| 1. |
- Batra, Gorav, et al.
(författare)
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Biomarker-Based Prediction of Recurrent Ischemic Events in Patients With Acute Coronary Syndromes
- 2022
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 80:18, s. 1735-1747
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In patients with acute coronary syndrome (ACS), there is residual and variable risk of recurrent ischemic events.OBJECTIVES: This study aimed to develop biomarker-based prediction models for 1-year risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with ACS undergoing percutaneous coronary intervention.METHODS: We included 10,713 patients from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial in the development cohort and externally validated in 3,508 patients from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial. Variables contributing to risk of CV death/MI were assessed using Cox regression models, and a score was derived using subsets of variables approximating the full model.RESULTS: There were 632 and 190 episodes of CV death/MI in the development and validation cohorts. The most important predictors of CV death/MI were the biomarkers, growth differentiation factor 15, and N-terminal pro-B-type natriuretic peptide, which had greater prognostic value than all candidate variables. The final model included 8 items: age (A), biomarkers (B) (growth differentiation factor 15 and N-terminal pro-B-type natriuretic peptide), and clinical variables (C) (extent of coronary artery disease, previous vascular disease, Killip class, ACS type, P2Y12 inhibitor). The model, named ABC-ACS ischemia, was well calibrated and showed good discriminatory ability for 1-year risk of CV death/MI with C-indices of 0.71 and 0.72 in the development and validation cohorts, respectively. For CV death, the score performed better, with C-indices of 0.80 and 0.84 in the development and validation cohorts, respectively.CONCLUSIONS: An 8-item score for the prediction of CV death/MI was developed and validated for patients with ACS undergoing percutaneous coronary intervention. The ABC-ACS ischemia score showed good calibration and discrimination and might be useful for risk prediction and decision support in patients with ACS. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872; Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER]; NCT00527943)
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| 2. |
- Bonaca, Marc P., et al.
(författare)
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Growth Differentiation Factor-15 and Risk of Recurrent Events in Patients Stabilized After Acute Coronary Syndrome Observations From PROVE IT-TIMI 22
- 2011
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 31:1, s. 203-210
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Tidskriftsartikel (refereegranskat)abstract
- Objective-To investigate growth differentiation factor (GDF)-15 at hospital discharge for assessment of the risk of death, recurrent myocardial infarction (MI), and congestive heart failure, and to determination of whether these risks can be modified by statins. Methods and Results-GDF-15 is a transforming growth factor-beta-related cytokine induced in response to tissue injury. GDF-15 concentration is associated with all-cause mortality in patients with acute coronary syndrome (ACS). We measured GDF-15 in 3501 patients after ACS, treated with moderate or intensive statin therapy in PROVE IT-TIMI 22. By using established cutoff points, GDF-15 (< 1200, 1200-1800, and > 1800 ng/L) was associated with 2-year risk of death or MI (5.7%, 8.1%, and 15.1%, respectively; P < 0.001), death (P < 0.001), MI (P < 0.001), and congestive heart failure (P < 0.001). After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, smoking, MI, qualifying event, renal function, B-type natriuretic peptide, and high-sensitivity C-reactive protein, GDF-15 was associated with the risk of death or MI (adjusted hazard ratio per ln increase GDF-15, 2.1 [95% CI, 1.6 to 2.9]; P < 0.001), death (P < 0.001), MI (P < 0.001), and congestive heart failure (P < 0.001). There was no significant interaction between GDF-15 and intensive statin therapy for the risk of death or MI (P = 0.24 for the interaction). Conclusion-GDF-15 is associated with recurrent events after ACS, independent of clinical predictors, B-type natriuretic peptide, and high-sensitivity C-reactive protein. This finding supports GDF-15 as a prognostic marker in ACS and investigation of other therapies that modify this risk.
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| 3. |
- Eggers, Kai M, et al.
(författare)
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Change in Growth Differentiation Factor 15 Concentrations Over Time Independently Predicts Mortality in Community-Dwelling Elderly Individuals
- 2013
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 59:7, s. 1091-1098
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Growth differentiation factor 15 (GDF-15) is emerging as a powerful risk indicator in both cardiovascular disease patients and community-dwelling individuals. We investigated GDF-15 concentrations and their changes over 5 years in elderly individuals from the community, together with the underlying conditions and prognostic implications of these measurements.METHODS:We analyzed GDF-15 concentrations using a sandwich immunoassay in participants from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. Measurements were performed at both 70 (n = 1004) and 75 (n = 813) years of age. Median follow-up was 8.0 years.RESULTS:Over time, GDF-15 concentrations increased by 11.0% (P < 0.001). These changes were related to male sex, hypertension, diabetes, heart failure, renal function, and concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP). Significant relationships also emerged between changes in GDF-15 and NT-proBNP, C-reactive protein, and renal function between ages 70 and 75. The R2 value of this model was 0.20. GDF-15 concentrations independently predicted all-cause mortality [hazard ratio 4.0 (95% CI 2.7–6.0)] with results obtained at ages 70 and 75 as updated covariates. Baseline GDF-15 concentrations improved prognostic discrimination and reclassification [c-statistic 0.06 (P = 0.006); integrated discrimination improvement = 0.030 (P = 0.004); category-free net reclassification improvement = 0.281 (P = 0.006)]. Change in GDF-15 concentrations over time independently predicted even all-cause mortality occurring after age 75 [hazard ratio 3.6 (95% CI 2.2–6.0)].CONCLUSIONS:GDF-15 concentrations and their changes over time are powerful predictors of mortality in elderly community-dwelling individuals. GDF-15 concentrations increase with aging, and these changes are explained only partially by cardiovascular risk factors, indicators of neurohumoral activation and inflammation, and renal function. Thus GDF-15 reflects both cardiovascular and other biological processes closely related to longevity.
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| 4. |
- Eggers, Kai M, et al.
(författare)
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Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community
- 2016
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 62:3, s. 485-493
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is increasing interest in measurements of cardiovascular (CV) biomarker concentrations for risk prediction in the general population. We investigated the prognostic utility of a panel of novel CV biomarkers and their changes over time.METHODS: We measured concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional proadrenomedullin, high-sensitivity cardiac troponin I, growth-differentiation factor-15 (GDF-15), soluble ST2 (sST2), and galectin-3 at baseline and 5 years later in 1016 elderly individuals participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Assessed outcomes included all-cause mortality and fatal and nonfatal CV events (in participants without CV disease at baseline) during 10 years of follow-up.RESULTS: GDF-15 exhibited the strongest association with all-cause mortality (n = 158) with a hazard ratio (HR) per 1-SD increase in standardized ln GDF-15 of 1.68 (95% CI, 1.44-1.96). NT-proBNP was the only biomarker to predict CV events (n = 163; HR 1.54 [95% CI, 1.30-1.84]). GDF-15 and NT-proBNP also improved metrics of discrimination and reclassification of the respective outcomes. Changes in GDF-15 concentrations between 70 and 75 years predicted all-cause mortality whereas changes in NT-proBNP predicted both outcomes. The other biomarkers and their temporal changes provided only moderate prognostic value apart from sST2 which had a neutral relationship with adverse events.CONCLUSIONS: Evaluation of temporal changes in GDF-15 and NT-proBNP concentrations improves risk prediction in an elderly population. These findings are of considerable interest given the emphasis on biomarkers as tools to identify and monitor at-risk individuals with preclinical and potentially modifiable stages of CV disease.
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| 5. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Growth-differentiation factor-15 for early risk stratification in patients with acute chest pain
- 2008
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:19, s. 2327-2335
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Growth-differentiation factor-15 (GDF-15) has emerged as a biomarker of increased mortality and recurrent myocardial infarction (MI) in patients diagnosed with non-ST-elevation acute coronary syndrome. We explored the usefulness of GDF-15 for early risk stratification in 479 unselected patients with acute chest pain. METHODS AND RESULTS: Sixty-nine per cent of the patients presented with GDF-15 levels above the previously defined upper reference limit (1200 ng/L). The risks of the composite endpoint of death or (recurrent) MI after 6 months were 1.3, 5.1, and 12.6% in patients with normal (<1200 ng/L), moderately elevated (1200-1800 ng/L), or markedly elevated (>1800 ng/L) levels of GDF-15 on admission, respectively (P < 0.001). By multivariable analysis that included clinical characteristics, ECG findings, peak cardiac troponin I levels within 2 h (cTnI(0-2 h)), N-terminal pro-B-type natriuretic peptide, C-reactive protein, and cystatin C, GDF-15 remained an independent predictor of the composite endpoint. The ability of the ECG combined with peak cTnI(0-2 h) to predict the composite endpoint was markedly improved by addition of GDF-15 (c-statistic, 0.74 vs. 0.83; P < 0.001). CONCLUSION: GDF-15 improves risk stratification in unselected patients with acute chest pain and provides prognostic information beyond clinical characteristics, the ECG, and cTnI.
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| 6. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Growth-differentiation factor-15 for long-term risk prediction in patients stabilized after an episode of non-ST-segment-elevation acute coronary syndrome
- 2010
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Ingår i: Circulation: Cardiovascular Genetics. - 1942-3268. ; 3:1, s. 88-96
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Growth-differentiation factor-15 (GDF-15) has emerged as a prognostic biomarker in patients with non-ST-segment-elevation acute coronary syndrome. This study assessed the time course and the long-term prognostic relevance of GDF-15 levels measured repetitively in patients with non-ST-segment-elevation acute coronary syndrome during 6 months after the acute event. METHODS AND RESULTS: GDF-15 and other biomarkers were measured at randomization, after 6 weeks, and after 3 and 6 months in 950 patients with non-ST-segment-elevation acute coronary syndrome included in the FRagmin and Fast Revascularization during InStability in Coronary artery disease II study. Study end points were death, recurrent myocardial infarction, and their composite during 5-year follow-up. Median GDF-15 levels decreased slightly from 1357 ng/L at randomization to 1302 ng/L at 6 months (P<0.001). GDF-15 was consistently related to cardiovascular risk factors and biochemical markers of hemodynamic stress, renal dysfunction, and inflammation. Moreover, GDF-15 was independently related to the 5-year risk of the composite end point when measured at both 3 months (adjusted hazard ratio, 1.8 [1.0 to 3.0]) and 6 months (adjusted hazard ratio, 2.3 [1.3 to 4.1]). Serial measurements of GDF-15 at randomization and 6 months helped to identify patient cohorts at different levels of risk, with patients with persistently elevated GDF-15 levels >1800 ng/L having the highest rate of the composite end point. CONCLUSIONS: GDF-15 is independently related to adverse events in non-ST-segment-elevation acute coronary syndrome both in the acute setting and for at least 6 months after clinical stabilization. Therefore, continued research on GDF-15 should be focused on the usefulness of GDF-15 for support of clinical management in acute and chronic ischemic heart disease.
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| 7. |
- Eggers, Kai M., et al.
(författare)
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Improving long-term risk prediction in patients with acute chest pain : The Global Registry of Acute Coronary Events (GRACE) risk score is enhanced by selected nonnecrosis biomarkers
- 2010
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 160:1, s. 88-94
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Tidskriftsartikel (refereegranskat)abstract
- Background The Global Registry of Acute Coronary Events (GRACE) risk score is widely recommended for risk assessment in patients with acute coronary syndrome. However, there is limited knowledge regarding the utility of this score for long-term risk prediction in unselected patients with acute chest pain and whether it might be improved by the integration of nonnecrosis biomarkers. Methods We calculated the GRACE risk score in 453 chest pain patients and assessed its value for risk assessment together with the additive prognostic information obtained from N-terminal pro-B-type natriuretic peptide, C-reactive protein, growth differentiation factor-15 (GDF-15), and cystatin C. Results After a median follow-up of 5.8 years, 92 patients (20.7%) had died. The GRACE risk score was significantly higher in patients who died (median 146 vs 93, P < .001) and provided a c-statistic regarding mortality of 0.78. A significant increase of the c-statistic was achieved only after addition of GDF-15 (c-statistic 0.81, P = .003) and, to a minor extent, after addition of cystatin C (c-statistic 0.81, P = .035). Assessment of the integrated discriminative improvement yielded similar results. N-terminal pro-B-type natriuretic peptide had only limited incremental prognostic value, and C-reactive protein was not predictive for outcome. Conclusion The GRACE risk score allows for the prediction of mortality in chest pain patients even after almost 6 years of follow-up. However, its predictive value could be further enhanced by the addition of selected nonnecrosis biomarkers, in particular GDF-15 or cystatin C. (Am Heart J 2010; 160: 88-94.)
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| 8. |
- Eggers, Kai M, et al.
(författare)
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Relations of growth-differentiation factor-15 to biomarkers reflecting vascular pathologies in a population-based sample of elderly subjects
- 2012
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 72:1, s. 45-51
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Tidskriftsartikel (refereegranskat)abstract
- Background. Growth-differentiation factor-15 (GDF-15) has recently emerged as a risk predictor in patients with cardiac diseases. GDF-15 is commonly related to cardiovascular risk factors, inflammatory activity and cardiac abnormalities. However, it is not clear whether it might be an indicator of vascular pathologies as well.Methods.Circulating levels of GDF-15 were measured in 1004 elderly community dwellers participating in the PIVUS study. The relations of GDF-15 to biomarkers of endothelial activation (E-selectin, P-selectin, ICAM-1, VCAM-1), extracellular matrix degradation (MMP-9, TIMP-1), coagulatory activity (D-dimer, von Willebrand factor, prothrombin fragment 1 + 2, factor VIIa), and fibrinolytic activity (PAI-1 activity, tPA-antigen) were assessed by multiple linear regressions.Results. The median GDF-15 level was 1135 ng/L. By linear correlation analysis, GDF-15 exhibited a moderate relation to von Willebrand factor (r = 0.30), and weak, albeit significant relations (r = 0.13-0.29) to E-selectin, P-selectin, ICAM-1, VCAM-1, MMP-9, TIMP-1, D-dimer, PAI-1 activity and tPA-antigen. The relations to the assessed biomarkers of endothelial activation, TIMP-1, D-dimer and von Willebrand factor remained significant applying multiple linear regression models adjusted for clinical covariates and echocardiographic data. There were no significant relations between GDF-15 and biomarkers solely reflecting coagulatory activity.Conclusions.In the elderly, GDF-15 reflects endothelial activation and vascular inflammation and thus, multiple pathways involved in the development and progression of atherosclerosis.
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| 9. |
- Kempf, Tibor, et al.
(författare)
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Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay
- 2007
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 53:2, s. 284-291
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-beta) cytokine superfamily. There has been increasing interest in using circulating GDF15 as a biomarker in patients, for example those with cardiovascular disease. METHODS: We developed an IRMA that uses a polyclonal, affinity chromatography-purified goat antihuman GDF15 IgG antibody, assessed the preanalytic characteristics of GDF15, and determined circulating GDF15 concentrations in 429 apparently healthy elderly individuals and 153 patients with chronic heart failure (CHF). RESULTS: The assay had a detection limit of 20 ng/L, an intraassay imprecision of < or =10.6%, and an interassay imprecision of < or =12.2%. Specificity was demonstrated with size-exclusion chromatography, parallel measurements with polyclonal and monoclonal anti-GDF15 antibody, and lack of cross-reactivity with TGF-beta. The assay was not appreciably influenced by the anticoagulant matrix or unrelated biological substances. GDF15 was stable at room temperature for 48 h and resistant to 4 freeze-thaw cycles. Apparently healthy, elderly individuals presented with a median GDF15 concentration of 762 ng/L (25th-75th percentiles, 600-959 ng/L). GDF15 concentrations were associated with age and with cystatin C and C-reactive protein concentrations. CHF patients had increased GDF15 concentrations that were closely related to disease severity. CONCLUSION: The IRMA can detect GDF15 in human serum and plasma with excellent sensitivity and specificity. The reference limits and confounding variables defined for apparently healthy elderly individuals and the favorable preanalytic characteristics of GDF15 are expected to facilitate future studies of GDF15 as a biomarker in various disease settings, including CHF.
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| 10. |
- Kempf, Tibor, et al.
(författare)
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Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction
- 2007
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 28:23, s. 2858-2865
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Tidskriftsartikel (refereegranskat)abstract
- Aims Growth-differentiation factor-15 (GDF-15) is a transforming growth factor-beta-related cytokine that is induced in the heart following ischaemia-reperfusion injury. We explored the prognostic utility of GDF-15 in patients with ST-segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy. Methods and results Circulating levels of GDF-15 were determined by an immunoradiometric assay in 741 STEMI patients who were included in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-2 and ASSENT-plus trials. About 72.7% of the patients presented with GDF-15 levels >= 1200 ng/L, the upper limit of normal in apparently healthy elderly individuals. Increased levels of GDF-15 were associated with a higher risk of death during 1-year follow-up. Mortality rates at 1 year were 2.1, 5.0, and 14.0% in patients with GDF-15 levels < 1200, 1200-1800, and > 1800 ng/L, respectively (P < 0.001). GDF-15 remained an independent predictor of mortality after adjustment for clinical variables, troponin T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). GDF-15 provided prognostic information in clinically relevant patient subgroups, defined according to age, gender, cardiovascular risk factors, haemodynamic status, and the TIMI risk score. Moreover, GDF-15 added prognostic information to the established biomarkers of adverse prognosis in STEMI, troponin T, and NT-proBNP. Conclusion GDF-15 is a new biomarker in STEMI that provides prognostic information beyond established clinical and biochemical markers.
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