in patients with stable (7.22; 5.06 to 10.41 microg/ml; p < 0.001 for both) and unstable angina (6.72; 4.08 to 10.08 microg/ml; p < 0.001 for both). By a logistic regression analysis, low adiponectin levels were identified as a significant independent predictor for stable and unstable angina (p < 0.001 for both). No significant differences of adiponectin were observed, neither between the stable and unstable angina group, nor between any classes of angina according to the Canadian Cardiovascular Society (CCS) Angina Score for stable angina. CONCLUSIONS: These results suggest, that decreased adiponectin levels are indicative for symptomatic CAD, but are not further influenced by the progression of this disease.
Assuntos
Adiponectina/sangue , Doença da Artéria Coronariana/sangue , Idoso , Índice de Massa Corporal , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/etiologia , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fumar/efeitos adversos , Triglicerídeos/sangueRESUMO
AIMS: Reduced homoarginine plasma levels are associated with unfavourable cardiovascular outcome in chronic kidney disease (CKD). Cardiovascular events in CKD are fostered by vascular calcification, an active process promoted by hyperphosphatemia and involving osteo-/chondrogenic transformation of vascular smooth muscle cells (VSMCs). The present study explored the effect of homoarginine on phosphate-induced osteo-/chondrogenic signalling and vascular calcification. METHODS AND RESULTS: Experiments were performed in hyperphosphatemic klotho-hypomorphic mice (kl/kl), in subtotal nephrectomy and vitamin D3-overload mouse calcification models and in primary human aortic smooth muscle cells (HAoSMCs). As a result, plasma homoarginine levels were lower in kl/kl mice than in wild-type mice and in both genotypes significantly increased by lifelong treatment with homoarginine. Surprisingly, homoarginine treatment of kl/kl mice and of mice with renal failure after subtotal nephrectomy augmented vascular calcification and enhanced the transcript levels of plasminogen activator inhibitor 1 (Pai1) and of osteogenic markers Msx2, Cbfa1, and Alpl. Similarly, homoarginine treatment of HAoSMCs increased phosphate-induced calcium deposition, ALP activity, as well as PAI1, MSX2, CBFA1, and ALPL mRNA levels. Homoarginine alone up-regulated osteo-/chondrogenic signalling and indicators of oxidative stress in HAoSMCs. Furthermore, homoarginine reduced citrulline formation from arginine by nitric oxide (NO) synthase (NOS) isoforms. NO formation by NOS was reduced when using homoarginine as a substrate instead of arginine. The osteoinductive effects of homoarginine were mimicked by NOS inhibitor L-NAME and abolished by additional treatment with the NO donors DETA-NONOate and PAPA-NONOate or the antioxidants TEMPOL and TIRON. Furthermore, homoarginine augmented vascular calcification and aortic osteo-/chondrogenic signalling in mice after vitamin D3-overload, effects reversed by the NO donor molsidomine. CONCLUSION: Homoarginine augments osteo-/chondrogenic transformation of VSMCs and vascular calcification, effects involving impaired NO formation from homoarginine.