| 1. |
- Neumann, Johannes Tobias, et al.
(author)
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Prognostic value of cardiovascular biomarkers in the population
- 2024
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In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 331:22, s. 1898-1909
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Journal article (peer-reviewed)abstract
- Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies.Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors.Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years.Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein.Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses.Results: The analyses included 164054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people.Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality..
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| 2. |
- Kimenai, Dorien M., et al.
(author)
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Sex-Specific Versus Overall Clinical Decision Limits for Cardiac Troponin I and T for the Diagnosis of Acute Myocardial Infarction : A Systematic Review
- 2018
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In: Clinical Chemistry. - : American Association for Clinical Chemistry. - 0009-9147 .- 1530-8561. ; 64:7, s. 1034-1043
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Research review (peer-reviewed)abstract
- BACKGROUND: The overall clinical decision limits of high-sensitivity cardiac troponin I (hs-cTnI; 26 ng/L) and T (hs-cTnT; 14 ng/L) may contribute to underdiagnosis of acute myocardial infarction in women. We performed a systematic review to investigate sex-specific and overall 99th percentiles of hs-cTnI and hs-cTnT derived from healthy reference populations. CONTENT: We searched in PubMed and EMBASE for original studies, and by screening reference lists. Reference populations designed to establish 99th percentiles of hs-cTnI (Abbott) and/or hs-cTnT (Roche), published between January 2009 and October 2017, were included. Sex-specific and overall 99th percentile values of hs-cTnI and hs-cTnT were compared with overall clinical decision ranges (hs-cTnI, 23-30 ng/L; hs-cTnT, 13-25 ng/L). Twenty-eight studies were included in the systematic review. Of 16 hs-cTnI and 18 hs-cTnT studies, 14 (87.5%) and 11 (61.1%) studies reported lower femalespecific hs-cTn cutoffs than overall clinical decision ranges, respectively. Conversely, male-specific thresholds of both hs-cTnI and hs-cTnT were in line with currently used overall thresholds, particularly hs-cTnT (90% concordance). The variation of estimated overall 99th percentiles was much higher for hs-cTnI than hs-cTnT (29.4% vs 80.0% of hs-cTnI and hs-cTnT studies reported values within the current overall clinical decision range, respectively). SUMMARY: Our data show substantially lower femalespecific upper reference limits of hs-cTnI and hs-cTnT than overall clinical decision limits of 26 ng/L and 14 ng/L, respectively. The statistical approach strongly affects the hs-cTnI threshold. Downward adjustment of hs-cTn thresholds in women may be warranted to reduce underdiagnosis of acute myocardial infarction in women.
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| 3. |
- Eggers, Kai M, et al.
(author)
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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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In: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 59:7, s. 1091-1098
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Journal article (peer-reviewed)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., 1962-, et al.
(author)
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Clinical and prognostic implications of C-reactive protein levels in myocardial infarction with nonobstructive coronary arteries
- 2021
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In: Clinical Cardiology. - : John Wiley & Sons. - 0160-9289 .- 1932-8737. ; 44:7, s. 1019-1027
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Journal article (peer-reviewed)abstract
- Background Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous condition. Recent studies suggest that MINOCA patients may have a proinflammatory disposition. The role of inflammation in MINOCA may thus be distinct to myocardial infarction with significant coronary artery disease (MI-CAD). Hypothesis We hypothesized that inflammation reflected by C-reactive protein (CRP) levels might carry unique clinical information in MINOCA. Methods This retrospective registry-based cohort study (SWEDEHEART) included 9916 patients with MINOCA and 97 970 MI-CAD patients, used for comparisons. Multivariable-adjusted regressions were applied to investigate the associations of CRP levels with clinical variables, all-cause mortality and major cardiovascular events (MACE) during a median follow-up of up to 5.3 years. Results Median admission CRP levels in patients with MINOCA and MI-CAD were 5.0 (interquartile range 2.0-9.0) mg/dl and 5.0 (interquartile range 2.1-10.0 mg/dl), respectively. CRP levels in MINOCA exhibited independent associations with various cardiovascular risk factors, comorbidities and estimates of myocardial damage. The association of CRP with peripheral artery disease tended to be stronger compared to MI-CAD. The associations with female sex, renal dysfunction and myocardial damage were stronger in MI-CAD. CRP independently predicted all-cause mortality in MINOCA (hazard ratio 1.22 [95% confidence interval 1.17-1.26]), similar to MI-CAD (p interaction = 0.904). CRP also predicted MACE (hazard ratio 1.08 [95% confidence interval 1.04-1.12]) but this association was weaker compared to MI-CAD (p interaction<.001). Conclusions We found no evidence indicating the presence of a specific inflammatory pattern in acute MINOCA compared to MI-CAD. However, CRP levels were independently, albeit moderately associated with adverse outcome.
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| 5. |
- Eggers, Kai M., et al.
(author)
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Clinical and prognostic implications of circulating pentraxin 3 levels in non ST-elevation acute coronary syndrome
- 2013
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In: Clinical Biochemistry. - : Elsevier BV. - 0009-9120 .- 1873-2933. ; 46:16-17, s. 1655-1659
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Journal article (peer-reviewed)abstract
- Objectives: Pentraxin 3 (PTX3) is the prototype of the long pentraxin family. PTX3 is involved in inflammatory processes affecting the cardiovascular system, and PTX3 levels have been shown to be elevated and independently prognostic in ST-elevation myocardial infarction. Data on PTX3 levels in non-ST-elevation acute coronary syndrome (NSTE-ACS), in contrast, are limited. The aim of the present analysis was to investigate the implications of PTX3 levels in a fairly large sample of NSTE-ACS patients and in comparison to levels of C-reactive protein (CRP). Design and methods: We measured levels of PTX3 and CRP in both 82 healthy controls and 401 NSTE-ACS patients from the GUSTO IV study, and studied the associations of these biomarkers to clinical data and 1-year mortality. Results: NSTE-ACS patients had significantly higher median PTX3 levels compared to healthy controls (3.8 vs. 1.9 mu g/L; p < 0.001). PTX3 levels in patients with NSTE-ACS were independently related to female sex and cardiac troponin T levels, but not to age or cardiovascular risk factors. PTX3 levels were higher in patients who died within 1 year but did not emerge as an independent predictor of 1-year mortality (adjusted OR 1,2 [95% Cl 0.6-2.31). This was in contrast to CRP (adjusted OR 1.5 [95% Cl 1.1-2.3]). Neither PTX3 nor CRP yielded significant discriminative value regarding mortality prediction. Conclusions: PTX3 levels are elevated in NSTE-ACS. However, the prognostic information provided by PTX3 levels is limited and inferior compared to CRP. Our data, thus, do not support the measurement of PTX3 in patients with NSTE-ACS.
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| 6. |
- Eggers, Kai M, et al.
(author)
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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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In: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 62:3, s. 485-493
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Journal article (peer-reviewed)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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| 7. |
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| 8. |
- Eggers, Kai M., 1962-, et al.
(author)
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Growth-differentiation factor-15 for early risk stratification in patients with acute chest pain
- 2008
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:19, s. 2327-2335
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Journal article (peer-reviewed)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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| 9. |
- Eggers, Kai M., 1962-, et al.
(author)
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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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In: Circulation: Cardiovascular Genetics. - 1942-3268. ; 3:1, s. 88-96
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Journal article (peer-reviewed)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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