Use of Multiple Biomarkers to Improve the Prediction of Death from Cardiovascular Causes

Zethelius, Björn; Berglund, Lars; Sundström, Johan; Ingelsson, Erik; Basu, Samar; Larsson, Anders; Venge, Per; Ärnlöv, Johan

doi:10.1056/nejmoa0707064

Cited by 769 publications

(403 citation statements)

References 29 publications

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“…As the CPC/EPC enumeration is usually by guest on May 11, 2018 http://circres.ahajournals.org/ performed on fresh samples, to yield a sufficient statistical power in the analysis of event-free survival with relatively small sample size and short follow-up, high-risk patients need to be enrolled. Because biomarkers perform better in high-risk than in low-risk populations, 3,49 whether the levels of CPCs/EPCs provide prognostic information also in the general population remains unclear. Some observations suggest that the prognostic power of CPCs/EPCs is proportional to the baseline cardiovascular risk.…”

Section: Discussionmentioning

confidence: 99%

Levels of Circulating Progenitor Cells, Cardiovascular Outcomes and Death

Rigato

Avogaro

Fadini

2016

Circulation Research

113

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Methods and Results:We screened the English-language literature for longitudinal studies reporting the association between baseline CPC/EPC levels, future cardiovascular events, and death. We retrieved 28 studies, 21 of which contained poolable data and entered the meta-analysis, for a total of 4155 patients, mostly with a high baseline cardiovascular risk. Sixty percent of the studies met at least 11 of 16 items of quality assessment. Overall, reduced CPC/EPC levels were associated with a ≈2-fold increased risk of future cardiovascular events and cardiovascular death. The most predictive phenotype was CD34 + CD133 + : low versus high levels predicted cardiovascular events, restenosis after endovascular intervention, cardiovascular death, and all-cause mortality. Heterogeneity among studies and according to the CPC/EPC phenotype was generally high. Excluding studies for which the risk estimate had to be extrapolated or limiting the analyses to higher quality studies still indicated a significant risk for future cardiovascular events and death in patients with low versus high progenitor cell counts. Conclusions: This meta-analysis shows that a reduction in the levels

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Section: Discussionmentioning

confidence: 99%

Levels of Circulating Progenitor Cells, Cardiovascular Outcomes and Death

Rigato

Avogaro

Fadini

2016

Circulation Research

113

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“…Clinically, NT-pro-BNP is used as markers for heart failure, 2 but those proteins have also been identified as risk factors for all-cause mortality, 18 cardiovascular mortality, 19 myocardial infarction, 20 and atrial fibrillation. 21 However, data on BNP and NT-pro-BNP about risk of stroke in the community are sparse.…”

Section: N-terminal Pro-b-type Natriuretic Peptidementioning

confidence: 99%

Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip

Lind

Siegbahn

Lindahl

et al. 2015

Stroke

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Eligible subjects were 70 years of age and living in the city of Uppsala, Sweden. Subjects were chosen at random from the Total Background and Purpose-Emerging technologies have made it possible to simultaneously evaluate a large number of circulating proteins as potential new stroke risk markers. Methods-We explored associations between 85 cardiovascular proteins, assessed by a proteomics chip, and incident ischemic stroke in 2 independent cohorts of elderly (Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS]: n=977; 50% women, mean age=70.1 years, 71 fatal/nonfatal ischemic stroke events during 10.0 years; and Uppsala Longitudinal Study in Adult Men [ULSAM]: n=720, mean age=77.5 years, 75 ischemic stroke events during 9.5 years). The proteomics chip uses 2 antibodies for each protein and a polymerase chain reaction step to achieve a highspecific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations. Results-In PIVUS, 16 proteins were related to incident ischemic stroke using a false discovery rate of 5%. Of these, N-terminal pro-B-type natriuretic peptide (P=0.0032), adrenomedullin (P=0.018), and eosinophil cationic protein (P=0.0071) were replicated in ULSAM after adjustment for established stroke risk factors. In predefined secondary metaanalyses of individual data, interleukin-27 subunit α, growth/differentiation factor 15, urokinase plasminogen activator surface receptor, tumor necrosis factor receptor superfamily member 6, macrophage colony-stimulating factor 1, and matrix metalloproteinase-7 were also potential risk markers for ischemic stroke after adjustment for multiple comparisons (P<0.0006). The addition of N-terminal pro-B-type natriuretic peptide, adrenomedullin, and eosinophil cationic protein to a model with established risk factors increased the C-statistic from 0.629 to 0.689 (P=0.001). Conclusions-Our data suggest that large-scale proteomics analysis is a promising way of discovering novel biomarkers that could substantially improve the prediction of ischemic stroke. Lind et al New Risk Markers for Ischemic Stroke 3341Population Register. In total, 1016 individuals of 2025 invited took part in the investigation (50.1%) at age 70 years when also the blood sample for proteomics was collected. 12 A follow-up of incident ischemic stroke was performed after 10 years, without any loss of follow-up. After exclusion of the 39 individuals with stroke before the baseline investigation in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), 71 of remaining 977 subjects experienced an ischemic stroke during a median follow-up of 10.0 years (range, 0.04-10.9 years), resulting in an incidence rate of 7.9 per 1000 person years at risk. ULSAM StudyUppsala Longitudinal Study in Adult Men (ULSAM) is a longitudinal population-based study including men born between 1920 and 1924 in Uppsala County, Sweden, being invited for the first time at age 50 years (n=2322). 13 This study used the 77-year examination cycle as base...

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“…There is a known correlation between NT-proBNP and ABP 6 ; however, in a recent study, we showed that NT-proBNP was a predictive marker independent of ABP in patients with peripheral arterial disease. 9 Zethelius et al 5 have previously reported additive value of a panel of biomarkers (including NT-proBNP) when added to a traditional CVD risk model, both in risk prediction and in discrimination with CVD death as outcome. NT-proBNP is highly associated with congestive heart failure because NT-proBNP is secreted from cardiac myocytes when stimulated by myocardial stretch.…”

Section: Discussionmentioning

confidence: 99%

Amino-Terminal Pro-B-Type Natriuretic Peptide Improves Discrimination for Incident Atherosclerotic Cardiovascular Disease Beyond Ambulatory Blood Pressure in Elderly Men

et al. 2015

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Improvement of risk prediction for atherosclerotic cardiovascular disease (ASCVD) is needed. Both ambulatory blood pressure (ABP) and biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein and cystatin C improve risk prediction but they have not been evaluated in relation to each other. We analyzed whether NT-proBNP, high-sensitivity C-reactive protein, or cystatin C improved risk prediction beyond traditional ASCVD risk factors combined with 24-hour systolic BP (SBP). Secondary aim was to evaluate whether ABP improved risk prediction when compared with models with the biomarkers. We followed up 907 70-year-old men, free of baseline disease, for incident ASCVD defined as fatal or nonfatal myocardial infarction or fatal or nonfatal stroke for a median of 10 years. Cox regression was used to estimate the association between variables in the models and incident ASCVD. Biomarkers were added to a model containing both traditional risk factors and ABP and the models were compared on C-statistics and net reclassification improvement. Twenty-four hour SBP improved discrimination for incident ASCVD when compared with office SBP in a traditional risk factor model (area under the receiver-operating characteristic curve, +2.4%). NT-proBNP further improved reclassification (+18.7%–19.9%; P <0.01) when added to ABP models, whereas high-sensitivity C-reactive protein and cystatin C did not. Twenty-four hour SBP significantly improved net reclassification when added to a traditional risk factor model that included NT-proBNP. The combination of 24-hour SBP and NT-proBNP improved discrimination and net reclassification for incident ASCVD when compared with office SBP in elderly men. NT-proBNP, but not high-sensitivity C-reactive protein or cystatin C, improved risk prediction and discrimination when added to a model that included ABP.

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Use of Multiple Biomarkers to Improve the Prediction of Death from Cardiovascular Causes

Cited by 769 publications

References 29 publications

Levels of Circulating Progenitor Cells, Cardiovascular Outcomes and Death

Levels of Circulating Progenitor Cells, Cardiovascular Outcomes and Death

Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip

Amino-Terminal Pro-B-Type Natriuretic Peptide Improves Discrimination for Incident Atherosclerotic Cardiovascular Disease Beyond Ambulatory Blood Pressure in Elderly Men

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