Direct Comparison of Cardiac Myosin-Binding Protein C With Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI. METHODS: Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality. RESULTS: Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L, P<0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.924), hs-cTnT (AUC, 0.927), and hs-cTnI (AUC, 0.922) and superior to cTnI measured by a contemporary sensitivity assay (AUC, 0.909). The combination of cMyC with hs-cTnT or standard-sensitivity cTnI (but not hs-cTnI) led to an increase in AUC to 0.931 (P<0.0001) and 0.926 (P=0.003), respectively. Use of cMyC more accurately classified patients with a single blood test into rule-out or rule-in categories: Net Reclassification Improvement +0.149 versus hs-cTnT, +0.235 versus hs-cTnI (P<0.001). In early presenters (chest pain <3 h), the improvement in rule-in/rule-out classification with cMyC was larger compared with hs-cTnT (Net Reclassification Improvement +0.256) and hs-cTnI (Net Reclassification Improvement +0.308; both P<0.001). Comparing the C statistics, cMyC was superior to hs-cTnI and standard sensitivity cTnI (P<0.05 for both) and similar to hs-cTnT at predicting death at 3 years. CONCLUSIONS: cMyC at presentation provides discriminatory power comparable to hs-cTnT and hs-cTnI in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Direct Comparison of 4 Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I.

BACKGROUND: Four strategies for very early rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I (hs-cTnI) have been identified. It remains unclear which strategy is most attractive for clinical application. METHODS: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. Hs-cTnI levels were measured at presentation and after 1 hour in a blinded fashion. We directly compared all 4 hs-cTnI-based rule-out strategies: limit of detection (LOD, hs-cTnI<2 ng/L), single cutoff (hs-cTnI<5 ng/L), 1-hour algorithm (hs-cTnI<5 ng/L and 1-hour change<2 ng/L), and the 0/1-hour algorithm recommended in the European Society of Cardiology guideline combining LOD and 1-hour algorithm. RESULTS: Among 2828 enrolled patients, acute myocardial infarction was the final diagnosis in 451 (16%) patients. The LOD approach ruled out 453 patients (16%) with a sensitivity of 100% (95% confidence interval [CI], 99.2%-100%), the single cutoff 1516 patients (54%) with a sensitivity of 97.1% (95% CI, 95.1%-98.3%), the 1-hour algorithm 1459 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%), and the 0/1-hour algorithm 1463 patients (52%) with a sensitivity of 98.4% (95% CI, 96.8%-99.2%). Predefined subgroup analysis in early presenters (≤2 hours) revealed significantly lower sensitivity (94.2%, interaction P=0.03) of the single cutoff, but not the other strategies. Two-year survival was 100% with LOD and 98.1% with the other strategies (P<0.01 for LOD versus each of the other strategies). CONCLUSIONS: All 4 rule-out strategies balance effectiveness and safety equally well. The single cutoff should not be applied in early presenters, whereas the 3 other strategies seem to perform well in this challenging subgroup. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Misdiagnosis of Myocardial Infarction Related to Limitations of the Current Regulatory Approach to Define Clinical Decision Values for Cardiac Troponin.

BACKGROUND: Misdiagnosis of acute myocardial infarction (AMI) may significantly harm patients and may result from inappropriate clinical decision values (CDVs) for cardiac troponin (cTn) owing to limitations in the current regulatory process. METHODS AND RESULTS: In an international, prospective, multicenter study, we quantified the incidence of inconsistencies in the diagnosis of AMI using fully characterized and clinically available high-sensitivity (hs) cTn assays (hs-cTnI, Abbott; hs-cTnT, Roche) among 2300 consecutive patients with suspected AMI. We hypothesized that the approved CDVs for the 2 assays are not biologically equivalent and might therefore contribute to inconsistencies in the diagnosis of AMI. Findings were validated by use of sex-specific CDVs and parallel measurements of other hs-cTnI assays. AMI was the adjudicated diagnosis in 473 patients (21%). Among these, 86 patients (18.2%) had inconsistent diagnoses when the approved uniform CDV was used. When sex-specific CDVs were used, 14.1% of female and 22.7% of male AMI patients had inconsistent diagnoses. Using biologically equivalent CDV reduced inconsistencies to 10% (P<0.001). These findings were confirmed with parallel measurements of other hs-cTn assays. The incidence of inconsistencies was only 7.0% for assays with CDVs that were nearly biologically equivalent. Patients with inconsistent AMI had long-term mortality comparable to that of patients with consistent diagnoses (P=NS) and a trend toward higher long-term mortality than patients diagnosed with unstable angina (P=0.05). CONCLUSIONS: Currently approved CDVs are not biologically equivalent and contribute to major inconsistencies in the diagnosis of AMI. One of 5 AMI patients will receive a diagnosis other than AMI if managed with the alternative hs-cTn assay. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction.

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.

Safety and efficacy of the 0 h/3 h protocol for rapid rule out of myocardial infarction.

BACKGROUND: The early and accurate diagnosis of acute myocardial infarction (AMI) is an important medical and economic challenge. We aimed to prospectively evaluate the performance of the new European Society of Cardiology rapid 0-hour/3-hour (0 h/3 h) rule out protocol for AMI. METHODS: We enrolled 2,727 consecutive patients presenting with suspected AMI without persistent ST-segment elevation to the emergency department in a prospective international multicenter study. The final diagnosis was adjudicated by 2 independent cardiologists. The performance of the 0 h/3 h rule out protocol was evaluated using 4 high-sensitivity (primary analysis) and 3 sensitive cardiac troponin (cTn) assays. RESULTS: Acute myocardial infarction was the final diagnosis in 473 patients (17.3%). Using the 4 high-sensitivity cTn assays, the 0-hour rule out protocol correctly ruled out 99.8% (95% [confidence interval] CI, 98.7%-100%), 99.6% (95% CI, 98.5%-99.9%), 100% (95% CI, 97.9%-100%), and 100% (95% CI, 98.0%-100%) of late presenters (>6 h from chest pain onset). The 3-hour rule out protocol correctly ruled out 99.9% (95% CI, 99.1%-100%), 99.5% (95% CI, 98.3%-99.9%), 100% (95% CI, 98.1%-100%), and 100% (95% CI, 98.2%-100%) of early presenters (<6 h from chest pain onset). Using the 3 sensitive cTn assays, the 0-hour rule out protocol correctly ruled out 99.6% (95% CI, 98.6%-99.9%), 99.0% (95% CI, 96.9%-99.7%), and 99.1% (95% CI, 97.2%-99.8%) of late presenters; and the 3-hour rule out protocol correctly ruled out 99.4% (95% CI, 98.3%-99.8%), 99.2% (95% CI, 97.3%-99.8%), and 99.0% (95% CI, 97.2%-99.7%) of early presenters. Overall, the 0 h/3 h rule out protocol assigned 40% to 60% of patients to rule out. None of the patients assigned rule out died during 3-months follow-up. CONCLUSIONS: The 0 h/3 h rule out protocol seems to allow the accurate rule out of AMI using both high-sensitivity and sensitive cTn measurements in conjunction with clinical assessment. Additional studies are warranted for external validation.

Clinical benefit of high-sensitivity cardiac troponin I in the detection of exercise-induced myocardial ischemia.

BACKGROUND: A pilot study using a novel high-sensitivity cardiac troponin I (hs-cTnI) assay suggested that cTnI might be released into blood during exercise-induced myocardial ischemia. We investigated the potential clinical value of this signal. METHODS: We included 819 patients with suspected exercise-induced myocardial ischemia referred for rest/bicycle myocardial perfusion single-photon emission computed tomography. The treating cardiologist used all available clinical information to quantify clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: prior and after stress testing. High-sensitivity cTnI measurements were obtained before, immediately after peak stress, and 2 hours after stress testing in a blinded manner. Myocardial ischemia was adjudicated using perfusion single-photon emission computed tomography and coronary angiography findings. RESULTS: Exercise-induced myocardial ischemia was detected in 278 (34%) patients. High-sensitivity cTnI levels were significantly higher at all time points in patients with myocardial ischemia as compared with those without (P < .001 for all). Combining clinical judgment prior exercise testing with baseline hs-cTnI levels increased diagnostic accuracy as quantified by the area under the receiver operating characteristics curve (AUC) from 0.672 to 0.757 (P < .001). Combining clinical judgment after exercise testing (AUC 0.704) with baseline or poststress hs-cTnI levels also increased the diagnostic accuracy (AUC 0.761-0.771, P < .001 for all). In contrast, exercise-induced changes in hs-cTnI during exercise did not seem useful, as they were small and similar in patients with or without myocardial ischemia. CONCLUSIONS: High-sensitivity cTnI concentrations at rest and after exercise, but not its exercise-induced changes, provide substantial incremental value to clinical judgment including exercise electrocardiography regarding the presence of myocardial ischemia.

One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I.

UNLABELLED: We aimed to prospectively derive and validate a novel 0-/1-hour algorithm using high-sensitivity cardiac troponin I (hs-cTnI) for the early "rule-out" and "rule-in" of acute myocardial infarction (AMI). METHODS: In a prospective multicenter diagnostic study, we enrolled 1,500 patients presenting with suspected AMI to the emergency department. The final diagnosis was centrally adjudicated by 2 independent cardiologists blinded to hs-cTnI concentrations. The hs-cTnI (Siemens Vista) 0-/1-hour algorithm incorporated measurements performed at baseline and absolute changes within 1 hour, was derived in the first 750 patients (derivation cohort), and then validated in the second 750 (validation cohort). RESULTS: Overall, AMI was the final diagnosis in 16% of patients. Applying the hs-cTnI 0-/1-hour algorithm developed in the derivation cohort to the validation cohort, 57% of patients could be classified as "rule-out"; 10%, as "rule-in"; and 33%, as "observe." In the validation cohort, the sensitivity and the negative predictive value for AMI in the "rule-out" zone were 100% (95% CI 96%-100%) and 100% (95% CI 99%-100%), respectively. The specificity and the positive predictive value (PPV) for AMI in the "rule-in" zone were 96% (95% CI 94%-97%) and 70% (95% CI 60%-79%), respectively. Negative predictive value and positive predictive value of the 0-/1-hour algorithm were higher compared to the standard of care combining hs-cTnI with the electrocardiogram (both P < .001). CONCLUSION: The hs-cTnI 0-/1-hour algorithm performs very well for early rule-out as well as rule-in of AMI. The clinical implications are that used in conjunction with all other clinical information, the 0-/1-hour algorithm will be a safe and effective approach to substantially reduce time to diagnosis.

Diurnal Rhythm of Cardiac Troponin: Consequences for the Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point. The aim of this study was to challenge this diagnostic concept. METHODS: Study 1 examined the presence of a diurnal hs-cTn rhythm by hourly blood sampling, day and night, in 24 individuals without a recent history of AMI. Study 2 assessed morning vs evening diagnostic accuracy of hs-cTnT and hs-cTnI in a prospective multicenter diagnostic study of 2782 unselected patients, presenting to the emergency department with acute chest pain. RESULTS: In study 1, hs-cTnT, but not hs-cTnI, exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime, to peak concentrations in the morning (mean 16.2 ng/L at 8:30 AM and 12.1 ng/L at 7:30 PM). In study 2, the hs-cTnT rhythm was confirmed by higher hs-cTnT concentrations in early-morning presenters compared to evening presenters with an adjudicated diagnosis of noncardiac disease. The diagnostic accuracy [area under the receiver-operation characteristics curve (AUC)] of hs-cTnT at presentation, 1 h, and for the combination of absolute changes with presenting concentration, were very high and comparable among patients presenting early morning as compared to evening (all AUC >0.93). hs-cTnI exhibited no diurnal rhythm with no differences in AUC among early-morning and evening presenters. CONCLUSIONS: Rhythmic diurnal variation of hs-cTnT is a general phenomenon that is not seen with hs-cTnI. While the diurnal hs-cTnT rhythm does not seem to affect the diagnostic accuracy of hs-cTnT for AMI, it should be considered when using hs-cTnT for screening purposes. CLINICAL TRIAL REGISTRATION: 1. Circadian Variation of Cardiac Troponin, NCT02091427, www.clinicaltrials.gov/ct2/show/NCT02091427. 2. Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) Study, NCT00470587, www.clinicaltrials.gov/ct2/show/NCT00470587.

Optimizing Early Rule-Out Strategies for Acute Myocardial Infarction: Utility of 1-Hour Copeptin.

BACKGROUND: Combined testing of high-sensitivity cardiac troponin T (hs-cTnT) and copeptin at presentation provides a very high-although still imperfect-negative predictive value (NPV) for the early rule-out of acute myocardial infarction (AMI). We hypothesized that a second copeptin measurement at 1 h might further increase the NPV. METHODS: In a prospective diagnostic multicenter study, we measured hs-cTnT and copeptin concentrations at presentation and at 1 h in 1439 unselected patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists blinded to copeptin concentrations. We investigated the incremental value of 1-h copeptin in the rule-out setting (0-h hs-cTnT negative and 0-h copeptin negative) and the intermediate-risk setting (0-h hs-cTnT negative and 0-h copeptin positive). RESULTS: The adjudicated diagnosis was AMI in 267 patients (18.6%). For measurements obtained at presentation, the NPV in the rule-out setting was 98.6% (95% CI, 97.4%-99.3%). Whereas 1-h copeptin did not increase the NPV significantly, 1-h hs-cTnT did, to 99.6% (95% CI, 98.7%-99.9%, P = 0.008). Similarly, in the intermediate-risk setting (NPV 92.8%, 95% CI, 88.7%-95.8%), 1-h copeptin did not significantly increase the NPV (P = 0.751), but 1-h hs-cTnT did, to 98.6 (95% CI, 96%-99.7%, P < 0.001). CONCLUSIONS: One-hour copeptin increased neither the safety of the rule-out process nor the NPV in the intermediate-risk setting. In contrast, the incremental value of 1-h hs-cTnT was substantial in both settings. ClinicalTrials.gov/NCT00470587.

Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay.

BACKGROUND: We aimed to prospectively validate a novel 1-hour algorithm using high-sensitivity cardiac troponin T measurement for early rule-out and rule-in of acute myocardial infarction (MI). METHODS: In a multicentre study, we enrolled 1320 patients presenting to the emergency department with suspected acute MI. The high-sensitivity cardiac troponin T 1-hour algorithm, incorporating baseline values as well as absolute changes within the first hour, was validated against the final diagnosis. The final diagnosis was then adjudicated by 2 independent cardiologists using all available information, including coronary angiography, echocardiography, follow-up data and serial measurements of high-sensitivity cardiac troponin T levels. RESULTS: Acute MI was the final diagnosis in 17.3% of patients. With application of the high-sensitivity cardiac troponin T 1-hour algorithm, 786 (59.5%) patients were classified as "rule-out," 216 (16.4%) were classified as "rule-in" and 318 (24.1%) were classified to the "observational zone." The sensitivity and the negative predictive value for acute MI in the rule-out zone were 99.6% (95% confidence interval [CI] 97.6%-99.9%) and 99.9% (95% CI 99.3%-100%), respectively. The specificity and the positive predictive value for acute MI in the rule-in zone were 95.7% (95% CI 94.3%-96.8%) and 78.2% (95% CI 72.1%-83.6%), respectively. The 1-hour algorithm provided higher negative and positive predictive values than the standard interpretation of highsensitivity cardiac troponin T using a single cut-off level (both p < 0.05). Cumulative 30-day mortality was 0.0%, 1.6% and 1.9% in patients classified in the rule-out, observational and rule-in groups, respectively (p = 0.001). INTERPRETATION: This rapid strategy incorporating high-sensitivity cardiac troponin T baseline values and absolute changes within the first hour substantially accelerated the management of suspected acute MI by allowing safe rule-out as well as accurate rule-in of acute MI in 3 out of 4 patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00470587.

Detecting Hexafluoroisopropanol Using Soft Chemical Ionization Mass Spectrometry and Analytical Applications to Exhaled Breath.

Here we explore the potential use of proton transfer reaction/selective reagent ion-time-of-flight-mass spectrometry (PTR/SRI-ToF-MS) to monitor hexafluoroisopropanol (HFIP) in breath. Investigations of the reagent ions H3O+, NO+, and O2+• are reported using dry (relative humidity (rH) ≈ 0%) and humid (rH ≈ 100%)) nitrogen gas containing traces of HFIP, i.e., divorced from the complex chemical environment of exhaled breath. HFIP shows no observable reaction with H3O+ and NO+, but it does react efficiently with O2+• via dissociative charge transfer resulting in CHF2+, CF3+, C2HF2O+, and C2H2F3O+. A minor competing hydride abstraction channel results in C3HF6O+ + HO2• and, following an elimination of HF, C3F5O+. There are two issues associated with the use of the three dominant product ions of HFIP, CHF2+, CF3+, and C2H2F3O+, to monitor it in breath. One is that CHF2+ and CF3+ also result from the reaction of O2+• with the more abundant sevoflurane. The second is the facile reaction of these product ions with water, which reduces analytical sensitivity to detect HFIP in humid breath. To overcome the first issue, C2H2F3O+ is the ion marker for HFIP. The second issue is surmounted by using a Nafion tube to reduce the breath sample's humidity prior to its introduction into drift tube. The success of this approach is illustrated by comparing the product ion signals either in dry or humid nitrogen gas flows and with or without the use of the Nafion tube, and practically from the analysis of a postoperative exhaled breath sample from a patient volunteer.

The course of adrenomedullin and endothelin levels in patients with vasodilatory shock after cardiac surgery compared to patients after uncomplicated elective cardiac surgery.

PURPOSE: The aim of this study was to analyse the course of adrenomedullin (ADM) and endothelin-1 (ET-1) levels in patients with vasodilatory shock after cardiac surgery and to explore differences compared to patients after uncomplicated coronary artery bypass graft (CABG) surgery. ADM and ET-1 are involved in the vasomotor response during vasodilatory shock. MATERIALS AND METHODS: We included 32 patients with vasodilatory shock (study group) and 10 patients after uncomplicated CABG surgery (control group). Daily measurements of MR-proADM and CT-proET-1 (stable surrogate markers for ADM and ET-1) were collected during the first 7 postoperative days. RESULTS: MR-proADM and CT-proET-1 levels were significantly elevated in the study group when compared to the control group. In addition, the course of both biomarkers was significantly different in the study versus control group. Higher levels of both biomarkers were associated with organ dysfunction (higher maximum multiple organ dysfunction score, acute kidney injury). CONCLUSIONS: Significantly higher levels of MR-proADM and CT-proET-1 and a different course of both biomarkers were observed in patients with vasodilatory shock after cardiac surgery and seemed to be associated with organ dysfunction.

Diagnostic and prognostic value of ST-segment deviation scores in suspected acute myocardial infarction.

BACKGROUND: Recent advances in digital electrocardiography technology allow evaluating ST-segment deviations in all 12 leads as quantitative variables and calculating summed ST-segment deviation scores. The diagnostic and prognostic utility of summed ST-segment deviation scores is largely unknown. METHODS: We aimed to explore the diagnostic and prognostic utility of the conventional and the modified ST-segment deviation score (Better Analysis of ST-segment Elevations and Depressions in a 12- Lead-ECG-Score (BASEL-Score): sum of elevations in the augmented voltage right - lead (aVR) plus absolute, unsigned ST-segment depressions in the remaining leads) in patients presenting with suspected non-ST-segment elevation myocardial infarction. The diagnostic endpoint was non-ST-segment elevation myocardial infarction, adjudicated by two independent cardiologists. Prognostic endpoint was mortality during two-year follow up. RESULTS: Among 1330 patients, non-ST-segment elevation myocardial infarction was present in 200 (15%) patients. Diagnostic accuracy for non-ST-segment elevation myocardial infarction as quantified by the area under the receiver-operating-characteristics curve was significantly higher for the BASEL-Score (0.73; 95% confidence interval 0.69-0.77) as compared to the conventional ST-segment deviation score (0.53; 95% confidence interval 0.49-0.57, p<0.001). The BASEL-Score provided additional independent diagnostic value to dichotomous electrocardiogram variables (ST-segment depression, T-inversion, both p<0.001) and to high-sensitivity cardiac troponin (p<0.001) as well as clinical judgment at 90 min (p<0.001). Similarly, only the BASEL-Score proved to be an independent predictor of two year mortality. CONCLUSIONS: The modified ST-segment deviation score BASEL-Score focusing on ST-segment elevation in aVR and ST-segment depressions in the remaining leads provides incremental diagnostic and prognostic information.

Prospective validation of current quantitative electrocardiographic criteria for ST-elevation myocardial infarction.

BACKGROUND: Rapid and reliable diagnosis of ST-elevation myocardial infarction (STEMI) as a surrogate for acute coronary occlusion is critical for early reperfusion therapy. OBJECTIVES: We aimed to examine the diagnostic performance of current guideline-recommended Electrocardiogram (ECG) STEMI criteria. METHODS: In a prospective diagnostic multicenter study, we objectively quantified the extent of ST-segment elevation in all ECG leads using an automated software-based analysis of the digital 12-lead-ECG in adult patients presenting to the emergency department (ED) with suspected myocardial infarction (MI). Classification according to current guideline-recommended ECG criteria for STEMI at ED presentation was compared against a final diagnosis adjudicated by two independent cardiologists after reviewing all available medical records including serial ECGs, cardiac imaging and coronary angiograms. RESULTS: Among 2486 patients, 52 (2%) were found to have significant ST-segment elevation on ECG at ED presentation according to current guideline-recommended ECG criteria for STEMI. Eighty-one (3%) patients received a final adjudicated diagnosis of STEMI. Only 35% (28 of 81) of all patients with a final diagnosis of STEMI were correctly identified (PPV 54% (95% CI 41-66%), sensitivity 35% (95% Cl 24-46%), NPV 97.8% (95% CI 97.5-98.1%). Four reasons for missing STEMIs emerged: timing (significant STE at an earlier/later time point) in 25%, incorrect measurement points in 30%, non or borderline-significant STE in 36% and inferoposterior MI localisation in 9%. CONCLUSIONS: A computerized analysis of current guideline-recommended ECG criteria for STEMI showed suboptimal diagnostic performance when applied to a single 12­lead ECG performed at ED presentation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Gender-specific uncertainties in the diagnosis of acute coronary syndrome.

BACKGROUND: It is unknown whether higher rates of delayed diagnosis and misdiagnosis of acute coronary syndrome (ACS) in women might have contributed to the poorer outcome of women. METHODS: In a prospective diagnostic multicenter study, we recruited patients presenting to the emergency department (ED) with any kind of chest discomfort/chest pain with onset or peak within the last 12 h. We quantified early diagnostic uncertainty for the presence of ACS among treating physicians at the ED after 90 min, possibly responsible for delayed diagnosis, using a visual analogue scale. Late diagnostic uncertainty, possibly responsible for misdiagnosis, was defined as disagreement among two independent cardiologists' adjudication of the final diagnosis after complete work-up. RESULTS: Among 2795 patients (897 women and 1898 men), ACS was the adjudicated final diagnosis in 24 % of women and 35 % of men. Early diagnostic accuracy of clinical judgment of the ED physician for ACS as quantified by the area under the receiver-operating characteristics curve was 0.89 (95 % CI 0.87-0.92) in women and 0.86 (95 % CI 0.85-0.88) in men (p = 0.046). Late diagnostic uncertainty regarding the diagnosis of ACS was 5 % in women and 7 % in men (p = 0.069). CONCLUSION: Diagnostic uncertainty for the presence of ACS in women is not more common as compared to men and does, therefore, not explain the poorer outcome observed in women with ACS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00470587.

Impact of haemoconcentration during acute heart failure therapy on mortality and its relationship with worsening renal function.

AIMS: Treatment goals in acute heart failure (AHF) are poorly defined. We aimed to characterize further the impact of in-hospital haemoconcentration and worsening renal function (WRF) on short- and long-term mortality. METHODS AND RESULTS: Haematocrit, haemoglobin, total protein, serum creatinine, and albumin levels were measured serially in 1019 prospectively enrolled AHF patients. Haemoconcentration was defined as an increase in at least three of four of the haemoconcentration-defining parameters above admission values at any time during the hospitalization. Patients were divided into early (Day 1-4) and late haemoconcentration (>Day 4). Ninety-day mortality was the primary endpoint. Haemoconcentration occurred in 392 (38.5%) patients, with a similar incidence of the early (44.6%) and late (55.4%) phenotype. Signs of decongestion (reduction in BNP blood concentrations, P = 0.003; weight loss, P = 0.002) were significantly more pronounced in haemoconcentration patients. WRF was more common in haemoconcentration patients (P = 0.04). After adjustment for established risk factors for AHF mortality, including WRF and HF therapy at discharge, haemoconcentration was significantly associated with a reduction in 90-day mortality [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.95, P = 0.01]. The beneficial effect of haemoconcentration seemed to be exclusive for late haemoconcentration (late vs. early: adjusted HR 0.41, 95% CI 0.19-0.90, P = 0.03) and persisted in patients with or without WRF. CONCLUSIONS: Haemoconcentration represents an inexpensive and easily assessable pathophysiological signal of adequate decongestion in AHF and is associated with lower mortality. WRF in the setting of haemoconcentration does not appear to offset the benefits of haemoconcentration.

Diagnostic and prognostic values of the V-index, a novel ECG marker quantifying spatial heterogeneity of ventricular repolarization, in patients with symptoms suggestive of non-ST-elevation myocardial infarction.

BACKGROUND: The V-index is an ECG marker quantifying spatial heterogeneity of ventricular repolarization. We prospectively assessed the diagnostic and prognostic values of the V-index in patients with suspected non-ST-elevation myocardial infarction (NSTEMI). METHODS: We prospectively enrolled 497 patients presenting with suspected NSTEMI to the emergency department (ED). Digital 12-lead ECGs of five-minute duration were recorded at presentation. The V-index was automatically calculated in a blinded fashion. Patients with a QRS duration >120ms were ruled out from analysis. The final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 24months of follow-up. RESULTS: NSTEMI was the final diagnosis in 14% of patients. V-index levels were higher in patients with AMI compared to other causes of chest pain (median 23ms vs. 18ms, p<0.001). The use of the V-index in addition to conventional ECG-criteria improved the diagnostic accuracy for the diagnosis of NSTEMI as quantified by area under the ROC curve from 0.66 to 0.73 (p=0.001) and the sensitivity of the ECG for AMI from 41% to 86% (p<0.001). Cumulative 24-month mortality rates were 99.4%, 98.4% and 88.3% according to tertiles of the V-index (p<0.001). After adjustment for age and important ECG and clinical parameters, the V-index remained an independent predictor of death. CONCLUSIONS: The V-index, an ECG marker quantifying spatial heterogeneity of ventricular repolarization, significantly improves the accuracy and sensitivity of the ECG for the diagnosis of NSTEMI and independently predicts mortality during follow-up.

Diagnostic value of ST-segment deviations during cardiac exercise stress testing: Systematic comparison of different ECG leads and time-points.

BACKGROUND: Exercise ECG stress testing is the most widely available method for evaluation of patients with suspected myocardial ischemia. Its major limitation is the relatively poor accuracy of ST-segment changes regarding ischemia detection. Little is known about the optimal method to assess ST-deviations. METHODS: A total of 1558 consecutive patients undergoing bicycle exercise stress myocardial perfusion imaging (MPI) were enrolled. Presence of inducible myocardial ischemia was adjudicated using MPI results. The diagnostic value of ST-deviations for detection of exercise-induced myocardial ischemia was systematically analyzed 1) for each individual lead, 2) at three different intervals after the J-point (J+40ms, J+60ms, J+80ms), and 3) at different time points during the test (baseline, maximal workload, 2min into recovery). RESULTS: Exercise-induced ischemia was detected in 481 (31%) patients. The diagnostic accuracy of ST-deviations was highest at +80ms after the J-point, and at 2min into recovery. At this point, ST-amplitude showed an AUC of 0.63 (95% CI 0.59-0.66) for the best-performing lead I. The combination of ST-amplitude and ST-slope in lead I did not increase the AUC. Lead I reached a sensitivity of 37% and a specificity of 83%, with similar sensitivity to manual ECG analysis (34%, p=0.31) but lower specificity (90%, p<0.001). CONCLUSION: When using ECG stress testing for evaluation of patients with suspected myocardial ischemia, the diagnostic accuracy of ST-deviations is highest when evaluated at +80ms after the J-point, and at 2min into recovery.

Early diagnosis of acute myocardial infarction in patients with mild elevations of cardiac troponin.

BACKGROUND: The early diagnosis of acute myocardial infarction (AMI) in patients with mild elevations of high-sensitivity cardiac troponin (hs-cTn) is a challenge. It is unclear whether copeptin, a marker of endogenous stress, or 1h-hs-cTn changes are better suited to address this important unmet clinical need. METHODS: We prospectively enrolled patients presenting with symptoms suggestive of AMI to the emergency department (ED). Two independent cardiologists adjudicated the final diagnosis. Mild hs-cTn elevations were defined as 26.2 ng/L (99th percentile) to 75 ng/L for hs-cTnI, and 14 ng/L (99th percentile) to 50 ng/L (biological-equivalent to 75 ng/L for hs-cTnI) for hs-cTnT. RESULTS: Among 1356 patients, 80 (6%) had mild hs-cTnI elevations at presentation. Within this group, AMI was the final diagnosis in 39 patients (49%). The diagnostic accuracy for the diagnosis of AMI as quantified by the area under the receiver operating characteristic curve (AUC) was 0.51 (95% CI 0.39-0.64) for hs-cTnI at presentation, 0.58 (95% CI 0.45-0.71) for copeptin at presentation, and 0.78 (95% CI 0.68-0.88) for 1h-hs-cTnI changes, which was significantly higher as compared to copeptin (p = 0.02) or hs-cTnI alone (p < 0.001). The additional use of 1h-hs-cTnI changes, but not of copeptin, improved diagnostic accuracy of hs-cTnI at presentation (AUC 0.80, 95% CI 0.70-0.90; p = 0.002 for comparison). Similar findings regarding copeptin and 1h-hs-cTnT/I changes were obtained for mild hs-cTnT elevations. CONCLUSIONS: About 6-22% of patients presenting with suggestive AMI to the ED have mild hs-cTnT/I elevations at presentation. In contrast to copeptin, the addition of 1h-hs-cTn changes substantially improves the early diagnosis of AMI.