Plasma metabolomic profiling in subclinical atherosclerosis: the Diabetes Heart Study

Chevli, Parag A; Freedman, Barry I.; Hsu, Fang‐Chi; Xu, Jianzhao; Rudock, Megan E.; Ma, Lijun; Parks, John S.; Palmer, Nicholette D.; Shapiro, Michael D.

doi:10.1186/s12933-021-01419-y

Cited by 29 publications

(16 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Chevli etc. [ 39 ] found fatty acid, androgenic steroids and other sub-pathways were associated with subclinical atherosclerosis in a family-based diabetes-enriched population and the associations vary in African and European Americans. Moreover, in studies on the general population, various chemical compounds of lysophosphatidylcholine have been frequently reported to be associated with atherosclerosis [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Serum metabolomic profiles associated with subclinical and clinical cardiovascular phenotypes in people with type 2 diabetes

Huang

Klarić

Krasauskaite

et al. 2022

Cardiovasc Diabetol

View full text Add to dashboard Cite

Background Atherosclerotic cardiovascular diseases (CVD) is the leading cause of death in diabetes, but the full range of biomarkers reflecting atherosclerotic burden and CVD risk in people with diabetes is unknown. Metabolomics may help identify novel biomarkers potentially involved in development of atherosclerosis. We investigated the serum metabolomic profile of subclinical atherosclerosis, measured using ankle brachial index (ABI), in people with type 2 diabetes, compared with the profile for symptomatic CVD in the same population. Methods The Edinburgh Type 2 Diabetes Study is a cohort of 1,066 individuals with type 2 diabetes. ABI was measured at baseline, years 4 and 10, with cardiovascular events assessed at baseline and during 10 years of follow-up. A panel of 228 metabolites was measured at baseline using nuclear magnetic resonance spectrometry, and their association with both ABI and prevalent CVD was explored using univariate regression models and least absolute shrinkage and selection operator (LASSO). Metabolites associated with baseline ABI were further explored for association with follow-up ABI and incident CVD. Results Mean (standard deviation, SD) ABI at baseline was 0.97 (0.18, N = 1025), and prevalence of CVD was 35.0%. During 10-year follow-up, mean (SD) change in ABI was + 0.006 (0.178, n = 436), and 257 CVD events occurred. Lactate, glycerol, creatinine and glycoprotein acetyls levels were associated with baseline ABI in both univariate regression [βs (95% confidence interval, CI) ranged from − 0.025 (− 0.036, − 0.015) to − 0.023 (− 0.034, − 0.013), all p < 0.0002] and LASSO analysis. The associations remained nominally significant after adjustment for major vascular risk factors. In prospective analyses, lactate was nominally associated with ABI measured at years 4 and 10 after adjustment for baseline ABI. The four ABI-associated metabolites were all positively associated with prevalent CVD [odds ratios (ORs) ranged from 1.29 (1.13, 1.47) to 1.49 (1.29, 1.74), all p < 0.0002], and they were also positively associated with incident CVD [ORs (95% CI) ranged from 1.19 (1.02, 1.39) to 1.35 (1.17, 1.56), all p < 0.05]. Conclusions Serum metabolites relating to glycolysis, fluid balance and inflammation were independently associated with both a marker of subclinical atherosclerosis and with symptomatic CVD in people with type 2 diabetes. Additional investigation is warranted to determine their roles as possible etiological and/or predictive biomarkers for atherosclerotic CVD.

show abstract

Section: Discussionmentioning

confidence: 99%

Serum metabolomic profiles associated with subclinical and clinical cardiovascular phenotypes in people with type 2 diabetes

Huang

Klarić

Krasauskaite

et al. 2022

Cardiovasc Diabetol

View full text Add to dashboard Cite

show abstract

“…It was consistent with recent studies that increased levels of 2-(dimethylamino) guanosine and β-pseudouridine levels were related to incident heart failure and LV remodeling [ 45 , 46 ]. Furthermore, 2-(dimethylamino) guanosine has been linked to increased risk of coronary artery calcium [ 47 ] and all-cause mortality in diabetes [ 48 ], and elevated circulating levels of β-pseudouridine were associated with atrial fibrillation [ 49 ], heart failure [ 50 ] and CAD [ 51 ]. Here we report for the first time that β-pseudouridine was also a metabolic marker for the risks of death and MACE in CAD.…”

Section: Discussionmentioning

confidence: 99%

Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease

et al. 2022

View full text Add to dashboard Cite

Background Coronary artery disease (CAD) is a metabolically perturbed pathological condition. However, the knowledge of metabolic signatures on outcomes of CAD and their potential causal effects and impacts on left ventricular remodeling remains limited. We aim to assess the contribution of plasma metabolites to the risk of death and major adverse cardiovascular events (MACE) as well as left ventricular remodeling. Results In a prospective study with 1606 Chinese patients with CAD, we have identified and validated several independent metabolic signatures through widely-targeted metabolomics. The predictive model respectively integrating four metabolic signatures (dulcitol, β-pseudouridine, 3,3ʹ,5-Triiodo-l-thyronine, and kynurenine) for death (AUC of 83.7% vs. 76.6%, positive IDI of 0.096) and metabolic signatures (kynurenine, lysoPC 20:2, 5-methyluridine, and l-tryptophan) for MACE (AUC of 67.4% vs. 59.8%, IDI of 0.068) yielded better predictive value than trimethylamine N-oxide plus clinical model, which were successfully applied to predict patients with high risks of death (P = 0.0014) and MACE (P = 0.0008) in the multicenter validation cohort. Mendelian randomisation analysis showed that 11 genetically inferred metabolic signatures were significantly associated with risks of death or MACE, such as 4-acetamidobutyric acid, phenylacetyl-l-glutamine, tryptophan metabolites (kynurenine, kynurenic acid), and modified nucleosides (β-pseudouridine, 2-(dimethylamino) guanosine). Mediation analyses show that the association of these metabolites with the outcomes could be partly explained by their roles in promoting left ventricular dysfunction. Conclusions This study provided new insights into the relationship between plasma metabolites and clinical outcomes and its intermediate pathological process left ventricular dysfunction in CAD. The predictive model integrating metabolites can help to improve the risk stratification for death and MACE in CAD. The metabolic signatures appear to increase death or MACE risks partly by promoting adverse left ventricular dysfunction, supporting potential therapeutic targets of CAD for further investigation. Graphical Abstract

show abstract

“…KEGG analysis revealed that six DEPs were enriched in the BCAA degradation pathway. Growing evidence suggests that BCAA degradation abnormalities and BCAA accumulation are important pathogenic mediators in the development of cardiovascular and metabolic diseases, including arteriosclerosis, coronary heart disease, hypertension, dilated cardiomyopathy, heart failure, and diabetes [ 26 – 30 ]. However, there have been no studies on SGLT2i and BCAA metabolism in the cardiovascular field.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin ameliorates diabetic cardiomyopathy via regulated branched-chain amino acid metabolism and mTOR/p-ULK1 signaling pathway-mediated autophagy

Lin

Zhang

Xie

et al. 2023

Diabetol Metab Syndr

View full text Add to dashboard Cite

Background Empagliflozin, a sodium–glucose co-transporter 2 inhibitor (SGLT2i), has been reported to significantly reduce the risk of heart failure in multiple clinical studies. However, the underlying mechanisms remain elusive. This study aimed to investigate the effect of empagliflozin on branched-chain amino acid (BCAA) metabolism in diabetic cardiomyopathy. Methods Thirty male 8-week KK Cg-Ay/J mice were used to study diabetic cardiomyopathy; here, 15 were used as the model group, and the remaining 15 were administered empagliflozin (3.75 mg/kg/day) by gavage daily for 16 weeks. The control group consisted of fifteen male 8-week C57BL/6J mice, whose blood glucose and body weight were measured simultaneously with the diabetic mice until 16 weeks without additional intervention. Echocardiography and histopathology were performed to evaluate cardiac structure and function. Proteomic sequencing and biogenic analysis were performed on mouse hearts. Parallel Reaction Monitoring and western blotting were performed to validate the expression levels of differentially expressed proteins. Results The results showed that empagliflozin improved ventricular dilatation and ejection fraction reduction in diabetic hearts, as well as the elevation of myocardial injury biomarkers hs-cTnT and NT-proBNP. At the same time, empagliflozin alleviates myocardial inflammatory infiltration, calcification foci deposition, and fibrosis caused by diabetes. The results of the proteomics assay showed that empagliflozin could improve the metabolism of various substances, especially promoting the BCAA metabolism of diabetic hearts by up-regulating PP2Cm. Furthermore, empagliflozin could affect the mTOR/p-ULK1 signaling pathway by reducing the concentration of BCAA in diabetic hearts. When mTOR/p-ULK1 protein was inhibited, ULK1, the autophagy initiation molecule, increased. Moreover, autophagy substrate p62 and autophagy marker LC3B were significantly reduced, indicating that the autophagy activity of diabetes inhibition was reactivated. Conclusions Empagliflozin may attenuate diabetic cardiomyopathy-related myocardial injury by promoting the catabolism of BCAA and inhibiting mTOR/p-ULK1 to enhance autophagy. These findings suggest that empagliflozin could be a potential candidate drug against BCAA increase and could be used for other cardiovascular diseases with a metabolic disorder of BCAA.

show abstract

Plasma metabolomic profiling in subclinical atherosclerosis: the Diabetes Heart Study

Cited by 29 publications

References 74 publications

Serum metabolomic profiles associated with subclinical and clinical cardiovascular phenotypes in people with type 2 diabetes

Serum metabolomic profiles associated with subclinical and clinical cardiovascular phenotypes in people with type 2 diabetes

Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease

Empagliflozin ameliorates diabetic cardiomyopathy via regulated branched-chain amino acid metabolism and mTOR/p-ULK1 signaling pathway-mediated autophagy

Contact Info

Product

Resources

About