Plasma metabolites mediate the effect of HbA1c on incident cardiovascular disease.
Ontology highlight
ABSTRACT: Background
We aim to discover whether HbA1c affects incident cardiovascular disease (CVD) through regulating endogenous metabolites.Methods and results
Totally, 2019 plasma samples were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Logistic regression and linear regression were used to screen metabolites which were associated with both CVD and HbA1c. The VanderWeele's mediation approach was performed to assess the direct effect and indirect effect (IE) in the counterfactual model. Forty-eight metabolites showed an association with both HbA1c and CVD risk. Forty-four of the 48 metabolites worked as mediators mediated in HbA1c's effect on CVD (odds ratio [OR]IE from 0.997 to 6.098, false discovery rate q < 0.05, mediated proportion from 0.4% to 85.4%). Pathway enrichment analysis indicated that different metabolic pathway showed significant IE (butanoate metabolism ORIE = 1.058, mediated proportion = 16.0%; alanine, aspartate and glutamate metabolism ORIE = 1.082, mediated proportion = 21.8%; TCA (citric acid) cycle metabolism ORIE = 1.048, mediated proportion = 13.8%; phenylalanine metabolism ORIE = 1.067, mediated proportion = 18.4%; glycerophospholipid metabolism ORIE = 3.007, mediated proportion = 82.2%; all the P ConclusionsOur findings suggest that metabolites mediate the effect of HbA1c on incident CVD and provide a new study sight into pathogenesis of CVD.
SUBMITTER: Dong X
PROVIDER: S-EPMC6788485 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Plasma metabolites mediate the effect of HbA1c on incident cardiovascular disease.
Dong Xuesi X Zhou Wei W Li Hu H Fan Yuanming Y Yin Xiaojian X Li Yong Y Chen Feng F Ma Gaoxiang G
Clinical cardiology 20190730 10
<h4>Background</h4>We aim to discover whether HbA1c affects incident cardiovascular disease (CVD) through regulating endogenous metabolites.<h4>Methods and results</h4>Totally, 2019 plasma samples were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Logistic regression and linear regression were used to screen metabolites which were associated with both CVD and HbA1c. The VanderWeele's mediation approach was performed to assess the direct effect and indirect effect ...[more]
Similar Datasets
Project description:Cadmium is a widespread toxic metal with potential cardiovascular effects, but no studies have evaluated cadmium and incident cardiovascular disease. We evaluated the association of urine cadmium concentration with cardiovascular disease incidence and mortality in a large population-based cohort.We conducted a prospective cohort study of 3348 American Indian adults 45-74 years of age from Arizona, Oklahoma, and North and South Dakota, who participated in the Strong Heart Study in 1989-1991. Urine cadmium was measured using inductively coupled plasma mass spectrometry. Follow-up extended through 31 December 2008.The geometric mean cadmium level in the study population was 0.94 ?g/g (95% confidence interval [CI] = 0.92-0.96). We identified 1084 cardiovascular events, including 400 deaths. After adjustment for sociodemographic and cardiovascular risk factors, the hazard ratios (HRs) (comparing the 80th to the 20th percentile of urine cadmium concentrations) was 1.43 for cardiovascular mortality (95% CI = 1.21-1.70) and 1.34 for coronary heart disease mortality (1.10-1.63). The corresponding HRs for incident cardiovascular disease, coronary heart disease, stroke, and heart failure were 1.24 (1.11-1.38), 1.22 (1.08-1.38), 1.75 (1.17-2.59), and 1.39 (1.01-1.94), respectively. The associations were similar in most study subgroups, including never-smokers.Urine cadmium, a biomarker of long-term exposure, was associated with increased cardiovascular mortality and increased incidence of cardiovascular disease. These findings support that cadmium exposure is a cardiovascular risk factor.
| S-EPMC4142588 | biostudies-other
Project description:BackgroundThe role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect.MethodsWe developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death.ResultsAfter adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05-2.76) and 2.09 (1.27-3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed.ConclusionsHigher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.
| S-EPMC4896732 | biostudies-literature
Project description:ImportanceAlthough rodent studies suggest that trimethylamine N-oxide (TMAO) influences glucose homeostasis and risk of type 2 diabetes, evidence in humans is limited.ObjectiveTo examine the associations of serial measures of plasma TMAO and related metabolite concentrations with incident type 2 diabetes, fasting plasma insulin and glucose levels, and the Gutt insulin sensitivity index (ISI).Design, setting, and participantsThis prospective cohort design assessed the association of plasma TMAO and related metabolite concentrations with diabetes outcome, whereas a cross-sectional design assessed the association with insulin and glucose levels and Gutt ISI. The participants were a cohort of older US adults from the Cardiovascular Health Study (CHS). Data from June 1989 to May 1990, from November 1992 to June 1993, and from June 1995 to June 1997 were included, with follow-up through June 2010. Levels of TMAO and related metabolites were measured in CHS plasma samples. Data were analyzed from July 2019 to September 2020.ExposuresPlasma concentrations of TMAO, carnitine, betaine, choline, crotonobetaine, and γ-butyrobetaine, measured by high-performance liquid chromatography and mass spectrometry.Main outcomes and measuresLinear regression for associations of TMAO and related metabolites with insulin and glucose levels and Gutt ISI, and proportional hazards regression for associations with diabetes.ResultsThe study included 4442 participants without diabetes at baseline (mean [SD] age, 73 [6] years at entry; 2710 [61%] women). In multivariable analyses, plasma TMAO, carnitine, crotonobetaine, and γ-butyrobetaine concentrations were positively associated with fasting insulin level (insulin mean geometric ratio comparing fifth with first quintiles of metabolite concentration: 1.07 [95% CI, 1.04-1.10] for TMAO; 1.07 [95% CI, 1.03-1.10] for carnitine; 1.05 [95% CI, 1.02-1.08] for crotonobetaine; and 1.06 [95% CI, 1.02-1.09] for γ-butyrobetaine). In contrast, betaine and choline concentrations were associated with greater insulin sensitivity (mean difference in Gutt ISI comparing fifth with first quintiles: 6.46 [95% CI, 4.32-8.60] and 2.27 [95% CI, 0.16-4.38], respectively). Incident diabetes was identified in 661 participants during a median 12.1 (interquartile range, 6.9-17.1) years of follow-up. In multivariable analyses, TMAO and metabolites were not significantly associated with type 2 diabetes risk (hazard ratios of diabetes comparing fifth with first quintile: 1.20 [95% CI, 0.94-1.55] for TMAO; 0.96 [95% CI, 0.74-1.24] for choline; 0.88 [95% CI, 0.67-1.15] for betaine; 1.07 [95% CI, 0.83-1.37] for carnitine; 0.79 [95% CI, 0.60-1.04] for γ-butyrobetaine; and 1.06 [95% CI, 0.83-1.35] for crotonobetaine).Conclusions and relevancePlasma TMAO and related metabolites were not significantly associated with type 2 diabetes among older adults. The metabolites TMAO, carnitine, γ-butyrobetaine, and crotonobetaine may be associated with insulin resistance, and betaine and choline may be associated with greater insulin sensitivity, but temporality of the associations was not established.
| S-EPMC8397925 | biostudies-literature
Project description:BACKGROUND:Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. METHODS:The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ?7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. RESULTS:The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49-3.83, Ptrend<0.001), 1.91 (1.21-3.01, Ptrend=0.003), 1.97 (1.21-3.20, Ptrend=0.004), and 1.73 (1.09-2.74, Ptrend=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36-3.49; Ptrend<0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (Pinteraction=0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. CONCLUSIONS:Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. CLINICAL TRIAL REGISTRATION:URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639.
| S-EPMC5496817 | biostudies-literature
Project description:Background and objectivesThe matricellular protein osteopontin is involved in the pathogenesis of both kidney and cardiovascular disease. However, whether circulating and urinary osteopontin levels are associated with the risk of these diseases is less studied.Design setting participants and measurementsA community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men [ULSAM]; n = 741; mean age: 77 years) was used to study the associations between plasma and urinary osteopontin, incident chronic kidney disease, and the risk of cardiovascular death during a median of 8 years of follow-up.ResultsThere was no significant cross-sectional correlation between plasma and urinary osteopontin (Spearman ρ = 0.07, p = 0.13). Higher urinary osteopontin, but not plasma osteopontin, was associated with incident chronic kidney disease in multivariable models adjusted for age, cardiovascular risk factors, baseline glomerular filtration rate, urinary albumin/creatinine ratio, and the inflammatory markers interleukin 6 and high-sensitivity C-reactive protein (odds ratio for 1 standard deviation [SD] of urinary osteopontin, 1.42, 95% CI 1.00-2.02, p = 0.048). Conversely, plasma osteopontin, but not urinary osteopontin, was independently associated with cardiovascular death (multivariable hazard ratio per SD increase, 1.35, 95% CI 1.14-1.58, p < 0.001, and 1.00, 95% CI 0.79-1.26, p = 0.99, respectively). The addition of plasma osteopontin to a model with established cardiovascular risk factors significantly increased the C-statistics for the prediction of cardiovascular death (p < 0.002).ConclusionsHigher urinary osteopontin specifically predicts incident chronic kidney disease, while plasma osteopontin specifically predicts cardiovascular death. Our data put forward osteopontin as an important factor in the detrimental interplay between the kidney and the cardiovascular system. The clinical implications, and why plasma and urinary osteopontin mirror different pathologies, remain to be established.
| S-EPMC5511996 | biostudies-literature
Project description:ObjectiveTo compare incidences and risk factors for diabetes using seven definitions, with combinations of pharmacological treatment, fasting plasma glucose (FPG) ?7.0 mmol/L, and HbA(1c) ?6.5%.Research design and methodsParticipants aged 30-65 years from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort were followed for 9 years.ResultsMore men had incident diabetes as defined by FPG ?7.0 mmol/L and/or treatment than by HbA(1c) ?6.5% and/or treatment: 7.5% (140/1,867) and 5.3% (99/1,874), respectively (P < 0.009); for women incidences were similar: 3.2% (63/1,958) and 3.4% (66/1,954). Known risk factors predicted diabetes for almost all definitions. Among those with incident diabetes by FPG alone versus HbA(1c) alone, there were more men (78 vs. 35%), case patients were 8 years younger, and fewer were alcohol abstainers (12 vs. 35%) (all P < 0.005). A diabetes risk score discriminated well between those with and without incident diabetes for all definitions.ConclusionsIn men, FPG definitions yielded more incident cases of diabetes than HbA(1c) definitions, in contrast with women. An FPG-derived risk score remained relevant for HbA(1c)-defined diabetes.
| S-EPMC3064057 | biostudies-literature
Project description:ImportanceThe American Heart Association 2020 Strategic Impact Goals target an improvement in overall cardiovascular health, as assessed by 7 health metrics (smoking, body weight, physical activity, diet, plasma glucose level, plasma cholesterol level, and blood pressure).ObjectiveTo examine whether trajectories of overall cardiovascular health over time, as assessed by the cardiovascular health score (CHS) in 2006, 2008, and 2010, are associated with subsequent risk of CVD.Design, setting, and participantsThe Kailuan study is a prospective, population-based study that began in 2006. The cohort included 74 701 Chinese adults free of myocardial infarction, stroke, and cancer in or before 2010. In the present study, CHS trajectories were developed from 2006 to 2010 to predict CVD risk from 2010 to 2015. Data analysis was performed from January 1, 2006, to December 31, 2015.ExposuresThe CHS trajectories during 2006-2010 were identified using latent mixture models.Main outcomes and measuresIncident CVD events (myocardial infarction and stroke) during 2010-2015 were confirmed by review of medical records. The CHS trajectories were determined using 7 cardiovascular health metrics scored as poor (0 points), intermediate (1 point), and ideal (2 points); total score ranges from 0 (worst) to 14 (best). Based on the baseline CHS and patterns over time, 5 trajectories were categorized (low-stable, moderate-increasing, moderate-decreasing, high-stable I, and high-stable II).ResultsOf the 74 701 adults included in the study (mean [SD] age at baseline, 49.6 [11.8] years), 58 216 (77.9%) were men and 16 485 (22.1%) were women. Five CHS trajectories were identified from 2006 to 2010: low-stable (n = 4393; range, 4.6-5.2), moderate-increasing (n = 4643; mean increase from 5.4 to 7.8), moderate-decreasing (n = 14 853; mean decrease from 7.4 to 6.3), high-stable I (n = 36 352; range, 8.8-9.0), and high-stable II (n = 14 461; range, 10.9-11.0). During 5 years of follow-up, 1852 incident CVD cases were identified. Relative to the low-stable trajectory, the high-stable II trajectory was associated with a lower subsequent risk of CVD (adjusted hazard ratio, 0.21; 95% CI, 0.16-0.26, after adjusting for age, sex, educational level, income, occupation, alcohol intake, and serum high-sensitivity C-reactive protein concentration at baseline).Conclusions and relevanceCardiovascular health trajectories may be associated with subsequent CVD risk.
| S-EPMC6547110 | biostudies-literature
Project description:The aim of this study was to investigate whether the association between baseline cardiovascular health (CVH) and incident cardiovascular disease differs according to coronary heart disease (CHD) and stroke subtypes, and to assess the mediating effect of inflammatory and hemostatic blood biomarkers. The association of ideal CVH with outcomes was derived in 9312 middle-aged men from Northern Ireland and France (whole cohort) in multivariable Cox proportional hazards regression analysis. The mediating effect of baseline inflammatory and hemostatic blood biomarkers was evaluated in a case-control study nested within the cohort after 10 years of follow-up. After a median follow-up of 10 years, 614 first CHD events and 117 first stroke events were adjudicated. Compared with those with poor CVH, those with an ideal CVH profile at baseline had a 72% lower risk of CHD (hazard ratio=0.28; 95% confidence interval, 0.17; 0.46) and a 76% lower risk of stroke (hazard ratio =0.24; 95% confidence interval, 0.06; 0.98). The magnitude of the risk reductions was similar for incident angina and myocardial infarction, but was lower for ischemic stroke. In the controls, the mean concentrations of high-sensitivity C-reactive protein, IL-6, and fibrinogen decreased with higher CVH status. Furthermore, the association of behavioral CVH with incident CHD was partly mediated by high-sensitivity C-reactive protein (16.69%), IL-6 (8.52%), and fibrinogen (7.30%) CONCLUSIONS: Our study shows no clear heterogeneity in the association of baseline CVH with the main subtypes of cardiovascular disease. This supports a universal promotion of ideal CVH for all cardiovascular disease subtypes. Furthermore, our mediation analysis suggests that the lower risk of CHD associated with ideal CVH is partly mediated by lower inflammatory and hemostatic blood biomarkers.
| S-EPMC5721848 | biostudies-literature
Project description:Background and objectivesModerate coffee consumption has been associated with lower risk of CKD; however, the exact biologic mechanisms underlying this association are unknown. Metabolomic profiling may identify metabolic pathways that explain the association between coffee and CKD. The goal of this study was to identify serum metabolites associated with coffee consumption and examine the association between these coffee-associated metabolites and incident CKD.Design, setting, participants, & measurementsUsing multivariable linear regression, we identified coffee-associated metabolites among 372 serum metabolites available in two subsamples of the Atherosclerosis Risk in Communities study (ARIC; n=3811). Fixed effects meta-analysis was used to pool the results from the two ARIC study subsamples. Associations between coffee and metabolites were replicated in the Bogalusa Heart Study (n=1043). Metabolites with significant associations with coffee in both cohorts were then evaluated for their prospective associations with incident CKD in the ARIC study using Cox proportional hazards regression.ResultsIn the ARIC study, mean (SD) age was 54 (6) years, 56% were daily coffee drinkers, and 32% drank >2 cups per day. In the Bogalusa Heart Study, mean (SD) age was 48 (5) years, 57% were daily coffee drinkers, and 38% drank >2 cups per day. In a meta-analysis of two subsamples of the ARIC study, 41 metabolites were associated with coffee consumption, of which 20 metabolites replicated in the Bogalusa Heart Study. Three of these 20 coffee-associated metabolites were associated with incident CKD in the ARIC study.ConclusionsWe detected 20 unique serum metabolites associated with coffee consumption in both the ARIC study and the Bogalusa Heart Study, and three of these 20 candidate biomarkers of coffee consumption were associated with incident CKD. One metabolite (glycochenodeoxycholate), a lipid involved in primary bile acid metabolism, may contribute to the favorable kidney health outcomes associated with coffee consumption. Two metabolites (O-methylcatechol sulfate and 3-methyl catechol sulfate), both of which are xenobiotics involved in benzoate metabolism, may represent potential harmful aspects of coffee on kidney health.
| S-EPMC8729408 | biostudies-literature
Project description:The marked excess in cardiovascular mortality that results from uremia remains poorly understood.In 2 independent, nested case-control studies, we applied liquid chromatography-mass spectrometry-based metabolite profiling to plasma obtained from participants of a large cohort of incident hemodialysis patients. First, 100 individuals who died of a cardiovascular cause within 1 year of initiating hemodialysis (cases) were randomly selected along with 100 individuals who survived for at least 1 year (controls), matched for age, sex, and race. Four highly intercorrelated long-chain acylcarnitines achieved the significance threshold adjusted for multiple testing (P<0.0003). Oleoylcarnitine, the long-chain acylcarnitine with the strongest association with cardiovascular mortality in unadjusted analysis, remained associated with 1-year cardiovascular death after multivariable adjustment (odds ratio per SD 2.3 [95% confidence interval, 1.4 to 3.8]; P=0.001). The association between oleoylcarnitine and 1-year cardiovascular death was then replicated in an independent sample (n=300, odds ratio per SD 1.4 [95% confidence interval, 1.1 to 1.9]; P=0.008). Addition of oleoylcarnitine to clinical variables improved cardiovascular risk prediction using net reclassification (NRI, 0.38 [95% confidence interval, 0.20 to 0.56]; P<0.0001). In physiologic profiling studies, we demonstrate that the fold change in plasma acylcarnitine levels from the aorta to renal vein and from pre- to posthemodialysis samples exclude renal or dialytic clearance of long-chain acylcarnitines as confounders in our analysis.Our data highlight clinically meaningful alterations in acylcarnitine homeostasis at the time of dialysis initiation, which may represent an early marker, effector, or both of uremic cardiovascular risk.
| S-EPMC3886735 | biostudies-literature