Identifying Novel Biomarkers for Cardiovascular Events or Death in People With Dysglycemia

Gerstein, Hertzel C.; Paré, Guillaume; McQueen, Matthew; Haenel, Heinz; Lee, Shun Fu; Pogue, Janice; Maggioni, Aldo P.; Yusuf, Salim; Hess, Sibylle

doi:10.1161/circulationaha.115.015744

Cited by 66 publications

(65 citation statements)

References 31 publications

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“…The overall adjusted risk ratio for the top third compared with the bottom third of NT‐proBNP found in that study was 1.94 (95% CI 1.57–2.39) and is of comparable magnitude to our results. Increments in c‐statistics after adding NT‐proBNP to conventional risk scores ranged from 0.01 to 0.10 in a variety of populations including patients with elevated CVE risk factors and stable cardiovascular disease at baseline, also in line with the present findings 9, 24. Further, the addition of NT‐proBNP resulted in an NRI of 0.198 in a large general population study, whereas the NRI increased to 0.386 in a sample of diabetic patients from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial 25, 26.…”

Section: Discussionsupporting

confidence: 88%

Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus

Leeuw

Beulens

Dieren

et al. 2016

JAHA

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BackgroundWe evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors.Methods and ResultsWe used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition‐NL (EPIC‐NL). The associations of 23 biomarkers (adiponectin, C‐reactive protein, epidermal‐type fatty acid binding protein, heart‐type fatty acid binding protein, basic fibroblast growth factor, soluble FMS‐like tyrosine kinase‐1, soluble intercellular adhesion molecule‐1 and ‐3, matrix metalloproteinase [MMP]‐1, MMP‐3, MMP‐9, N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E‐selectin, P‐selectin, tissue inhibitor of MMP‐1, thrombomodulin, soluble vascular cell adhesion molecule‐1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c‐statistic and net reclassification index (NRI; continuous and based on 10‐year risk strata 0–10%, 10–20%, 20–30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, and MMP‐3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c‐statistic with 0.03 (95% CI 0.01–0.05), and the continuous NRI was 0.37 (95% CI 0.21–0.52). In EPIC‐NL, the multimarker model increased the c‐statistic with 0.03 (95% CI 0.00–0.03), and the continuous NRI was 0.44 (95% CI 0.23–0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03–0.21) in SMART and 0.07 (95% CI −0.04–0.17) in EPIC‐NL.ConclusionsOf the 23 evaluated biomarkers from different pathophysiological pathways, N‐terminal prohormone of B‐type natriuretic peptide, osteopontin, MMP‐3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited.

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Section: Discussionsupporting

confidence: 88%

Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus

Leeuw

Beulens

Dieren

et al. 2016

JAHA

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“…113 Conversely, hepatocyte growth factor receptor, glutathione S transferase α, and chromogranin A were inversely associated with adverse cardiovascular events.…”

Section: High-risk Groups Within the General Populationmentioning

confidence: 99%

Novel Risk Markers and Risk Assessments for Cardiovascular Disease

Thomas

Lip

2017

Circulation Research

117

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Abstract:The use of risk markers has transformed cardiovascular medicine, exemplified by the routine assessment of troponin, for both diagnosis and assessment of prognosis in patients with chest pain. Clinical risk factors form the basis for risk assessment of cardiovascular disease and the addition of biochemical, cellular, and imaging parameters offers further refinement. Identifying novel risk factors may allow greater risk stratification and a steady, but gradual progression toward precision medicine. Indeed, the generation of data in this area of research is explosive and when combined with new technologies and techniques provides the potential for more refined, targeted approaches to cardiovascular medicine. Although discussing the most recent developments in this field, this review article aims to strike a balance between novelty and validity by focusing on recent large samplesize studies that have been validated in a separate cohort in most cases. Risk markers related to atherosclerosis, thrombosis, inflammation, cardiac injury, and fibrosis are introduced in the context of their pathophysiology. Rapidly developing new areas, such as assessment of micro-RNA, are also explored. Subsequently the prognostic ability of these risk markers in coronary artery disease, heart failure, and atrial fibrillation is discussed in detail. ( addition to these roles in the pathogenesis of coronary artery disease, lipid-related molecules have been identified to be markers of inflammation and oxidative stress (Table 1). Thrombosis-Related Risk MarkersAfter atherosclerotic plaque rupture, platelets adhere to exposed subendothelial components, such as collagen and von Willebrand factor, which promotes platelet activation and aggregation. 10 In addition, platelet activation is potentiated by exposure to released soluble agonists, such as thrombin and ADP.10 Activated platelets then further release ADP, which acts on platelet P2Y 12 ADP receptors and has a central role in amplifying the response of platelets to the initial stimulus. 10 Platelet reactivity to various agonists, including ADP, has been studied extensively in the context of acute coronary syndrome (ACS; Table 2). 11 The VerifyNow and Multiplate pointof-care tests allow for the measurement of platelet aggregation in response to stimulation, and it has been shown that high platelet reactivity is associated with adverse cardiovascular events. 26 Platelet microparticles are released on platelet activation, and their role in cardiovascular disease is an area of active investigation (Table 2). 15 Circulating microparticles are released from cells undergoing activation or apoptosis and are a type of small plasma membrane vesicle that retain defined properties from their original cell lineage. 15 Platelet activation and aggregation lead to the activation of the coagulation cascade and the formation of a stable crosslinked fibrin clot. The balance between prothrombotic factors and endogenous fibrinolysis determines whether the thrombus propagates or instead proceeds to dis...

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“…In this issue of Circulation, Gerstein et al, 2 representing the Outcome Reduction With an Initial Glargine Intervention (ORIGIN) Trial investigators, used a commercially available Luminex multiplex immunoassay platform to screen hundreds of distinct biomarkers for their ability to predict CVD events. Although the marker selection process was described as an unbiased approach, each of the biomarkers tested was a known protein preselected by either the company or the investigators on the basis of some a priori rationale for inclusion in the test panel, a strategy that may increase the yield of discovery while limiting the full scope of what can be discovered.…”

Section: Article See P 2297mentioning

confidence: 99%