GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction

Skau, Emma; Henriksen, Egil; Wagner, Philippe; Hedberg, Pär; Siegbahn, Agneta; Leppert, Jerzy

doi:10.1177/2047487317725017

Cited by 71 publications

(70 citation statements)

References 33 publications

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“…Raised circulating TRAIL-R2 levels have been linked with cerebral atherosclerosis [36] and increased mortality in acute myocardial infarction [37]. Possible mechanisms linking the TRAIL/TRAIL-R2 pathway to atherosclerotic disease involve the endothelial response to cholesterol deposits [37, 38] and the composition of circulating fatty acids, as a study in an Alaskan Inuit population found an association between plasma fatty acid levels and genetic variants of the TRAIL-R2 gene TNFRSF10B [39]. …”

Section: Discussionmentioning

confidence: 99%

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

et al. 2018

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Aims/hypothesisMultiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes.MethodsWe combined data from six prospective epidemiological studies of 30–77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample.ResultsOf 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (±SD) of 6.4 ± 2.3 years. We replicated associations (<5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit α (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample.Conclusions/interpretationWe identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4641-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionmentioning

confidence: 99%

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

et al. 2018

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“…The TRAILR2 protein (otherwise known as death receptor 5) is encoded by the TNFSF10 gene and is a receptor belonging to the TNF superfamily that preferentially induces apoptosis after binding of its ligand TRAIL 29,30 . Increased levels of TRAILR2 have been associated with adverse cardiovascular events in patients with myocardial infarction, probably due to intensified apoptotic activity 31 . Interleukins, as "upstream" biomarkers of inflammation converge on the central TNF signalling pathway, having major influence on atherosclerosis, and consequently on the risk of cardiovascular disease 32 .…”

Section: Inflammation and Apoptosis Clustermentioning

confidence: 99%

Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

Ferreira

Verdonschot

Collier

et al. 2019

Circ: Heart Failure

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Background: Identifying the mechanistic pathways potentially associated with incident HF may provide a basis for novel preventive strategies. Methods and Results:To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as first hospitalization for HF, a nestedmatched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20,000 individuals). Controls were matched on cohort, follow-up time, age, and sex.Two independent sample sets (a "discovery" set, with 286 cases and 591 controls and a "replication" set with 276 cases and 280 controls) were used to discover and replicate the findings. 252 circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase.These 38 proteins pointed to 4 main network clusters underlying incident HF: 1) inflammation and apoptosis, indicated by the expression of the TNF-family members; 2) extracellular matrix remodelling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function and vascular homeostasis; 3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin angiotensin aldosterone system; and 4) metabolism, associated with cholesterol and atherosclerosis.Conclusion: Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodelling, blood pressure control and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF.

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“…The results from previous studies have shown that increased circulating GDF15 levels were closely associated with the development and progression of various cardiovascular diseases (including myocardial ischaemia/reperfusion, heart failure, atherosclerosis, and acute coronary syndrome), and were shown to be a strong and independent predictor of mortality and disease progression in patients with atherosclerosis and coronary artery disease [5][6][7][8][9][10][31][32][33][34][35][36]. In diabetic patients, higher levels of lipids and chronic inflammation may directly damage the cardiovascular system [37].…”

Section: Discussionmentioning

confidence: 99%

“…However, the expression and secretion of GDF15 can be strongly induced in the case of cardiovascular injury, such as pressure overload, myocardial infarction, heart failure, and atherosclerosis [4]. In recent years, a series of clinical studies [5][6][7][8][9][10] have reported that high circulating GDF15 levels are an independent predictive factor for several cardiovascular diseases in patients with atherosclerosis and acute coronary syndrome, and that investigating the levels of GDF15 could improve risk prediction beyond traditional risk factors and biochemical indicators.…”

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confidence: 99%

The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes

et al. 2020

Cardiovasc Diabetol

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Background: Clinical and basic investigations have indicated a significant association between circulating growth differentiation factor 15 (GDF15) and cardiovascular disease; however, the relationship between GDF15 and lower extremity atherosclerotic disease (LEAD) has been less studied. The present study aimed to explore the association between GDF15 and LEAD in Chinese patients with type 2 diabetes mellitus (T2DM). Considering that obesity is an important factor associated with circulating GDF15 levels, whether the relationship between serum GDF15 levels and LEAD is affected by body mass index (BMI) was also analysed.Methods: A total of 376 hospitalized T2DM patients were enrolled (161 with LEAD and 215 without LEAD). A sandwich enzyme-linked immunosorbent assay was used to detect the serum GDF15 levels. The femoral intima-media thickness (F-IMT) and LEAD were assessed by ultrasonography.Results: Patients with LEAD had significantly higher serum GDF15 levels than those without LEAD, regardless of whether their BMI was < 25 kg/m 2 or ≥ 25 kg/m 2 (both P < 0.05). Serum GDF15 levels were independently positively related to the F-IMT (standardized β = 0.162, P = 0.002). After adjusting for confounding factors, per 1-standard deviation (SD) increase in the serum GDF15 levels was significantly related to an approximately 1.4-fold increased risk of LEAD in the total population (P < 0.05). Regardless of whether the BMI was < 25 kg/m 2 or ≥ 25 kg/m 2 , this association remained significant, with approximately 1.6-and 1.4-fold increased risks of LEAD, respectively (both P < 0.05). Conclusions: High serum GDF15 levels were significantly correlated with an increased risk of LEAD in T2DM patients, and this relationship was independent of BMI.

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GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction

Cited by 71 publications

References 33 publications

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes

Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

The association between serum growth differentiation factor 15 levels and lower extremity atherosclerotic disease is independent of body mass index in type 2 diabetes

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