Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 376
Filtrar
2.
J Am Heart Assoc ; 11(11): e024388, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35621206

RESUMO

Background Elevated plasma levels of alpha-aminoadipic acid (2-AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown. Methods and Results We identified genetic determinants of plasma 2-AAA through meta-analysis of genome-wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women's and Men's Health Studies. No single nucleotide polymorphisms reached genome-wide significance across all samples. However, the top associations from the meta-analysis included single-nucleotide polymorphisms in the known 2-AAA pathway gene DHTKD1, and single-nucleotide polymorphisms in genes involved in mitochondrial respiration (NDUFS4) and macrophage function (MSR1). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2-AAA and cardiometabolic phenotypes in large disease genome-wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2-AAA and lower high-density lipoprotein cholesterol (P=0.005). We further characterized the genetically predicted relationship through measurement of plasma 2-AAA and high-density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2-AAA and high-density lipoprotein (rs=-0.53, P<0.0001). Conclusions 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.


Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Ácido 2-Aminoadípico/genética , Aterosclerose/genética , China , HDL-Colesterol , LDL-Colesterol , Feminino , Estudo de Associação Genômica Ampla , Humanos , Complexo Cetoglutarato Desidrogenase/genética , Análise da Randomização Mendeliana , Nucleotídeos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos
3.
JACC Heart Fail ; 10(4): 254-262, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35361444

RESUMO

OBJECTIVES: This study aims to examine whether greater frequency of depressive symptoms associates with increased risk of incident heart failure (HF). BACKGROUND: Depressive symptoms associate with adverse prognosis in patients with prevalent HF. Their association with incident HF is less studied, particularly in low-income and minority individuals. METHODS: We studied 23,937 Black or White Southern Community Cohort Study participants (median age: 53 years, 70% Black, 64% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services coverage. Cox models adjusted for traditional HF risk factors, socioeconomic and behavioral factors, social support, and antidepressant medications were used to quantify the association between depressive symptoms assessed at enrollment via the Center for Epidemiologic Studies Depression Scale (CESD-10) and incident HF ascertained from Centers for Medicare and Medicaid Services International Classification of Diseases-9th Revision (ICD-9) (code: 428.x) and ICD-10 (codes: I50, I110) codes through December 31, 2016. RESULTS: The median CESD-10 score was 9 (IQR: 5 to 13). Over a median 11-year follow-up, 6,081 (25%) participants developed HF. The strongest correlates of CESD-10 score were antidepressant medication use, age, and socioeconomic factors, rather than traditional HF risk factors. Greater frequency of depressive symptoms associated with increased incident HF risk (per 8-U higher CESD-10 HR: 1.04; 95% CI: 1.00 to 1.09; P = 0.038) without variation by race or sex. The association between depressive symptoms and incident HF varied by antidepressant use (interaction-P = 0.03) with increased risk among individuals not taking antidepressants. CONCLUSIONS: In this high-risk, low-income, cohort of predominantly Black participants, greater frequency of depressive symptoms significantly associates with higher risk of incident HF.


Assuntos
Depressão , Insuficiência Cardíaca , Idoso , Estudos de Coortes , Depressão/epidemiologia , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Medicare , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos/epidemiologia
4.
Prog Cardiovasc Dis ; 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35114251

RESUMO

Prior studies have reported improvements in population-level risk factor burden and cardiovascular disease (CVD) outcomes using polypills for CVD risk reduction. However, a comprehensive assessment of the impact of polypills on CVD outcomes, mortality, adherence, and side effects across different settings has not previously been reported. We performed a systematic review and meta-analysis of randomized controlled trials examining the association between polypill therapy and CVD outcomes published before February 2021. The primary outcome of interest was the risk of major adverse CVD events (MACE). Risk ratios for dichotomous outcomes were converted to log RR and pooled using a generic inverse variance weighted random-effects model. Data for continuous outcomes were pooled using random-effects modeling and presented as mean differences with 95% CIs. Eight studies representing 25,584 patients were included for analysis. In the overall pooled analysis, the use of polypills was associated with a non-significant reduction in the risk of MACE (RR: 0.85; 95% CI: 0.70-1.02) and significant reductions in the risk of all-cause mortality (RR: 0.90; 95% CI: 0.81-1.00). The reductions in the risk of MACE with polypill use varied by baseline risk and nature of the study population (primary prevention vs. secondary prevention), with the most significant risk reduction among lower-risk cohorts, including within primary prevention populations [RR 0.70 (0.62, 0.79)]. Among measures of CVD risk factors, modest but significant reductions were observed for systolic and diastolic blood pressure [systolic: mean difference 1.99 mmHg (95% CI: -3.07 to -0.91); diastolic: mean difference 1.30 mmHg (95% CI: -2.42 to -0.19), but not for levels of total or low-density lipoprotein-cholesterol. Use of the polypill strategy significantly improved drug adherence (RR: 1.31; 95% CI: 1.11-1.55) with no association between polypill use and rates of adverse events or drug discontinuation. The use of polypill formulations is associated with significant reductions in CVD risk factors and the risk of all-cause mortality and MACE, particularly in the low-risk and primary prevention population.

5.
Ann Intern Med ; 175(4): 574-589, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34978851

RESUMO

Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.


Assuntos
Americanos Asiáticos , Havaiano Nativo ou Outro Ilhéu do Pacífico , Hawaii , Promoção da Saúde , Humanos , National Institutes of Health (U.S.) , Estados Unidos/epidemiologia
6.
Circulation ; 145(5): 357-370, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34814699

RESUMO

BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, ß=0.61±0.05, P=3.27×10-30) and MMP-3 (ß=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, ß=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudo de Associação Genômica Ampla/métodos , Proteoma/metabolismo , Adulto , Feminino , Humanos , Masculino
7.
JAMA Cardiol ; 7(2): 184-194, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851361

RESUMO

Importance: African American individuals have disproportionate rates of coronary heart disease (CHD) but lower levels of coronary artery calcium (CAC), a marker of subclinical CHD, than non-Hispanic White individuals. African American individuals may have distinct metabolite profiles associated with incident CHD risk compared with non-Hispanic White individuals, and examination of these differences could highlight important processes that differ between them. Objectives: To identify novel biomarkers of incident CHD and CAC among African American individuals and to replicate incident CHD findings in a multiethnic cohort. Design, Setting, and Participants: This analysis targeted plasma metabolomic profiling of 2346 participants in the Jackson Heart Study (JHS), a prospective population-based cohort study that included 5306 African American participants who were examined at baseline (2000-2004) and 2 follow-up visits. Replication of CHD-associated metabolites was sought among 1588 multiethnic participants from the Women's Health Initiative (WHI), a prospective population-based multiethnic cohort study of 161 808 postmenopausal women who were examined at baseline (1991-1995) and ongoing follow-up visits. Regression analyses were performed for each metabolite to examine the associations with incident CHD and CAC scores. Data were collected from the WHI between 1994 and 2009 and from the JHS between 2000 and 2015. All data were analyzed from November 2020 to August 2021. Exposures: Plasma metabolites. Main Outcomes and Measures: Incident CHD was defined as definite or probable myocardial infarction or definite fatal CHD in both the JHS and WHI cohorts. In the JHS cohort, silent myocardial infarction between examinations (as determined by electrocardiography) and coronary revascularization were included in the incident CHD analysis. Coronary artery calcium was measured using a 16-channel computed tomographic system and reported as an Agatston score. Results: Among 2346 African American individuals in the JHS cohort, the mean (SD) age was 56 (13) years, and 1468 individuals (62.6%) were female. Among 1588 postmenopausal women in the WHI cohort, the mean (SD) age was 67 (7) years; 217 individuals (13.7%) self-identified as African American, 1219 (76.8%) as non-Hispanic White, and 152 (9.6%) as other races or ethnicities. In the fully adjusted model including 1876 individuals, 46 of 303 targeted metabolites were associated with incident CHD (false discovery rate q <0.100). Data for 32 of the 46 metabolites were available in the WHI cohort, and 13 incident CHD-associated metabolites from the JHS cohort were replicated in the WHI cohort. A total of 1439 participants from the JHS cohort with available CAC scores received metabolomic profiling. Nine metabolites were associated with CAC scores. Minimal overlap was found between the results from the incident CHD and CAC analyses, with only 3 metabolites shared between the 2 analyses. Conclusions and Relevance: This cohort study identified metabolites that were associated with incident CHD among African American individuals, including 13 incident CHD-associated metabolites that were replicated in a multiethnic population and 9 novel metabolites that included N-acylamides, leucine, and lipid species. These findings may help to elucidate common and distinct metabolic processes that may be associated with CHD among individuals with different self-identified race.


Assuntos
Afro-Americanos , Doença da Artéria Coronariana/metabolismo , Doença das Coronárias/metabolismo , Metabolômica , Calcificação Vascular/metabolismo , Adulto , Idoso , Estudos de Coortes , Doença da Artéria Coronariana/epidemiologia , Doença das Coronárias/epidemiologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estados Unidos/epidemiologia , Calcificação Vascular/epidemiologia
8.
J Hepatol ; 76(1): 25-33, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34600973

RESUMO

BACKGROUND & AIMS: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD. METHODS: We used aptamer-based proteomics to measure 4,783 proteins in 2 cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modeling-logistic regression assessed the ability of candidate proteins to classify fibrosis. RESULTS: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n = 62) and B (n = 98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n = 71) and D (n = 84). The A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and fibrosis-4 score. CONCLUSION: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis; they exhibited superior diagnostic performance compared to standard of care fibrosis scores. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy.


Assuntos
Proteínas ADAMTS/análise , Cirrose Hepática/diagnóstico , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Adulto , Área Sob a Curva , Biomarcadores/análise , Biópsia/métodos , Biópsia/estatística & dados numéricos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Modelos Logísticos , Masculino , Massachusetts , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Estudos Prospectivos , Curva ROC
9.
Eur J Heart Fail ; 24(1): 169-180, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34730265

RESUMO

AIMS: To evaluate the performance of the WATCH-DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). METHODS AND RESULTS: Adults with diabetes/pre-diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning- [WATCH-DM(ml)] and integer-based [WATCH-DM(i)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C-index) and calibration by the Greenwood-Nam-D'Agostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C-index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH-DM(ml) and WATCH-DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C-indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P ≥0.10). The C-index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (<13) vs. high (≥13) WATCH-DM(i) scores [0.71 (95% confidence interval 0.68-0.74) vs. 0.64 (95% confidence interval 0.61-0.66)]. When NP levels were combined with the WATCH-DM(i) score, HF risk discrimination improvement and NRI varied across the spectrum of risk with greater improvement observed at low/intermediate risk [WATCH-DM(i) <13] vs. high risk [WATCH-DM(i) ≥13] (C-index = 0.73 vs. 0.71; NRI = 0.45 vs. 0.17). CONCLUSION: The WATCH-DM risk score can accurately predict incident HF risk in community-based individuals with dysglycaemia. The addition of NP levels is associated with greater improvement in the HF risk prediction performance among individuals with low/intermediate risk than those with high risk.


Assuntos
Transtornos do Metabolismo de Glucose/epidemiologia , Insuficiência Cardíaca , Peptídeos Natriuréticos , Adulto , Estudos de Coortes , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Medição de Risco/métodos , Fatores de Risco
11.
Sci Rep ; 11(1): 15652, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341450

RESUMO

Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3-/- mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q < 0.05) with the SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk.


Assuntos
Cinurenina , Polimorfismo de Nucleotídeo Único , Animais , Biomarcadores , Proteína C-Reativa , Inflamação , Masculino , Camundongos , Triptofano/metabolismo
12.
Genes (Basel) ; 12(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34440357

RESUMO

Epigenetics is a mechanism underlying cardiovascular disease. It is unknown whether DNA hydroxymethylation is prospectively associated with the risk for cardiovascular death independent of germline and common environment. Male twin pairs middle-aged in 1969-1973 and discordant for cardiovascular death through December 31, 2014, were included. Hydroxymethylation was quantified in buffy coat DNA collected in 1986-1987. The 1893 differentially hydroxymethylated regions (DhMRs) were identified after controlling for blood leukocyte subtypes and age among 12 monozygotic (MZ) pairs (Benjamini-Hochberg False Discovery Rate < 0.01), of which the 102 DhMRs were confirmed with directionally consistent log2-fold changes and p < 0.01 among additional 7 MZ pairs. These signature 102 DhMRs, independent of the germline, were located on all chromosomes except for chromosome 21 and the Y chromosome, mainly within/overlapped with intergenic regions and introns, and predominantly hyper-hydroxymethylated. A binary linear classifier predicting cardiovascular death among 19 dizygotic pairs was identified and equivalent to that generated from MZ via the 2D transformation. Computational bioinformatics discovered pathways, phenotypes, and DNA motifs for these DhMRs or their subtypes, suggesting that hydroxymethylation was a pathophysiological mechanism underlying cardiovascular death that might be influenced by genetic factors and warranted further investigations of mechanisms of these signature regions in vivo and in vitro.


Assuntos
Doenças Cardiovasculares/genética , Metilação de DNA , Doenças do Recém-Nascido/genética , Sequenciamento Completo do Genoma/métodos , Doenças Cardiovasculares/patologia , Biologia Computacional , Epigênese Genética , Humanos , Recém-Nascido
13.
Circ Genom Precis Med ; 14(5): e003341, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34463132

RESUMO

BACKGROUND: Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known. METHODS: Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring Study; n=663). Systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, triglycerides, smoking, and waist circumference or body mass index were measured at the visit 1 exam of each study, and coronary artery calcium, a measure of coronary atherosclerosis, was assessed at year 15 (CARDIA) or year 30 (FOS). A previously validated PRS for coronary heart disease was computed for each subject. The C statistic and integrated discrimination improvement were used to compare improvements in prediction of elevated coronary artery calcium between models containing the PRS, risk factors, or both. RESULTS: There were 62 (5%) and 93 (14%) participants with a coronary artery calcium score >20 (CARDIA) and >300 (FOS), respectively. At these thresholds, the C statistic changes of adding the PRS to a risk factor-based model were 0.015 (0.004-0.028) and 0.020 (0.001-0.039) in CARDIA and FOS, respectively. When adding risk factors to a PRS-based model, the respective changes were 0.070 (0.033-0.109) and 0.051 (0.017-0.079). The integrated discrimination improvement, when adding the PRS to a risk factor model, was 0.027 (-0.006 to 0.054) in CARDIA and 0.039 (0.0005-0.072) in FOS. CONCLUSIONS: Among young adults, a PRS improved model discrimination for coronary atherosclerosis, but improvements were smaller than those associated with modifiable risk factors.


Assuntos
Cálcio/sangue , HDL-Colesterol/sangue , Doença das Coronárias/sangue , Triglicerídeos/sangue , Adolescente , Adulto , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Masculino , Risco , Medição de Risco , Fumar/efeitos adversos , Fumar/sangue , Adulto Jovem
15.
Gut ; 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127525

RESUMO

OBJECTIVE: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota. METHOD: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites. RESULTS: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using Firmicutes. We identified a novel association between a host functional LCT variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut Bifidobacterium, a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut Bifidobacterium and serum indolepropionate only among genetically lactase non-persistent individuals. CONCLUSION: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.

18.
J Am Heart Assoc ; 10(10): e017727, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33960201

RESUMO

Background Experimental and observational studies have suggested a link between vitamin D and cardiovascular and metabolic disease, but this has not been confirmed in randomized controlled trials. We sought to determine whether vitamin D supplementation reduces biomarkers of insulin resistance, inflammation, neurohormonal activation, and lipids. Methods and Results This was a prespecified, secondary analysis of the DAYLIGHT (Vitamin D Therapy in Individuals at High Risk of Hypertension) randomized controlled trial. We measured circulating homeostatic model assessment of insulin resistance, hs-CRP (high-sensitivity C-reactive protein), N-terminal pro-B-type natriuretic peptide, renin, aldosterone, and lipids at baseline and at 6 months in 289 individuals with low vitamin D status (25-hydroxyvitamin-D [25-OH-D] ≤25 ng/mL) receiving low-dose (400 IU/d) versus high-dose (4000 IU/d) vitamin D3 for 6 months. A meta-analysis of randomized controlled trials reporting biomarker changes after vitamin D supplementation was then performed. Levels of 25-OH-D increased in the high-dose relative to the low-dose vitamin D group (+15.5 versus +4.6 ng/mL, P<0.001). Changes in biomarkers of glycemia, inflammation, and neurohormonal activation did not differ by dose. Lipids did not differ between groups, other than triglycerides, which increased in the high-dose compared with the low-dose group (+11.3 versus -6.2 mg/dL, P<0.001). The meta-analysis showed potential modest decreases in homeostatic model assessment of insulin resistance and hs-CRP, but no changes in low-density lipoprotein, after vitamin D supplementation compared with control groups. Conclusions In the DAYLIGHT randomized controlled trial, high-dose vitamin D supplementation did not improve biomarkers of glycemia, inflammation, neurohormonal activation, or lipids. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01240512.


Assuntos
Glicemia/metabolismo , Doenças Cardiovasculares/terapia , Suplementos Nutricionais , Vitamina D/administração & dosagem , Adolescente , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Resistência à Insulina/fisiologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Vitaminas/administração & dosagem , Adulto Jovem
19.
J Am Coll Cardiol ; 77(18): 2291-2303, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33958126

RESUMO

BACKGROUND: Diurnal variation of natriuretic peptide (NP) levels and its relationship with 24-h blood pressure (BP) rhythm has not been established. Obese individuals have a relative NP deficiency and disturbed BP rhythmicity. OBJECTIVES: This clinical trial evaluated the diurnal rhythmicity of NPs (B-type natriuretic peptide [BNP], mid-regional pro-atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [NT-proBNP]) and the relationship of NP rhythm with 24-h BP rhythm in healthy lean and obese individuals. METHODS: On the background of a standardized diet, healthy, normotensive, lean (body mass index 18.5 to 25 kg/m2) and obese (body mass index 30 to 45 kg/m2) individuals, age 18 to 40 years, underwent 24-h inpatient protocol involving ambulatory BP monitoring starting 24 h prior to the visit, controlled light intensity, and repeated blood draws for assessment of analytes. Cosinor analysis of normalized NP levels (normalized to 24-h mean value) was conducted to assess the diurnal NP rhythm and its relationship with systolic BP. RESULTS: Among 52 participants screened, 40 participants (18 lean, 22 obese; 50% women; 65% Black) completed the study. The median range spread (percentage difference between the minimum and maximum values) over 24 h for MR-proANP, BNP, and NT-proBNP levels was 72.0% (interquartile range [IQR]: 50.9% to 119.6%), 75.5% (IQR: 50.7% to 106.8%), and 135.0% (IQR: 66.3% to 270.4%), respectively. A cosine wave-shaped 24-h oscillation of normalized NP levels (BNP, MR-proANP, and NT-proBNP) was noted both in lean and obese individuals (prhythmicity <0.05 for all). A larger phase difference between MR-proANP BP rhythm (-4.9 h vs. -0.7 h) and BNP BP rhythm (-3.3 h vs. -0.9 h) was seen in obese compared with lean individuals. CONCLUSIONS: This human physiological trial elucidates evidence of diurnal NP rhythmicity and the presence of an NP-BP rhythm axis. There exists a misalignment of the NP-BP diurnal rhythm in the obese, which may contribute to the disturbed diurnal BP pattern observed among obese individuals. (The Diurnal Rhythm in Natriuretic Peptide Levels; NCT03834168).


Assuntos
Pressão Sanguínea/fisiologia , Peptídeos Natriuréticos/sangue , Obesidade/sangue , Obesidade/fisiopatologia , Adolescente , Adulto , Fenômenos Cronobiológicos , Feminino , Humanos , Masculino , Adulto Jovem
20.
Circ Genom Precis Med ; 14(3): e003191, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34019435

RESUMO

BACKGROUND: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort. METHODS: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women). RESULTS: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; ß=0.04; P=2×10-8; hazard ratio, 1.48; P=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; ß=0.05; P=5×10-15). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups. CONCLUSIONS: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.


Assuntos
Afro-Americanos , Quimiocina CX3CL1/sangue , Ecocardiografia , Insuficiência Cardíaca , Hipertrofia Ventricular Esquerda , Adulto , Idoso , Biomarcadores/sangue , Cistatina C/sangue , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Incidência , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fatores Sexuais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...