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Background: It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined., Methods and Results: In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease-estimated glomerular filtration rate <60 mL·min(-1)·1.73 m(-2)). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%-80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve-derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9-3.4)., Conclusions: More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587., (© 2015 The Authors.)

Aim: It is unknown whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the early diagnosis of acute myocardial infarction without ST segment elevation (NSTEMI)., Methods and Results: In a prospective multicentre study, we measured cTnI and cTnT using clinically available high-sensitivity assays (hs-cTnI Abbott and hs-cTnT Roche) and compared their diagnostic and prognostic accuracies in consecutive patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by two independent cardiologists using all information pertaining to the individual patient. The mean follow-up was 24 months. Among 2226 consecutive patients, 18% had an adjudicated final diagnosis of NSTEMI. Diagnostic accuracy at presentation as quantified by the area under the receiver-operating-characteristics curve (AUC) for NSTEMI was very high and similar for hs-cTnI [AUC: 0.93, 95% confidence interval (CI) 0.92-0.94] and hs-cTnT (0.94, 95% CI: 0.92-0.94) P = 0.62. In early presenters (<3 h since chest pain onset) hs-cTnI showed a higher diagnostic accuracy (AUC: 0.92, 95% CI: 0.89-0.94) when compared with hs-cTnT AUC (0.89, 95% CI: 0.86-0.91) (P = 0.019), while hs-cTnT was superior in late presenters [AUC hs-cTnT 0.96 (95% CI: 0.94-0.96)  vs. hs-cTnI 0.94 (95% CI: 0.93-0.95); P = 0.007]. The prognostic accuracy for all-cause mortality, quantified by AUC, was significantly higher for hs-cTnT (AUC: 0.80; 95% CI: 0.78-0.82) when compared with hs-cTnI (AUC: 0.75; 95% CI: 0.73-0.77; P < 0.001)., Conclusion: Both hs-cTnI and hs-cTnT provided high diagnostic and prognostic accuracy. The direct comparison revealed small but potentially important differences that might help to further improve the clinical use of hs-cTn., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Several high-sensitivity cardiac troponin (hs-cTn) assays have recently been developed. It is unknown which hs-cTn provides the most accurate prognostic information and to what extent early changes in hs-cTn predict mortality., Methods and Results: In a prospective, international multicentre study, cTn was simultaneously measured with three novel [high-sensitivity cardiac Troponin T (hs-cTnT), Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI, Siemens] and a conventional assay (cTnT, Roche Diagnostics) in a blinded fashion in 1117 unselected patients with acute chest pain. Patients were followed up 2 years regarding mortality. Eighty-two (7.3%) patients died during the follow-up. The 2-year prognostic accuracy of hs-cTn was most accurate for hs-cTnT [area under the receivers operating characteristic curve (AUC) 0.78 (95% CI: 0.73-0.83) and outperformed both hs-cTnI (Beckman-Coulter, 0.71 (95% CI: 0.65-0.77; P = 0.001 for comparison), hs-cTnI (Siemens) 0.70 (95% CI: 0.64-0.76; P < 0.001 for comparison)] and cTnT 0.67 (95% CI: 0.61-0.74; P < 0.001 for comparison). Absolute changes of hs-cTnT were more accurate than relative changes in predicting mortality, but inferior to presentation values of hs-cTnT. Combining changes of hs-cTnT within the first 6 h with their presentation values did not further improve prognostic accuracy. Similar results were obtained for both hs-cTnI assays regarding the incremental value of changes. Hs-cTn concentrations remained predictors of death in clinically challenging subgroups such as patients with pre-existing coronary artery disease, impaired renal function, and patients older than 75 years., Conclusion: High-sensitivity cardiac Troponin T is more accurate than hs-cTnI in the prediction of long-term mortality. Changes of hs-cTn do not seem to further improve risk stratification beyond initial presentation values.

Importance: Whether sex-specific chest pain characteristics (CPCs) would allow physicians in the emergency department to differentiate women with acute myocardial infarction (AMI) from women with other causes of acute chest pain more accurately remains unknown. OBJECTIVE To improve the management of suspected AMI in women by exploring sex-specific CPCs., Design, Setting, and Participants: From April 21, 2006, through August 12, 2012, we enrolled 2475 consecutive patients (796 women and 1679 men) presenting with acute chest pain to 9 emergency departments in a prospective multicenter study. The final diagnosis of AMI was adjudicated by 2 independent cardiologists., Interventions: Treatment of AMI in the emergency department., Main Outcomes and Measures: Sex-specific diagnostic performance of 34 predefined and uniformly recorded CPCs in the early diagnosis of AMI., Results: Acute myocardial infarction was the adjudicated final diagnosis in 143 women (18.0%) and 369 men (22.0%). Although most CPCs were reported with similar frequency in women and men, several CPCs were reported more frequently in women (P < .05). The accuracy of most CPCs in the diagnosis of AMI was low in women and men, with likelihood ratios close to 1. Thirty-one of 34 CPCs (91.2%) showed similar likelihood ratios for the diagnosis of AMI in women and men, and only 3 CPCs (8.8%) seemed to have a sex-specific diagnostic performance with P < .05 for interaction. These CPCs were related to pain duration (2-30 and >30 minutes) and dynamics (decreasing pain intensity). However, because their likelihood ratios were close to 1, the 3 CPCs did not seem clinically helpful. Similar results were obtained when examining combinations of CPCs (all interactions, P ≥ .05)., Conclusions and Relevance: Differences in the sex-specific diagnostic performance of CPCs are small and do not seem to support the use of women-specific CPCs in the early diagnosis of AMI. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00470587.

Background: Endothelial dysfunction plays a major role in cardiovascular diseases, including acute myocardial infarction (AMI). However, its quantification has not been available as a clinical tool., Methods: In a prospective international multicentre study, we analyzed the diagnostic and prognostic utility of endothelial dysfunction as quantified by C-terminal proendothelin-1 (CT-proET-1) in 658 consecutive patients presenting with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long-term for mortality., Results: The adjudicated final diagnosis was AMI in 145 patients (22%). The diagnostic performance of CT-proET-1 for AMI was moderate; its area under the receiver operating characteristic (ROC) curve amounted to 0.66 (95% confidence interval [CI], 0.61-0.72; P < 0.001). There was no significant increase in the AUC when CT-proET-1 was added to either cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT). Seventy four percent of patients who died during the first 24 months (n = 50) were in the fourth quartile of the CT-proET-1 presentation value (>82 pmol/L). The prognostic accuracy of CT-proET-1 regarding mortality was tantamount to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and outperformed cTnT and hs-cTnT both in patients with AMI and in patients without acute coronary syndrome. CT-proET-1 at presentation yielded high prognostic accuracy that was similar to that of the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score could be significantly improved by adding CT-proET-1 (integrated discriminatory improvement [IDI] of 0.074 P = 0.004)., Conclusions: Use of CT-proET-1 improves risk stratification of unselected patients with suspected AMI. CT-proET-1 did not provide additional diagnostic value., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: To analyse whether levels of high-sensitivity cardiac troponin (hs-cTn) below their respective 99th percentile can be used as a single parameter to rule out acute myocardial infarction (AMI) at presentation., Design: Prospective, multicentre study., Main Outcome Measures: We measured hs-cTn using four different methods (hs-cTnT Roche, hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting to the emergency department with acute chest pain. Two independent cardiologists adjudicated the final diagnosis. Patients were followed for death or AMI during a mean period of 24 months., Results: Among 2072 consecutive patients with hs-cTnT measurements available, 21.4% had an adjudicated diagnosis of AMI (sensitivity 89.6%, 95% CI 86.4% to 92.3%, negative predictive value (NPV): 96.5%, 95% CI 95.4% to 97.4%). Among 1180 consecutive patients with hs-cTnI Siemens measurements available, 20.0% had AMI (sensitivity 94.1%, 95% CI 90.3% to 96.7%, NPV: 98.0%, 95% CI: 96.6% to 98.9%). Among 1151 consecutive patients with hs-cTnI Beckman Coulter measurements available, 19.7% had AMI (sensitivity 92.1%, 95% CI 87.8% to 95.2%, NPV: 97.5%, 95% CI 96.0% to 98.5%). Among 1567 consecutive patients with hs-cTnI Abbott measurements available, 20.0% had AMI (sensitivity 77.2%, 95% CI 72.1% to 81.7%, NPV: 94.3%, 95% CI 92.8% to 95.5%)., Conclusions: Normal hs-cTn levels at presentation should not be used as a single parameter to rule out AMI as 6%-23% of adjudicated AMI cases had normal levels of hs-cTn levels at presentation. Our data highlight the lack of standardisation among hs-cTnI assays resulting in substantial differences in sensitivity and NPV at the 99th percentile.

Background: We examined whether undetectable levels of high-sensitivity cardiac Troponin (hs-cTn) can be used to rule out acute myocardial infarction (AMI) with a single blood draw at presentation to the emergency department (ED)., Methods and Results: In a prospective multicenter study we used 4 different hs-cTn assays (hs-cTnT Roche, and hs-cTnI Siemens, hs-cTnI Beckman Coulter and hs-cTnI Abbott) in consecutive patients presenting with acute chest pain. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available data including serial hs-cTnT levels. Mean follow up was 24 months. Among 2072 consecutive patients with available hs-cTnT levels, 21% had an adjudicated diagnosis of AMI. Among AMI patients, 98.2% had initially detectable levels of hs-cTnT (sensitivity 98.2%, 95%CI 96.3%-99.2%, negative predictive value (NPV) 98.6%, 95%CI 97.0%-99.3%). Undetectable levels of hs-cTnT ruled out AMI in 26.5% of patients at presentation. The NPV was similar with the three hs-cTnI assays: among 1180 consecutive patients with available hs-cTnI (Siemens), the NPV was 98.8%; among 1151 consecutive patients with available hs-cTnI (Beckman Coulter), the NPV was 99.2%; among 1567 consecutive patients with available hs-cTnI (Abbott), the NPV was 100.0%. The percentage of patients with undetectable levels of hs-cTnI was similar among the three hs-cTnI assays and ranged from 11.4% to 13.9%., Conclusions: Undetectable levels of hs-cTn at presentation have a very high NPV and seem to allow the simple and rapid rule out of AMI. This criteria applies to much more patients with hs-TnT as compared to the investigated hs-cTnI assays., (© 2013.)

Background: Current guidelines require a change (rise and/or fall) in levels of cardiac troponin (cTn) for the diagnosis of acute myocardial infarction (AMI). It is unknown whether absolute or relative changes provide higher accuracy when using high-sensitivity cTnI assays., Methods: In a prospective international multicentre study, we assessed the diagnostic accuracy of early absolute and relative changes in cTnI measured with two novel pre-commercial high-sensitivity assays (Siemens and Beckman Coulter) in 943 unselected patients presenting to the ED with suspected AMI. The final diagnosis of AMI was adjudicated using all available data including serial hs-cTnT levels by two independent cardiologists., Results: The diagnostic accuracy of absolute changes in the diagnosis of AMI as quantified by the area under the receiver operating characteristics curve (AUC) was very high (e.g. at 2 h, Siemens high-sensitivity cTnI AUC 0.93, 95%Cl 0.90-0.96; Beckman Coulter high-sensitivity cTnI AUC 0.93, 95%Cl 0.90-0.96) and superior to relative changes at all time points (p < 0.001). The results were consistent in clinically important subgroups. Direct comparison of the absolute changes in the two high-sensitivity cTnI assays showed similar accuracy. When combined with the baseline cTnI levels, the difference between absolute and relative changes became much smaller and remained statistically significant only for the Siemens assay., Conclusions: As single variables early absolute changes in high-sensitivity cTnI levels have significantly higher diagnostic accuracy than relative changes. When combined with the baseline cTn level, reflecting clinical practice, both absolute and relative changes provided very high accuracy with much smaller differences between both approaches., (© 2013.)

Background: Absolute changes in high-sensitivity cardiac troponin T (hs-cTnT) seem to have higher diagnostic accuracy in the early diagnosis of acute myocardial infarction compared with relative changes. It is unknown whether the same applies to high-sensitivity cardiac troponin I (hs-cTnI) assays and whether the combination of absolute and relative change might further increase accuracy., Methods: In a prospective, international multicenter study, high-sensitivity cardiac troponin (hs-cTn) was measured with 3 novel assays (hs-cTnT, Roche Diagnostics Corp, Indianapolis, Ind; hs-cTnI, Beckman Coulter Inc, Brea, Calif; hs-cTnI, Siemens, Munich, Germany) in a blinded fashion at presentation and after 1 and 2 hours in a blinded fashion in 830 unselected patients with suspected acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists., Results: The area under the receiver operating characteristic curve for diagnosing acute myocardial infarction was significantly higher for 1- and 2-hour absolute versus relative hs-cTn changes for all 3 assays (P < .001). The area under the receiver operating characteristic curve of the combination of 2-hour absolute and relative change (hs-cTnT 0.98 [95% confidence interval {CI}, 0.97-0.99]; hs-cTnI, Beckman Coulter Inc, 0.97 [95% CI, 0.96-0.99]; hs-cTnI, Siemens, 0.96 [95% CI, 0.93-0.99]) were high and provided some benefit compared with the use of absolute change alone for hs-cTnT, but not for the hs-cTnI assays. Reclassification analysis confirmed the superiority of absolute changes versus relative changes., Conclusions: Absolute changes seem to be the preferred metrics for both hs-cTnT and hs-cTnI in the early diagnosis of acute myocardial infarction. The combination of absolute and relative changes provides a small added value for hs-cTnT, but not for hs-cTnI., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Concerns have been raised about possible gender disparities in cardiac investigations and/or outcome. This study sought to examine and compare the diagnostic and prognostic performance of selected cardiac biomarkers in women versus men., Methods: In a prospective, multicenter cohort of patients with acute chest pain cardiac troponin T (cTnT) (fourth-generation Roche assay), high-sensitivity cTnT (hs-cTnT), and copeptin were measured at presentation., Results: Of 1,247 patients, 420 were women and 827 were men. Although the rate of acute myocardial infarction was similar in women (14.5%) and men (16.6%, P = .351), women more frequently had cardiac but noncoronary causes of chest pain (17.4% vs 10.8%, P = .001) and less frequently had unstable angina (8.8% vs 16.6%, P = .002) than men. Diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (AUC) for acute myocardial infarction in women was 0.90 (95% CI 0.84-0.95) for cTnT, which was lower than the AUC for hs-cTnT alone (0.94, 95% CI [0.91-0.98]), the combination of cTnT with copeptin (0.96, 95% CI [0.94-0.98]) or the combination of hs-cTnT with copeptin (0.96, 95% CI [0.93-0.98]) (P = .008, P = .006, and P = .002, respectively). Prognostic accuracy as quantified by the AUCs for 1-year mortality was 0.69 (0.56-0.83), 0.86 (0.79-0.93), 0.87 (0.81-0.94), and 0.87 (0.80-0.94), respectively. No relevant gender differences in AUCs were observed., Conclusion: The diagnostic and prognostic performance of cTnT, hs-cTnT, and copeptin is as good in women as in men. High-sensitivity cTnT and the combination of cTnT and copeptin outperform cTnT alone, both in women and men., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: To investigate the diagnostic and prognostic role of heart-type fatty acid-binding protein (hFABP) compared with copeptin and in addition to high-sensitivity cardiac troponin T (hs-cTnT) in patients with chest pain suspected of acute myocardial infarction (AMI)., Design: Diagnostic and prognostic performances of hFABP, copeptin and hs-cTnT were evaluated and compared. The final diagnosis was adjudicated by two independent cardiologists., Setting: This prospective observational multicentre study took place in four primary and one secondary hospital from April 2006 to September 2009., Patients: We enrolled 1247 consecutive patients with suspected AMI to the emergency department. For analysis, patients were included, if baseline levels for hs-cTnT and hFABP were available (n=1074), patients with ST-segment elevation myocardial infarction (STEMI) were excluded for the diagnostic analysis (n=43)., Interventions: Treatment was left to the discretion of the emergency physician., Main Outcome Measures: AMI and mortality., Results: 4% of the patients had STEMI and 16% of the patients had non-STEMI. Patients with AMI had significantly higher levels of hFABP at presentation (p<0.001). Neither the combination with hFABP nor with copeptin increased the diagnostic accuracy of hs-cTnT at admission, quantified by the area under the receiver operating characteristic curve (AUC) (p>0.05). The negative predictive value regarding 90-day, 1-year and 2-year mortality was 100% (99-100), 99% (98-100) and 98% (96-99), respectively, for hFABP levels below the median (p<0.001). The accuracy of hFABP to predict 90-day mortality was moderate (AUC 0.83; 95% CI 0.77 to 0.90)., Conclusions: hFABP and copeptin do not improve the diagnosis of patients with chest pain without ST-segment elevation, but may be useful for risk stratification beyond hs-TnT.

Background: It is unknown whether unstable angina (UA) results in previously nondetectable low-level myocardial necrosis. We compared the pattern of myocardial necrosis between patients with UA, acute myocardial infarction (AMI), and noncardiac chest pain (NCCP) using 3 high-sensitive cardiac troponin (hs-cTn) assays., Methods: In a multicenter study, we enrolled 842 unselected patients with acute chest pain in the emergency department. Roche hs-cTnT, Beckman Coulter hs-cTnI, and Siemens hs-cTnI were determined in a blinded fashion at presentation and after 1, 2, 3, and 6 hours. The final diagnosis was adjudicated by 2 independent cardiologists., Results: A change in hs-cTn of ≥2 ng/L within the first hour after presentation as assessed with Roche hs-cTnT, Beckman Coulter hs-cTnI, and Siemens hs-cTnI was observed in 26%, 31%, and 32% of patients with UA (n = 115) compared with 91%, 92%, and 96% in patients with AMI (n = 120) and 12%, 23%, and 16% in patients with NCCP (n = 415; P < .001 for all comparisons between UA and AMI, P > .05 for all comparisons between UA and NCCP). In patients with UA, such a 1-hour change in hs-cTn of ≥2 ng/L was associated with an increased risk of death or AMI during the 30-day follow-up (P = .003, .03, .03) and 2-year follow-up (P < .001, .002, and .006)., Conclusions: In marked contrast to patients with AMI, most patients with UA do not exhibit relevant hs-cTn changes. The minority of UA with hs-cTn changes, however, has a significantly worse short- and long-term outcome., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Hypoxia precedes cardiomyocyte necrosis in acute myocardial infarction (AMI). We therefore hypothesized that uric acid - as a marker of oxidative stress and hypoxia - might be useful in the early diagnosis and risk stratification of patients with suspected AMI., Materials and Methods: In this prospective observational study, uric acid was measured at presentation in 892 consecutive patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by two independent cardiologists. Patients were followed 24 months regarding mortality. Primary outcome was the diagnosis of AMI, secondary outcome was short- and long-term mortality., Results: Uric acid at presentation was higher in patients with AMI than in patients without (372 μM vs. 336 μM; P < 0·001). The diagnostic accuracy of uric acid for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0·60 (95%Cl 0·56-0·65). When added to cardiac troponin T (cTnT), uric acid significantly increased the AUC of cTnT from 0·89 (95%Cl 0·85-0·93) to 0·92 (95%Cl 0·89-0·95, P = 0·020 for comparison). Cumulative 24-month mortality rates were 2·2% in the first, 5·4% in the second and the third and 15·6% in the fourth quartile of uric acid (P < 0·001 for log-rank). Uric acid predicted 24-month mortality independently. Adding uric acid to TIMI and GRACE risk score improved their prognostic accuracy as shown by an integrated discrimination improvement of 0·04 (P = 0·007) respective 0·02 (P = 0·021)., Conclusions: Uric acid, an inexpensive widely available biomarker, improves both the early diagnosis and risk stratification of patients with suspected AMI., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: The study objective was to compare the incidence and prognosis of acute myocardial infarction when using high-sensitivity cardiac troponin assays instead of a standard cardiac troponin assay for the diagnosis of acute myocardial infarction., Methods: In a prospective international multicenter study, we enrolled 1124 consecutive patients presenting with suspected acute myocardial infarction. Final diagnoses were adjudicated by 2 independent cardiologists 2 times using all available clinical information: first using standard cardiac troponin levels and second using high-sensitivity cardiac troponin T levels for adjudication. Patients were followed up for a mean of 19±9 months., Results: The use of high-sensitivity cardiac troponin T instead of standard cardiac troponin resulted in an increase in the incidence of acute myocardial infarction from 18% to 22% (242 vs 198 patients), a relative increase of 22%. Of the 44 additional acute myocardial infarctions, 35 were type 1 acute myocardial infarctions and 9 were type 2 acute myocardial infarctions. This was accompanied by a reciprocal decrease in the incidence of unstable angina (unstable angina, 11% vs 13%). The most pronounced increase was observed in patients adjudicated with cardiac symptoms of origin other than coronary artery disease with cardiomyocyte damage (83 vs 31 patients, relative increase of 268%). Cumulative 30-month mortality rates were 4.8% in patients without acute myocardial infarction, 16.4% in patients with a small acute myocardial infarction detected only by high-sensitivity cardiac troponin T but not standard cardiac troponin, and 23.9% in patients with a moderate/large acute myocardial infarction according to standard cardiac troponin assays and high-sensitivity cardiac troponin T (P<.001)., Conclusions: The introduction of high-sensitivity cardiac troponin assays leads to only a modest increase in the incidence of acute myocardial infarction. The novel sensitive assays identify an additional high-risk group of patients with increased mortality, therefore appropriately classified with acute myocardial infarction (Advantageous Predictors of Acute Coronary Syndromes Evaluation; NCT00470587)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: High-sensitivity cardiac troponin (hs-cTn) assays seem to improve the early diagnosis of acute myocardial infarction (AMI), but it is unknown how to best use them in clinical practice. Our objective was to develop and validate an algorithm for rapid rule-out and rule-in of AMI., Methods: A prospective multicenter study enrolling 872 unselected patients with acute chest pain presenting to the emergency department. High-sensitivity cardiac troponin T (hs-cTnT) was measured in a blinded fashion at presentation and after 1 hour. The final diagnosis was adjudicated by 2 independent cardiologists. An hs-cTnT algorithm incorporating baseline values as well as absolute changes within the first hour was derived from 436 randomly selected patients and validated in the remaining 436 patients. The primary prognostic end point was death during 30 days of follow-up., Results: Acute myocardial infarction was the final diagnosis in 17% of patients. After applying the hs-cTnT algorithm developed in the derivation cohort to the validation cohort, 259 patients (60%) could be classified as "rule-out," 76 patients (17%) as "rule-in," and 101 patients (23%) as in the "observational zone" within 1 hour. Overall, this resulted in a sensitivity and negative predictive value of 100% for rule-out, a specificity and positive predictive value of 97% and 84%, respectively, for rule-in, and a prevalence of AMI of 8% in the observational zone group. Cumulative 30-day survival was 99.8%, 98.6%, and 95.3% (P < .001) in patients classified as rule-out, observational zone, and rule-in, respectively., Conclusions: Using a simple algorithm incorporating hs-cTnT baseline values and absolute changes within the first hour allowed a safe rule-out as well as an accurate rule-in of AMI within 1 hour in 77% of unselected patients with acute chest pain. This novel strategy may obviate the need for prolonged monitoring and serial blood sampling in 3 of 4 patients.

Background: We hypothesized that high-sensitivity cardiac troponin (hs-cTn) and its early change are useful in distinguishing acute myocardial infarction (AMI) from acute cardiac noncoronary artery disease., Methods and Results: In a prospective, international multicenter study, hs-cTn was measured with 3 assays (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI Siemens) in a blinded fashion at presentation and serially thereafter in 887 unselected patients with acute chest pain. Accuracy of the combination of presentation values with serial changes was compared against a final diagnosis adjudicated by 2 independent cardiologists. AMI was the adjudicated final diagnosis in 127 patients (15%); cardiac noncoronary artery disease, in 124 (14%). Patients with AMI had higher median presentation values of hs-cTnT (0.113 μg/L [interquartile range, 0.049-0.246 μg/L] versus 0.012 μg/L [interquartile range, 0.006-0.034 μg/L]; P<0.001) and higher absolute changes in hs-cTnT in the first hour (0.019 μg/L [interquartile range, 0.007-0.067 μg/L] versus 0.001 μg/L [interquartile range, 0-0.003 μg/L]; P<0.001) than patients with cardiac noncoronary artery disease. Similar findings were obtained with the hs-cTnI assays. Adding changes of hs-cTn in the first hour to its presentation value yielded a diagnostic accuracy for AMI as quantified by the area under the receiver-operating characteristics curve of 0.94 for hs-cTnT (0.92 for both hs-cTnI assays). Algorithms using ST-elevation, presentation values, and changes in hs-cTn in the first hour accurately separated patients with AMI and those with cardiac noncoronary artery disease. These findings were confirmed when the final diagnosis was readjudicated with the use of hs-cTnT values and validated in an independent validation cohort., Conclusion: The combined use of hs-cTn at presentation and its early absolute change excellently discriminates between patients with AMI and those with cardiac noncoronary artery disease., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Background: The appropriate management of patients discharged from the emergency department (ED) with increased high-sensitivity cardiac troponin T (hs-cTnT) but normal or borderline-high conventional cardiac troponin concentrations is unknown., Methods: We investigated 643 consecutive ED patients with acute chest pain who had been discharged for outpatient management after acute myocardial infarction (AMI) had been ruled out by serial measurements of conventional cardiac troponin. hs-cTnT was measured blindly, and we calculated the rates of all-cause mortality (primary endpoint) and subsequent AMI (secondary endpoint) at 30, 90, and 360 days., Results: hs-cTnT concentrations were increased (>14 ng/L) in 114 patients (18%) but <30 ng/L in 95% of these patients. Of those 114 patients, 96 (84%) had an adjudicated noncoronary cause of chest pain. Thirty-day mortality (95% CI) was 0.9% (0.1%-6.1%), 90-day mortality was 2.7% (0.9%-8.1%), and 360-day mortality was 5.2% (2.2%-11.9%) in patients with increased hs-cTnT; respective rates (95% CI) of AMI were 0.0%, 1.9% (0.5%-7.2%), and 7.6% (3.7%-15.3%). Increased hs-cTnT was associated with increased mortality and AMI at 90 days (P = 0.006 and P = 0.081, respectively) and 360 days (P = 0.001 for both)., Conclusions: hs-cTnT is a strong prognosticator of intermediate and long-term mortality and AMI in low-risk patients discharged from the ED after AMI has been ruled out. The relatively low rate of 30-day events may suggest that patients without acute coronary syndrome and small increases in cardiac troponin are in need of further investigations and treatments, but not necessarily immediate hospitalization.

We hypothesized that midregional pro-A-type natriuretic peptide (MR-proANP), the stable midregional epitope of proANP, might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI). In this multicenter study we measured MR-proANP, cardiac troponin T (cTnT), and high-sensitive cTnT (hs-cTnT) at presentation in 675 consecutive patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed 360 days for mortality and AMI. AMI was the final diagnosis in 119 patients (18%). Median MR-proANP levels at presentation were significantly higher in patients with AMI (189 pmol/L, interquartile range 97 to 341) versus patients with another final diagnosis (83 pmol/L, 49 to 144, p <0.001). However, neither the combination of MR-proANP with cTnT nor its combination with hs-cTnT significantly improved diagnostic accuracy as quantified by area under the receiver operating characteristic curve (0.91 vs 0.89 for cTnT alone, p = 0.086; 0.95 vs 0.96 for hs-cTnT, respectively, p = 0.02). Cumulative 360-day mortality/AMI rates were 2.4% in the first, 3.6% in the second, 9.5% in the third, and 18.8% in the fourth quartiles of MR-proANP (p <0.001). MR-proANP (area under the curve 0.76) predicted mortality/AMI independently of and more accurately than cTnT (area under the curve 0.62), hs-cTnT (area under the curve 0.71), and Thrombolysis In Myocardial Infarction risk score (area under the curve 0.72). Net reclassification improvements offered by the additional use of MR-proANP were 0.388 (p <0.001), 0.425 (p <0.001), and 0.217 (p = 0.007), respectively. In conclusion, MR-proANP improves risk prediction for 360-day mortality/AMI but does not seem to help in the early diagnosis of AMI., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: We sought to examine the diagnostic and prognostic utility of sensitive cardiac troponin (cTn) assays in patients with pre-existing coronary artery disease (CAD)., Methods and Results: We conducted a multicentre study to examine the diagnostic accuracy of one high-sensitive and two sensitive cTn assays in 1098 consecutive patients presenting with symptoms suggestive of acute myocardial infarction (AMI), of whom 401 (37%) had pre-existing CAD. Measurements of Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, Abbott-Architect cTnI and the standard assay (Roche cTnT) were performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the final diagnosis in 19% of CAD patients. Among patients with diagnoses other than AMI, baseline cTn levels were elevated above the 99th percentile with Roche hs-cTnT in 40%, with Siemens TnI-Ultra in 15%, and Abbott-Architect cTnI in 13% of them. In patients with pre-existing CAD, the diagnostic accuracy at presentation, quantified by the area under the receiver operator characteristic curve (AUC), was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.92; Siemens cTnI-Ultra, 0.94; and Abbott-Architect cTnI, 0.93 vs. AUC for the standard assay, 0.87; P < 0.01 for all comparisons). Elevated levels of cTn measured with the sensitive assays predicted mortality irrespective of pre-existing CAD, age, sex, and cardiovascular risk factors., Conclusion: Sensitive cTn assays have high-diagnostic accuracy also in CAD patients. Mild elevations are common in non-AMI patients and test-specific optimal cut-off levels tend to be higher in CAD patients than in patients without history of CAD. Sensitive cTn assays also retain prognostic value. (ClinicalTrials.gov number, NCT00470587).

Objective: The early diagnosis of acute myocardial infarction (AMI) can be particularly challenging in patients with known coronary artery disease (CAD) due to pre-existing ECG changes and chronic increases in cardiac troponin (cTn) levels., Design: Of 1170 consecutive patients presenting with symptoms suggestive of AMI, 433 (37%) with pre-existing CAD were analysed in a prospective multicentre study and the diagnostic and prognostic impact of copeptin in combination with either fourth generation cardiac troponin T (cTnT) or high-sensitivity cTnT (hs-cTnT) was evaluated., Results: AMI was the final diagnosis in 78 patients with pre-existing CAD (18%). Copeptin was significantly higher in patients with AMI than in those without (26 pmol/l (IQR 9-71) vs 7 pmol/l (IQR 4-16), p<0.001). The diagnostic accuracy for AMI as quantified by the area under the receiver operating characteristic curve (AUC) was significantly higher for the combination of copeptin and cTnT than for cTnT alone (0.94 vs 0.86, p<0.001). The combination of copeptin and hs-cTnT (0.94) was trending to superiority compared with hs-cTnT alone (0.92, p=0.11). The combination of copeptin and the cTn assays was able to improve the negative predictive value up to 99.5% to rule out AMI. Copeptin was a strong and independent predictor of 1-year mortality (HR 4.18-4.63). Irrespective of cTn levels, patients with low levels of copeptin had an excellent prognosis compared with patients with raised levels of both copeptin and cTn (360-day mortality 2.8-3.6% vs 23.1-33.8%, p<0.001)., Conclusion: In patients with pre-existing CAD, copeptin significantly improves the diagnostic accuracy if used in addition to cTnT, but only trended to superiority compared with hs-cTnT alone. Copeptin provides independent prognostic information, largely by overcoming the challenging interpretation of mild increases in hs-cTnT., Clinical Trial Registration Number: ClinicalTrials Gov number NCT00470587.

Cardiac troponin (cTn) I and T are structural proteins unique to the heart. Detection of cTn in peripheral blood indicates cardiomyocyte damage. As acute myocardial infarction (AMI) is the most important cause of cardiomyocyte damage, cTns have become an integral part in the diagnosis of AMI. For this indication, cTns are superior to all other biomarkers and therefore are the preferred marker for the diagnosis of AMI. However, cTn indicates and provides an estimate of cardiomyocyte damage irrespective of its cause. The major limitation of contemporary cTn assays is that they are often not elevated during the initial hours of AMI. Recent advances in assay technology have led to more sensitive and precise cTn assays that will have a profound impact on clinical practice. High-sensitive cTn (hs-cTn) assays have two differentiating features from contemporary cTn assays: (i) detection of cTn in a majority of healthy persons and (ii) precise definition of what is 'normal' (=the 99th percentile). Recent multicentre studies have shown that hs-cTn assays improve the early diagnosis of patients with suspected AMI, particularly the early rule-out. To achieve best clinical use, cTn has to be interpreted as a quantitative variable. Rising and/or falling levels differentiate acute from chronic cardiomyocyte damage. The terms 'troponin-positive' and 'troponin negative' should therefore be avoided. 'Detectable' levels will become the norm and will have to be differentiated from 'elevated' levels. The differential diagnosis of a small amount of cardiomyocyte damage and therefore minor elevations of cTn is broad and includes acute and chronic cardiac disorders. The differential diagnosis of larger amount of injury and therefore more substantial elevations of cTn is largely restricted to AMI, myocarditis, and a rare patient with tako-tsubo cardiomyopathy.

Background: Plaque erosion and plaque rupture occur early in the pathophysiology of acute myocardial infarction (AMI). We hypothesized that markers of plaque instability might be useful in the early diagnosis and risk stratification of AMI., Methods: In this multicenter study, we examined 4 markers of plaque instability, myeloperoxidase (MPO), myeloid-related protein 8/14 (MRP-8/14), pregnancy-associated plasma protein-A (PAPP-A), and C-reactive protein (CRP) in 398 consecutive patients presenting to the emergency department with acute chest pain and compared them to normal and high-sensitivity cardiac troponin T (cTnT and hs-cTnT). The final diagnosis was adjudicated by 2 independent cardiologists. Primary prognostic end point was death during a median follow-up of 27 months., Results: The adjudicated final diagnosis was AMI in 76 patients (19%). At emergency department presentation, concentrations of all 4 biomarkers of plaque instability were significantly higher in patients with AMI than in patients with other diagnoses. However, their diagnostic accuracy as quantified by the area under the ROC curve (AUC) was low (MPO 0.63, MRP-8/14 0.65, PAPP-A 0.62, CRP 0.59) and inferior to both normal and high-sensitivity cardiac troponin T (cTnT 0.88, hs-cTnT 0.96; P<0.001 for all comparisons). Thirty-nine patients (10%) died during follow-up. Concentrations of MPO, MRP-8/14, and CRP were higher in nonsurvivors than in survivors and predicted all-cause mortality with moderate accuracy., Conclusions: Biomarkers of plaque instability do not seem helpful in the early diagnosis of AMI but may provide some incremental value in the risk stratification of patients with acute chest pain.

Background: High-sensitivity cardiac troponin assays have better analytical precision and sensitivity than earlier-generation assays when measuring cardiac troponin at low concentrations. We evaluated whether use of a high-sensitivity assay could further improve risk stratification compared with a standard cardiac troponin assay., Methods: We enrolled consecutive patients presenting with acute chest pain, 30% of whom were diagnosed with acute coronary syndrome. Blood samples were drawn at the time of presentation. We measured cardiac troponin T with a standard fourth-generation assay (cTnT) and a high-sensitivity assay (hs-cTnT) (both Roche Diagnostics) and followed the patients for 24 months., Results: Of the 1159 patients, 76 died and 42 developed an acute myocardial infarction (AMI). Prognostic accuracy of hs-cTnT for death was significantly higher [area under ROC curve (AUC) 0.79, 95% CI 0.74-0.84] than that of cTnT (AUC 0.69, 95% CI 0.62-0.76; P < 0.001). After adjustment for Thrombolysis in Myocardial Infarction (TIMI) risk score (that included the cTnT assay result), hs-cTnT above the 99th percentile (0.014 μg/L) was associated with a hazard ratio for death of 2.60 (95% CI 1.42-4.74). Addition of hs-cTnT to the risk score improved the reclassification of patients (net reclassification improvement 0.91; 95% CI 0.67-1.14; P < 0.001). Subgroup analyses showed that this effect resulted from the better classification of patients without AMI at time of testing. hs-cTnT outperformed cTnT in the prediction of AMI during follow-up (P=0.02), but was not independently predictive for this endpoint., Conclusions: Concentrations of hs-cTnT >0.014 μg/L improve the prediction of death but not subsequent AMI in unselected patients presenting with acute chest pain.

Background: As the clinical, electrocardiographic and laboratory presentation of Tako-Tsubo cardiomyopathy (TTC) and acute myocardial infarction (AMI) is similar, both entities are in general only distinguishable by coronary angiography. The purpose of this study was to examine the endogenous stress response at presentation, quantified by the copeptin level, of patients with TTC and patients with AMI, as copeptin may be useful in the non-invasive differentiation between both diseases., Methods: We compared the endogenous stress response at initial presentation, quantified by the plasma copeptin levels, in 21 consecutive patients finally diagnosed with TTC and 21 patients finally diagnosed with AMI matched for sex and time since chest pain onset., Results: The prevalence of cardiovascular risk factors and initial cardiac troponin T levels were comparable in TTC and AMI. Copeptin levels were significantly lower in patients with TTC when compared to patients with AMI (median 4·8 [interquartile range, IQR 3·5-13·5] pM vs. 25·6 [IQR 12·1-63·9] pM, P = 0·002). The accuracy for diagnosing TTC as quantified by the area under the receiver operating characteristics curve was significantly higher for copeptin than for cardiac troponin T (0·782 vs. 0·549, P = 0·031). The optimal cut-off value for differentiation between TTC and AMI was found at a copeptin level of 7·8 pM (sensitivity 67% at a specificity of 86%, negative predictive value 72%, positive predictive value 82%)., Conclusions: The endogenous stress response, quantified by a novel sensitive biomarker, seems to be different in patients with TTC and AMI. Copeptin levels may be helpful in the non-invasive differentiation between TTC and AMI., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Myocardial ischemia is a strong trigger of N-terminal pro-B-type natriuretic peptide (NT-proBNP) release. As ischemia precedes necrosis in acute myocardial infarction, we hypothesized that NT-proBNP might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction., Methods: In a prospective multicenter study, NT-proBNP was measured at presentation in 658 consecutive patients with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long term regarding mortality., Results: Acute myocardial infarction was the adjudicated final diagnosis in 117 patients (18%). NT-proBNP levels at presentation were significantly higher in acute myocardial infarction as compared with patients with other final diagnoses (median 886 pg/mL vs 135 pg/mL, P <.001). The diagnostic accuracy of NT-proBNP for acute myocardial infarction as quantified by the area under the receiver operating characteristic curve (AUC) was 0.79 (95% confidence interval [CI], 0.75-0.83). When added to cardiac troponin T, NT-proBNP significantly increased the AUC from 0.89 (95% CI, 0.84-0.93) to 0.91 (95% CI, 0.88-0.94; P=.033). Cumulative 24-month mortality rates were 0% in the first, 1.3% in the second, 8.3% in the third, and 23.3% in the fourth quartile of NT-proBNP (P <.001). NT-proBNP (AUC 0.85, 95% CI, 0.81-0.89) predicted all-cause mortality independently of and more accurately than both cardiac troponin T (AUC 0.66, 95% CI, 0.58-0.74; P <.001) and the Thrombolysis in Myocardial Infarction risk score (AUC 0.79, 95% CI, 0.74-0.84; P <.001). Net reclassification improvement (Thrombolysis in Myocardial Infarction vs additionally NT-proBNP) was 0.188 (P <.009), and integrated discrimination improvement was 0.100 (P <.001)., Conclusions: Use of NT-proBNP improves the early diagnosis and risk stratification of patients with suspected acute myocardial infarction., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Current guidelines for the diagnosis of acute myocardial infarction (AMI), among other criteria, also require a rise and/or fall in cardiac troponin (cTn) levels. It is unknown whether absolute or relative changes in cTn have higher diagnostic accuracy and should therefore be preferred., Methods and Results: In a prospective, observational, multicenter study, we analyzed the diagnostic accuracy of absolute (Δ) and relative (Δ%) changes in cTn in 836 patients presenting to the emergency department with symptoms suggestive of AMI. Blood samples for the determination of high-sensitive cTn T and cTn I ultra were collected at presentation and after 1 and 2 hours in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists. The area under the receiver operating characteristic curve for diagnosing AMI was significantly higher for 2-hour absolute (Δ) versus 2-hour relative (Δ%) cTn changes (area under the receiver operating characteristic curve [95% confidence interval], high-sensitivity cTn T: 0.95 [0.92 to 0.98] versus 0.76 [0.70 to 0.83], P<0.001; cTn I ultra: 0.95 [0.91 to 0.99] versus 0.72 [0.66 to 0.79], P<0.001). The receiver operating characteristic curve-derived cutoff value for 2-hour absolute (Δ) change was 0.007 μg/L for high-sensitivity cTn T and 0.020 μg/L for cTn I ultra (both cutoff levels are half of the 99th percentile of the respective cTn assay). Absolute changes were superior to relative changes in patients with both low and elevated baseline cTn levels., Conclusions: Absolute changes of cTn levels have a significantly higher diagnostic accuracy for AMI than relative changes, and seem therefore to be the preferred criteria to distinguish AMI from other causes of cTn elevations., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT00470587.

Background: Neutrophils are rapidly released into the circulation upon acute stress such as trauma or acute myocardial infarction (AMI). We hypothesized that neutrophil count might provide incremental value in the early diagnosis and risk stratification of AMI., Methods: We conducted a prospective observational multicenter study to examine the diagnostic accuracy of the combination of neutrophil count and cardiac troponin T from 1125 consecutive patients who presented to the Emergency Department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists., Results: Neutrophil count was higher in patients with acute myocardial infarction compared with other diagnoses (median 6.7 vs. 5.0×10(9)/L, respectively, P <.001). The accuracy of the neutrophil count for diagnosing acute myocardial infarction, quantified by the area under the receiver operating characteristic curve (AUC) was 0.69, which was significantly lower than that of cardiac troponin T (AUC 0.89, P <.001). The combination of the neutrophil count and cardiac troponin T did not improve the early diagnosis of acute myocardial infarction versus cardiac troponin T alone (P=.79). The prognostic accuracy of neutrophil count for death and AMI was significantly lower than that of cardiac troponin T. However, patients in the highest tertile of neutrophil count had a significantly increased risk of death and AMI at 90 and 360 days compared with patients in the lowest tertile (hazard ratios 2.47 [95% confidence interval, 1.63-3.72] and 2.28 [95% confidence interval, 1.55-3.36], respectively)., Conclusion: The neutrophil count does not improve the early diagnosis of AMI in patients presenting with chest pain but identifies patients at increased risk of death., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: To examine the diagnostic accuracy of sensitive cardiac troponin (cTn) assays in elderly patients, since elevated levels with sensitive cTn assays were reported in 20% of elderly patients without acute myocardial infarction (AMI)., Methods and Results: In this multi-centre study, we included 1098 consecutive patients presenting with symptoms suggestive of AMI, 406 (37%) were >70 years old. Measurement of three investigational sensitive cTn assays [Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, and Abbott-Architect cTnI) and the standard assay (Roche cTnT) was performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the adjudicated final diagnosis in 24% of elderly patients. Among elderly patients without AMI, baseline cTn levels were elevated above the 99th percentile in 51% with Roche hs-cTnT, in 17% with Siemens TnI-Ultra, and 13% with Abbott-Architect cTnI. The diagnostic accuracy as quantified by the area under the receiver operating characteristic (ROC) curve (AUC) was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.94; Siemens cTnI-Ultra, 0.95; and Abbott-Architect cTnI, 0.95 vs. AUC for the standard assay, 0.90; P < 0.05 for comparisons). The best cut-offs for the sensitive cTn-assays determined by the ROC-curve in elderly patients differed clearly from those in younger patients. Furthermore, the prognostic value regarding 90-day mortality varied among the sensitive cTn assays., Conclusion: Sensitive cTn assays have high diagnostic accuracy also in the elderly. Mild elevations are common in elderly non-AMI patients, therefore the optimal cut-off levels are substantially higher in elderly as compared with younger patients. Furthermore, sensitive cTn assays yielded different prognostic value.

Cardiac troponin I and T (cTn) are structural proteins unique to the heart. Detection of cTn in peripheral blood indicates cardiomyocyte necrosis. As acute myocardial infarction (AMI) is the most important cause of cardiomyocyte necrosis, cTns have become an integral part in the diagnosis of AMI. In this indication, cTns are superior to all other biomarkers indicating cardiomyocyte necrosis such as CK-MB and myoglobin, and are therefore considered the preferred marker in the diagnosis of AMI. It is important to highlight that cTn indicates and quantifies cardiomyocyte necrosis irrespective of its cause? The major limitation of contemporary cTn assays is a sensitivity deficit in the first few hours of AMI due to a delayed increase of circulating levels. Recent advances in assay technology have lead to a refinement in cardiac troponin (cTn) assays that have had a profound impact on clinical practice. High-sensitive cTn assays have two differentiating features from contemporary cTn assays: 1) detection of cTn in healthy persons and 2) a precise definition of what is "normal" (= the 99th percentile). Recent multicentre studies have shown that high-sensitive cTn assays improve the early diagnosis of AMI. To achieve the best clinical use, cTn has to be interpreted as a quantitative variable. Rising and/or falling levels differentiate acute from chronic cardiomyocyte necrosis. The term "troponin-positive" should therefore be avoided. "Detectable" levels will become the norm and have to be clearly differentiated from "elevated" levels. The differential diagnosis of a small amount of cardiomyocyte necrosis and therefore mild elevation of cTn is broad and includes acute and chronic cardiac disorders. The differential diagnosis of a large amount of cardiomyocyte necrosis and therefore substantial elevation of cTn is much smaller and largely restricted to AMI, myocarditis and tako-tsubo cardiomyopathy.

Background: Myocardial ischemia is a strong trigger of B-type natriuretic peptide (BNP) release. As ischemia precedes necrosis in acute myocardial infarction, we hypothesized that BNP might be useful in the early diagnosis and risk stratification of patients with acute chest pain., Methods: In a prospective, international multicenter study, BNP was measured in 1075 unselected patients with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed long term regarding mortality., Results: Acute myocardial infarction was the adjudicated final diagnosis in 168 patients (16%). BNP levels at presentation were significantly higher in acute myocardial infarction as compared with patients with other diagnoses (median 224 pg/mL vs. 56 pg/mL, P <.001). The diagnostic accuracy of BNP for the diagnosis of acute myocardial infarction as quantified by the area under the receiver operating characteristic curve (AUC) (0.74; 95% confidence interval [CI], 0.70-0.78) was lower compared with cardiac troponin T at presentation (AUC 0.88; 95% CI, 0.84-0.92; P <.001). Cumulative 24-month mortality rates were 0.5% in the first, 2.1% in the second, 7.0% in the third, and 22.9% in the fourth quartile of BNP (P <.001). BNP predicted all-cause mortality independently of and more accurately than cardiac troponin T: AUC 0.81 (95% CI, 0.76-0.86) versus AUC 0.70 (95% CI, 0.62-0.77; P <.001). Net reclassification improvement for BNP was 0.10 (P=.04), and integrated discrimination improvement 0.068 (P=.01)., Conclusions: BNP accurately predicts mortality in unselected patients with acute chest pain independently of and more accurately than cardiac troponin T, but does not seem to help in the early diagnosis of acute myocardial infarction., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: Angiogenic factors play an important role in the development of atherosclerosis and show pronounced changes during acute myocardial infarction (AMI). We analysed the impact of placental growth factor (PlGF) and its endogen opponent, soluble fms-like tyrosine kinase-1 (sFlt-1), on clinical outcome and the early diagnosis of AMI., Methods and Results: This multicentre study enrolled patients presenting with symptoms suggestive of AMI. The final diagnosis was adjudicated by two independent physicians. Levels of sFlt-1 and PlGF were compared with results of a standard troponin T and a novel high-sensitive troponin (hsTnT) assay. Of the 763 patients enrolled, 132 were diagnosed with AMI. Multivariable Cox regression analysis demonstrated sFlt-1 >84 ng/L [hazard ratios (HR) 2.6, 95% confidence intervals (CI) 1.2-5.4, P=0.01] and PlGF >20 ng/L (HR 3.6, 95% CI 1.3-10.4, P=0.02) as predictors for mortality during 1-year follow-up, independent from information provided by troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP). However, only sFlt-1 persisted as independent predictor for mortality when analysed together with hsTnT and NT-proBNP, and after adjusting for significant clinical parameters. For the diagnosis of AMI, the combination of troponin T and sFlt-1 improved the performance of troponin T alone and led to a negative predictive value of 98.3% already at time of presentation. However, sFlt-1 and PlGF added only limited diagnostic information when used together with hsTnT., Conclusion: Only sFlt-1 but not PlGF provides overall independent prognostic information in patients presenting with symptoms suggestive of AMI. After the introduction of hsTnT in clinical routine, sFlt-1 and PlGF can only add limited diagnostic information for the detection or exclusion of AMI., Clinical Trial Registration Information: ClinicalTrials.gov, NCT00470587.

Aims While cardiac troponin measurements have significantly improved the early diagnosis of myocardial infarction, the timely biomarker-based diagnosis of unstable angina pectoris (UAP) remains a major unmet clinical challenge. The aim of this study was to assess levels of circulating microRNAs (miRNAs) as possible novel biomarkers in patients with UAP. Methods and results A three-phase approach was conducted, comprising (i) profiling of miRNAs in patients with UAP and controls groups; (ii) replication of significant miRNAs in an independent patient cohort, (iii) validation of a multi-miRNAs panel in a third cohort. Out of 25 miRNAs selected for replication, 8 miRNAs remained significantly associated with UAP. In a validation phase, a miRNA panel including miR-132, miR-150, and miR-186 showed the highest discriminatory power [area under the receiver-operating-characteristic curve (AUC): 0.91; CI: 0.84–0.98]. Conclusion Using a profiling-replication-validation model, we identified eight miRNAs, which may facilitate the diagnosis of UAP. [ABSTRACT FROM PUBLISHER]

Objective: To compare the accuracy of the GRACE score, a strong prognosticator in acute coronary syndrome (ACS) that is calculated using conventional cardiac troponin (cTn) assays, with that calculated with highsensitivity cTn (hs-cTn) and with the combination of the GRACE score with hs-cTn or B-type natriuretic peptide (BNP). Design: Prospective international cohort. Settings University Hospital. Patients Patients enrolled in the Predictors of Acute Coronary Syndromes Evaluation prospective study with proven ACS. Main outcome measured The capacity to predict in-hospital mortality, 1-year mortality and combined death/acute myocardial infarction (AMI) at 1 year. Results: 370 patients were enrolled (173 with unstable angina and 197 with AMI). In-hospital mortality was 4.1%; 1-year mortality was 12.5%. The GRACE score was significantly higher in patients who died than in those discharged alive (200 (174e222) vs 125 (98e155); p<0.001), and in those who died than in those who survived for 1 year (151 (133e169) vs 104 (85e125); p<0.001). The area under the curve of the GRACE score was 0.87 regarding in-hospital mortality and 0.88 for 1-year mortality; if calculated with hs-cTn, it was 0.87 and 0.88, respectively (p¼NS for all comparisons). The addition of hs-cTn to the GRACE score resulted in no increased value, whereas the addition of BNP tended to improve 1-year mortality prediction (p¼0.058). Conclusion: The GRACE score is accurate for determining both in-hospital and long-term mortality in patients with ACS in the era of hs-cTn. The addition of hs-cTn or BNP to the GRACE score does not significantly improve risk prediction. [ABSTRACT FROM AUTHOR]

Abstract: Background: The introduction of high-sensitivity cardiac troponin (hs-cTn) assays allows the assessment of clinical decision values below the 99th percentile. Methods: Final diagnosis and one-year mortality were adjudicated in a multicenter, prospective cohort of 1181 patients presenting with acute chest pain to the emergency department. Hs-cTnT (Roche) and cTnI-ultra (Siemens) were measured in a blinded fashion. Results: At presentation hs-cTnT and cTnI-ultra were below the limit of blank (LOB) in 201 (17%) and 549 (47%) patients, below the 75th percentile in 379 (32%) and 623 (53%) patients, below the 95th percentile in 603 (51%) and 808 (68%), and below the 99th percentile in 748 (63%) and 913 (77%), respectively. Sensitivities for the diagnosis of AMI were 100.0% and 96.8% respectively for hs-cTnT and cTnI-ultra (LOB as cut-off value), 99.5% and 96.2% (75th percentile), 96.8% and 93.0% (95th percentile), and 94.1% and 88.1% (99th percentile). The proportion of patients correctly classified as having or not AMI increased from 32.9% (LOB as cut-off value) to 47.8% (75th percentile), 65.9% (95th percentile) and 77.3% (99th percentile) for hs-cTnT and from 61.2% to 67.3%, 81.9% and 89.3% respectively for cTnI-ultra. At 1year, all-cause mortality was very low and similar for patients below all of these cut-off levels (between 0.7% and 1.5%, p=0.748 for all-groups comparison). Conclusion: cTn should be considered as a continuous variable. Decision values below the 99th percentile (e.g. the 75th percentile) are associated with a very high NPV for the diagnosis of AMI, but have a lower accuracy than the 99th percentile. [Copyright &y& Elsevier]

Abstract: Background: It is unknown to what extent noncardiac causes, including renal dysfunction, may contribute to high-sensitivity cardiac troponin T levels. Methods: In an observational international multicenter study, we enrolled consecutive patients presenting with acute chest pain to the emergency department. Of 1181 patients enrolled, 572 were adjudicated by 2 independent cardiologists to have a noncardiac cause of chest pain. Multiple linear regression analyses were used to determine the important predictors of log-transformed high-sensitivity cardiac troponin T. Kaplan-Meier curve was used to assess the prognostic significance of high-sensitivity cardiac troponin T>0.014 μg/L (99th percentile). Results: A total of 88 patients (15%) had high-sensitivity cardiac troponin T>0.014 μg/L. Less than 50% of cardiac troponins could be explained by known cardiac or noncardiac diseases. In decreasing order of importance, age, estimated glomerular filtration rate, hypertension, previous myocardial infarction, and chronic kidney disease (adjusted r 2 0.44) emerged as significant factors in linear regression analysis to predict high-sensitivity cardiac troponin T. High-sensitivity cardiac troponin T was best explained by a linear curve with age as≤0.014 μg/L. Patients with high-sensitivity cardiac troponin T levels>0.014 μg/L were at increased risk for all-cause mortality (hazard ratio 3.0; 95% confidence interval, 0.8-10.6; P=.02) during follow-up. Conclusion: Among the known covariates, age and not renal dysfunction is the most important determinant of high-sensitivity cardiac troponin T. Because known cardiac and noncardiac factors, including renal dysfunction, explain less than 50% of high-sensitivity cardiac troponin T levels among patients with a noncardiac cause of chest pain, unknown or underestimated cardiac involvement during the acute presenting condition seems to be the major cause of elevated high-sensitivity cardiac troponin T. [Copyright &y& Elsevier]