Kai M. Eggers

Persistent Cardiac Troponin I Elevation in Stabilized Patients After an Episode of Acute Coronary Syndrome Predicts Long-Term Mortality

Background— In patients with non–ST-elevation acute coronary syndrome, any troponin elevation is associated with an increased risk for cardiovascular events. However, the prevalence and prognostic importance of persistent troponin elevation in stabilized patients after an episode of non–ST-elevation acute coronary syndrome are unknown and were therefore assessed in this study. Methods and Results— Cardiac troponin I (cTnI) was measured in 1092 stabilized patients at 6 weeks and 3 and 6 months after enrollment in the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC-II) trial. cTnI was analyzed with the Access AccuTnI assay with the application of different prognostic cutoffs. Outcomes were assessed through 5 years. Elevated cTnI levels >0.01 &mgr;g/L were found in 48% of the study patients at 6 weeks, in 36% at 6 months, and in 26% at all 3 measurements. cTnI elevation was associated with increased age and other cardiovascular high-risk features. The lowest tested cTnI cutoff (0.01 &mgr;g/L) was prognostically most useful and was independently predictive of mortality (hazard ratio, 2.1 [95% confidence interval, 1.3 to 3.3]; P=0.001) on multivariable analysis adjusted for cardiovascular risk factors and randomization to an invasive versus noninvasive treatment strategy, whereas it was related to myocardial infarction only on univariate analysis. Conclusions— Persistent minor cTnI elevation can be detected frequently in patients stabilized after an episode of non–ST-elevation acute coronary syndrome with the use of a sensitive assay. Elevated cTnI levels >0.01 &mgr;g/L predict mortality during long-term follow-up. Our results emphasize the importance of further troponin testing in non–ST-elevation acute coronary syndrome patients after hospital discharge.

Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects

AIMS To evaluate the prevalence of cardiac troponin I (cTnI) elevation in an elderly community population and the association of cTnI levels with cardiovascular risk factors, vascular inflammation, atherosclerosis, cardiac performance, and areas indicative of infarcted myocardium identified by cardiac magnetic resonance imaging. METHODS AND RESULTS cTnI elevation defined as cTnI levels >0.01 microg/L (Access AccuTnI, Beckman Coulter) was found in 21.8% of the study participants (n = 1005). cTnI > 0.01 microg/L was associated with cardiovascular high-risk features, the burden of atherosclerosis in the carotid arteries, left-ventricular mass, and impaired left-ventricular systolic function. No associations were found between cTnI and inflammatory activity, diastolic dysfunction, or myocardial scars. Male gender (OR 1.6; 95% CI 1.1-2.4), ischaemic ECG changes (OR 1.7; 95% CI 1.1-2.7), and NT-pro-brain natriuretic peptide levels (OR 1.4; 95% CI 1.1-1.7) independently predicted cTnI > 0.01 microg/L. cTnI > 0.01 microg/L correlated also to an increased cardiovascular risk according to the Framingham risk score. CONCLUSION cTnI > 0.01 microg/L is relatively common in elderly subjects and is associated with cardiovascular high-risk features and impaired cardiac performance. Cardiac troponin determined by a highly sensitive assay might thus serve as an instrument for the identification of subjects at high cardiovascular risk in general populations.

Value of Cardiac Troponin I Cutoff Concentrations below the 99th Percentile for Clinical Decision-Making

BACKGROUND The aim of this study was to evaluate factors influencing the 99th percentile for cardiac troponin I (cTnI) when this cutoff value is established on a highly sensitive assay, and to compare the value of this cutoff to that of lower cutoffs in the prognostic assessment of patients with coronary artery disease. METHODS We used the recently refined Access AccuTnI assay (Beckman-Coulter) to assess the distribution of cTnI results in a community population of elderly individuals [PIVUS (Prospective Study of the Vasculature in Uppsala Seniors) study; n = 1005]. The utility of predefined cTnI cutoffs for risk stratification was then evaluated in 952 patients from the FRISC II (FRagmin and Fast Revascularization during InStability in Coronary artery disease) study at 6 months after these patients had suffered acute coronary syndrome. RESULTS Selection of assay results from a subcohort of PIVUS participants without cardiovascular disease resulted in a decrease of the 99th percentile from 0.044 microg/L to 0.028 microg/L. Men had higher rates of cTnI elevation with respect to the tested thresholds. Whereas the 99th percentile cutoff was not found to be a useful prognostic indicator for 5-year mortality, both the 90th percentile (hazard ratio 3.1; 95% CI 1.9-5.1) and the 75th percentile (hazard ratio 2.8; 95% CI 1.7-4.7) provided useful prognostic information. Sex-specific cutoffs did not improve risk prediction. CONCLUSIONS The 99th percentile of cTnI depends highly on the characteristics of the reference population from which it is determined. This dependence on the reference population may affect the appropriateness of clinical conclusions based on this threshold. However, cTnI cutoffs below the 99th percentile seem to provide better prognostic discrimination in stabilized acute coronary syndrome patients and therefore may be preferable for risk stratification.

Cardiac Troponin I Levels Measured With a High-Sensitive Assay Increase Over Time and Are Strong Predictors of Mortality in an Elderly Population

OBJECTIVES This study sought to assess changes in troponin levels, underlying conditions, and the prognostic implications in elderly subjects from the community. BACKGROUND Cardiac troponin levels are often detectable in community dwellers when sensitive assays are applied. However, information on the course of troponin levels over time is limited. METHODS Cardiac troponin I (cTnI) was measured by using a novel, high-sensitive assay in community dwellers aged 70 years from the Prospective Investigation of the Vasculature in Uppsala Seniors study. Measurements were performed at baseline (n = 1,004) and after 5 years (n = 814). Total follow-up was 8.0 years. RESULTS cTnI levels were detectable in 968 (96.4%) subjects at baseline and independently predicted all-cause mortality (adjusted hazard ratio [HR]: 1.44 [95% confidence interval (CI): 1.18 to 1.77]) and cardiovascular mortality (adjusted HR: 1.66 [95% CI: 1.20 to 2.29]) when levels from baseline and 5-year follow-up were used as updated covariates. The integrated discrimination improvement of cTnI regarding all-cause mortality was 0.014 (p = 0.04), and the category-free net reclassification improvement was 0.231 (p = 0.02). Median cTnI levels increased by 45% between both measurements. The change in cTnI levels was significantly related to male sex (p = 0.02), body mass index (p = 0.01), high-density lipoprotein cholesterol (p = 0.005), N-terminal pro-B-type natriuretic peptide (p = 0.004), and left ventricular ejection fraction (p = 0.04), and it independently predicted all-cause mortality occurring after 5-year follow-up (adjusted HR: 1.97 [95% CI: 1.14 to 3.40]; p = 0.02). CONCLUSIONS Using a novel high-sensitive assay, cTnI levels could be determined in nearly all elderly study subjects. cTnI levels increased over time and were a strong marker of mortality risk. Our data suggest that cTnI might offer utility for clinical assessment of subjects in the general population.

Growth-Differentiation Factor-15 for Long-Term Risk Prediction in Patients Stabilized After an Episode of Non–ST-Segment–Elevation Acute Coronary Syndrome

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.

Growth-differentiation factor-15 for early risk stratification in patients with acute chest pain

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 (cTnI0–2 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 cTnI0–2 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.

Will the Universal Definition of Myocardial Infarction Criteria Result in an Overdiagnosis of Myocardial Infarction

The Universal Definition of Myocardial Infarction (acute myocardial infarction [AMI]) requires detection of increasing or decreasing cardiac biomarkers (preferably cardiac troponin) with >or=1 value >99(th) percentile, together with either clinical symptoms, new ischemic electrocardiographic changes, or typical imaging findings indicative of myocardial necrosis as diagnostic criteria for AMI. However, a small cardiac troponin elevation together with ST-T segment abnormalities may also occur in clinically stable populations. Accordingly, 0.6% of elderly subjects from a community sample (PIVUS Study) and 6.7% of patients stabilized after an acute coronary syndrome (FRISC II Study) would have been labeled AMI following the Universal Definition of AMI when diagnostic classification had been based on a single cardiac troponin I result. In conclusion, our results emphasized the importance of a significant change in cardiac troponin to avoid misdiagnosis of AMI.

Diagnostic accuracy of combined cardiac troponin and copeptin assessment for early rule-out of myocardial infarction: : a systematic review and meta-analysis

Aims: This systematic review aimed to investigate the diagnostic accuracy of combined cardiac troponin (cTn) and copeptin assessment in comparison to cTn alone for early rule-out of acute myocardial infarction (AMI). Methods: Primary studies were eligible if they evaluated diagnostic accuracy for cTn with and without copeptin in patients with symptoms suggestive of AMI. AMI was defined according to the universal definition, using detection of cTn as a marker for myocardial necrosis. Eligible studies were identified by searching electronic databases (Medline, EMBASE, Science Citation Index Expanded, CINAHL, Pascal, and Cochrane) from inception to March 2013, reviewing conference proceedings and contacting field experts and the copeptin manufacturer. Results: In 15 studies totalling 8740 patients (prevalence of AMI 16%), adding copeptin improved the sensitivity of cTn assays (from 0.87 to 0.96, p=0.003) at the expense of lower specificity (from 0.84 to 0.56, p<0.001). In 12 studies providing data for 6988 patients without ST-segment elevation, the summary sensitivity and specificity estimates were 0.95 (95% CI 0.89 to 0.98) and 0.57 (95% CI 0.49 to 0.65) for the combined assessment of cTn and copeptin. When a high-sensitivity cTnT assay was used in combination with copeptin, the summary sensitivity and specificity estimates were 0.98 (95% CI 0.96 to 1.00) and 0.50 (95% CI 0.42 to 0.58). Conclusion: Despite substantial between-study heterogeneity, this meta-analysis demonstrates that copeptin significantly improves baseline cTn sensitivity. Management studies are needed to establish the effectiveness and safety of measuring copeptin in combination with high-sensitivity cTnT for early rule-out of AMI without serial testing.

GDF-15 for Prognostication of Cardiovascular and Cancer Morbidity and Mortality in Men

The objective was to evaluate the hypothesis that growth-differentiation factor 15 (GDF-15) is an independent marker of the long-term risk for both cardiovascular disease and cancer morbidity beyond clinical and biochemical risk factors. Plasma obtained at age 71 was available from 940 subjects in the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. Complete mortality and morbidity data were obtained from public registries. At baseline there were independent associations between GDF-15 and current smoking, diabetes mellitus, biomarkers of cardiac (high-sensitivity troponin-T, NT-proBNP) and renal dysfunction (cystatin-C) and inflammatory activity (C-reactive protein), and previous cardiovascular disease (CVD). During 10 years follow-up there occurred 265 and 131 deaths, 115 and 46 cardiovascular deaths, and 185 and 86 events with coronary heart disease mortality or morbidity in the respective total cohort (n=940) and non-CVD (n=561) cohort. After adjustment for conventional cardiovascular risk factors, one SD increase in log GDF-15 were, in the respective total and non-CVD populations, associated with 48% (95%CI 26 to 73%, p<0.001) and 67% (95%CI 28 to 217%, p<0.001) incremental risk of cardiovascular mortality, 48% (95%CI 33 to 67%, p<0.001) and 61% (95%CI 38 to 89%, p<0.001) of total mortality and 36% (95%CI 19 to 56%, p<0.001) and 44% (95%CI 17 to 76%, p<0.001) of coronary heart disease morbidity and mortality. The corresponding incremental increase for cancer mortality in the respective total and non-cancer disease (n=882) population was 46% (95%CI 21 to 77%, p<0.001) and 38% (95%CI 12 to 70%, p<0.001) and for cancer morbidity and mortality in patients without previous cancer disease 30% (95%CI 12 to 51%, p<0.001). In conclusion, in elderly men, GDF-15 improves prognostication of both cardiovascular, cancer mortality and morbidity beyond established risk factors and biomarkers of cardiac, renal dysfunction and inflammation.

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

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.