The electronic frailty index and outcomes in patients with myocardial infarction.

BACKGROUND: Frailty is increasingly present in patients with acute myocardial infarction. The electronic Frailty Index (eFI) is a validated method of identifying vulnerable older patients in the community from routine primary care data. Our aim was to assess the relationship between the eFI and outcomes in older patients hospitalised with acute myocardial infarction. STUDY DESIGN AND SETTING: Retrospective cohort study using the DataLoch Heart Disease Registry comprising consecutive patients aged 65 years or over hospitalised with a myocardial infarction between October 2013 and March 2021. METHODS: Patients were classified as fit, mild, moderate, or severely frail based on their eFI score. Cox-regression analysis was used to determine the association between frailty category and all-cause mortality. RESULTS: In 4670 patients (median age 77 years [71-84], 43% female), 1865 (40%) were classified as fit, with 1699 (36%), 798 (17%) and 308 (7%) classified as mild, moderate and severely frail, respectively. In total, 1142 patients died within 12 months of which 248 (13%) and 147 (48%) were classified as fit and severely frail, respectively. After adjustment, any degree of frailty was associated with an increased risk of all-cause death with the risk greatest in the severely frail (reference = fit, adjusted hazard ratio 2.87 [95% confidence intervals 2.24 to 3.66]). CONCLUSION: The eFI identified patients at high risk of death following myocardial infarction. Automatic calculation within administrative data is feasible and could provide a low-cost method of identifying vulnerable older patients on hospital presentation.

Implementation of high sensitivity troponin into routine clinical practice - results of the extended CARdiac MArkers guideline uptake in Europe group (CARMAGUE) survey.

BACKGROUND: Measurement of cardiac troponin (cTn) by a high sensitivity method is now the recommended strategy for the detection of myocardial injury. An international survey was undertaken to assess how this has been implemented. METHODS: A questionnaire based around 14 domains on cardiac biomarkers was distributed electronically with the aid of professional societies accessed by a web link within the invitation. Results were returned electronically then extracted into a relational database for analysis. RESULTS: Responses were obtained from 663 laboratories across 76 countries ranging from 1 to 69 largest country. The majority of responses (79.6%) came from the European area. Responses were grouped into broad geographic areas for analysis. Most responses came from hospitals providing a local and regional service of which the majority provided angioplasty. cTn measurement was the dominant biomarker. The majority of laboratories include creatine kinase (CK) in their cardiac profile and approximately 50% also offer the MB isoenzyme of CK. The majority of laboratories (91.9%) measure cTn by a high sensitivity method. Sex specific reference ranges were typically implemented for cardiac troponin I but not for cardiac troponin T. The preferred unit of measurement was nanograms/L. A structured decision-making pathway utilising high sensitivity cTn measurement was used by 83.3% of laboratories who responded. Single sample rule out is common but the majority used serial sampling strategy based on measurement on admission and three hours. CONCLUSIONS: Measurement of cTn by a high sensitivity method is now well established internationally, the use of rapid diagnostic protocols lags behind.

Application of the Universal Definition of Myocardial Infarction in Clinical Practice in Scotland and Sweden.

Importance: Whether the diagnostic classifications proposed by the universal definition of myocardial infarction (MI) to identify type 1 MI due to atherothrombosis and type 2 MI due to myocardial oxygen supply-demand imbalance have been applied consistently in clinical practice is unknown. Objective: To evaluate the application of the universal definition of MI in consecutive patients with possible MI across 2 health care systems. Design, Setting, and Participants: This cohort study used data from 2 prospective cohorts enrolling consecutive patients with possible MI in Scotland (2013-2016) and Sweden (2011-2014) to assess accuracy of clinical diagnosis of MI recorded in hospital records for patients with an adjudicated diagnosis of type 1 or type 2 MI. Data were analyzed from August 2022 to February 2023. Main Outcomes and Measures: The main outcome was the proportion of patients with a clinical diagnosis of MI recorded in the hospital records who had type 1 or type 2 MI, adjudicated by an independent panel according to the universal definition. Characteristics and risk of subsequent MI or cardiovascular death at 1 year were compared. Results: A total of 50 356 patients were assessed. The cohort from Scotland included 28 783 (15 562 men [54%]; mean [SD] age, 60 [17] years), and the cohort from Sweden included 21 573 (11 110 men [51%]; mean [SD] age, 56 [17] years) patients. In Scotland, a clinical diagnosis of MI was recorded in 2506 of 3187 patients with an adjudicated diagnosis of type 1 MI (79%) and 122 of 716 patients with an adjudicated diagnosis of type 2 MI (17%). Similar findings were observed in Sweden, with 970 of 1111 patients with adjudicated diagnosis of type 1 MI (87%) and 57 of 251 patients with adjudicated diagnosis of type 2 MI (23%) receiving a clinical diagnosis of MI. Patients with an adjudicated diagnosis of type 1 MI without a clinical diagnosis were more likely to be women (eg, 336 women [49%] vs 909 women [36%] in Scotland; P < .001) and older (mean [SD] age, 71 [14] v 67 [14] years in Scotland, P < .001) and, when adjusting for competing risk from noncardiovascular death, were at similar or increased risk of subsequent MI or cardiovascular death compared with patients with a clinical diagnosis of MI (eg, 29% vs 18% in Scotland; P < .001). Conclusions and Relevance: In this cohort study, the universal definition of MI was not consistently applied in clinical practice, with a minority of patients with type 2 MI identified, and type 1 MI underrecognized in women and older persons, suggesting uncertainty remains regarding the diagnostic criteria or value of the classification.

Uniform or Sex-Specific Cardiac Troponin Thresholds to Rule Out Myocardial Infarction at Presentation.

BACKGROUND: Myocardial infarction can be ruled out in patients with a single cardiac troponin measurement. Whether use of a uniform rule-out threshold has resulted in sex differences in care remains unclear. OBJECTIVES: The purpose of this study was to evaluate implementation of a uniform rule-out threshold in females and males with possible myocardial infarction, and to derive and validate sex-specific thresholds. METHODS: The implementation of a uniform rule-out threshold (<5 ng/L) with a high-sensitivity cardiac troponin I assay was evaluated in consecutive patients presenting with possible myocardial infarction. The proportion of low-risk patients discharged from the emergency department and incidence of myocardial infarction or cardiac death at 30 days were determined. Sex-specific thresholds were derived and validated, and proportion of female and male patients were stratified as low-risk compared with uniform threshold. RESULTS: In 16,792 patients (age 58 ± 17 years; 46% female) care was guided using a uniform threshold. This identified more female than male patients as low risk (73% vs 62%), but a similar proportion of low-risk patients were discharged from the emergency department (81% for both) with fewer than 5 (<0.1%) patients having a subsequent myocardial infarction or cardiac death at 30 days. Compared with a uniform threshold of <5 ng/L, use of sex-specific thresholds would increase the proportion of female (61.8% vs 65.9%) and reduce the proportion of male (54.8% vs 47.8%) patients identified as low risk. CONCLUSIONS: Implementation of a uniform rule-out threshold for myocardial infarction was safe and effective in both sexes. Sex-specific rule-out thresholds should be considered, but their impact on effectiveness and safety may be limited.

Implementation of a high sensitivity cardiac troponin I assay and risk of myocardial infarction or death at five years: observational analysis of a stepped wedge, cluster randomised controlled trial.

OBJECTIVE: To evaluate the impact of implementing a high sensitivity assay for cardiac troponin I on long term outcomes in patients with suspected acute coronary syndrome. DESIGN: Secondary observational analysis of a stepped wedge, cluster randomised controlled trial. SETTING: 10 secondary and tertiary care centres in Scotland, UK. PARTICIPANTS: 48 282 consecutive patients with suspected acute coronary syndrome. Myocardial injury was defined as any high sensitivity assay result for cardiac troponin I >99th centile of 16 ng/L in women and 34 ng/L in men. INTERVENTION: Hospital sites were randomly allocated to either early (n=5 hospitals) or late (n=5 hospitals) implementation of a high sensitivity cardiac troponin I assay with sex specific diagnostic thresholds. MAIN OUTCOME MEASURE: The main outcome was myocardial infarction or death at five years. RESULTS: 10 360 patients had cardiac troponin concentrations greater than the 99th centile, of whom 1771 (17.1%) were reclassified by the high sensitivity assay. The five year incidence of subsequent myocardial infarction or death before and after implementation of the high sensitivity assay was 29.4% (5588/18 978) v 25.9% (7591/29 304), respectively, in all patients (adjusted hazard ratio 0.97, 95% confidence interval 0.93 to 1.01), and 63.0% (456/720) v 53.9% (567/1051), respectively, in those reclassified by the high sensitivity assay (0.82, 0.72 to 0.94). After implementation of the high sensitivity assay, a reduction in subsequent myocardial infarction or death was observed in patients with non-ischaemic myocardial injury (0.83, 0.75 to 0.91) but not in those with type 1 or type 2 myocardial infarction (0.92, 0.83 to 1.01 and 0.98, 0.84 to 1.14). CONCLUSIONS: Implementation of a high sensitivity cardiac troponin I assay in the assessment of patients with suspected acute coronary syndrome was associated with a reduced risk of subsequent myocardial infarction or death at five years in those reclassified by the high sensitivity assay. Improvements in outcome were greatest in patients with non-ischaemic myocardial injury, suggesting a broader benefit beyond the identification of myocardial infarction. TRIAL REGISTRATION: ClinicalTrials.gov NCT01852123.

Troponin in acute chest pain to risk stratify and guide effective use of computed tomography coronary angiography (TARGET-CTCA): a randomised controlled trial.

BACKGROUND: The majority of patients with suspected acute coronary syndrome presenting to the emergency department will be discharged once myocardial infarction has been ruled out, although a proportion will have unrecognised coronary artery disease. In this setting, high-sensitivity cardiac troponin identifies those at increased risk of future cardiac events. In patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been ruled out, this trial aims to investigate whether outpatient computed tomography coronary angiography (CTCA) reduces subsequent myocardial infarction or cardiac death. METHODS: TARGET-CTCA is a multicentre prospective randomised open label with blinded endpoint parallel group event driven trial. After myocardial infarction and clear alternative diagnoses have been ruled out, participants with intermediate cardiac troponin concentrations (5 ng/L to 99th centile upper reference limit) will be randomised 1:1 to outpatient CTCA plus standard of care or standard of care alone. The primary endpoint is myocardial infarction or cardiac death. Secondary endpoints include clinical, patient-centred, process and cost-effectiveness. Recruitment of 2270 patients will give 90% power with a two-sided P value of 0.05 to detect a 40% relative risk reduction in the primary endpoint. Follow-up will continue until 97 primary outcome events have been accrued in the standard care arm with an estimated median follow-up of 36 months. DISCUSSION: This randomised controlled trial will determine whether high-sensitivity cardiac troponin-guided CTCA can improve outcomes and reduce subsequent major adverse cardiac events in patients presenting to the emergency department who do not have myocardial infarction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03952351. Registered on May 16, 2019.

Troponin in early presenters to rule out myocardial infarction.

AIMS: Whether a single cardiac troponin measurement can safely rule out myocardial infarction in patients presenting within a few hours of symptom onset is uncertain. The study aim was to assess the performance of troponin in early presenters. METHODS AND RESULTS: In patients with possible myocardial infarction, the diagnostic performance of a single measurement of high-sensitivity cardiac troponin I at presentation was evaluated and externally validated in those tested ≤3, 4-12, and >12 h from symptom onset. The limit-of-detection (2 ng/L), rule-out (5 ng/L), and sex-specific 99th centile (16 ng/L in women; 34 ng/L in men) thresholds were compared. In 41 103 consecutive patients [60 (17) years, 46% women], 12 595 (31%) presented within 3 h, and 3728 (9%) had myocardial infarction. In those presenting ≤3 h, a threshold of 2 ng/L had greater sensitivity and negative predictive value [99.4% (95% confidence interval 99.2%-99.5%) and 99.7% (99.6%-99.8%)] compared with 5 ng/L [96.5% (96.2%-96.8%) and 99.3% (99.1%-99.4%)]. In those presenting ≥3 h, the sensitivity and negative predictive value were similar for both thresholds. The sensitivity of the 99th centile was low in early and late presenters at 71.4% (70.6%-72.2%) and 92.5% (92.0%-93.0%), respectively. Findings were consistent in an external validation cohort of 7088 patients. CONCLUSION: In early presenters, a single measurement of high-sensitivity cardiac troponin I below the limit of detection may facilitate the safe rule out of myocardial infarction. The 99th centile should not be used to rule out myocardial infarction at presentation even in those presenting later following symptom onset.

Machine learning for diagnosis of myocardial infarction using cardiac troponin concentrations.

Although guidelines recommend fixed cardiac troponin thresholds for the diagnosis of myocardial infarction, troponin concentrations are influenced by age, sex, comorbidities and time from symptom onset. To improve diagnosis, we developed machine learning models that integrate cardiac troponin concentrations at presentation or on serial testing with clinical features and compute the Collaboration for the Diagnosis and Evaluation of Acute Coronary Syndrome (CoDE-ACS) score (0-100) that corresponds to an individual's probability of myocardial infarction. The models were trained on data from 10,038 patients (48% women), and their performance was externally validated using data from 10,286 patients (35% women) from seven cohorts. CoDE-ACS had excellent discrimination for myocardial infarction (area under curve, 0.953; 95% confidence interval, 0.947-0.958), performed well across subgroups and identified more patients at presentation as low probability of having myocardial infarction than fixed cardiac troponin thresholds (61 versus 27%) with a similar negative predictive value and fewer as high probability of having myocardial infarction (10 versus 16%) with a greater positive predictive value. Patients identified as having a low probability of myocardial infarction had a lower rate of cardiac death than those with intermediate or high probability 30 days (0.1 versus 0.5 and 1.8%) and 1 year (0.3 versus 2.8 and 4.2%; P < 0.001 for both) from patient presentation. CoDE-ACS used as a clinical decision support system has the potential to reduce hospital admissions and have major benefits for patients and health care providers.

Improving Risk Stratification for Patients With Type 2 Myocardial Infarction.

BACKGROUND: Despite poor cardiovascular outcomes, there are no dedicated, validated risk stratification tools to guide investigation or treatment in type 2 myocardial infarction. OBJECTIVES: The goal of this study was to derive and validate a risk stratification tool for the prediction of death or future myocardial infarction in patients with type 2 myocardial infarction. METHODS: The T2-risk score was developed in a prospective multicenter cohort of consecutive patients with type 2 myocardial infarction. Cox proportional hazards models were constructed for the primary outcome of myocardial infarction or death at 1 year using variables selected a priori based on clinical importance. Discrimination was assessed by area under the receiving-operating characteristic curve (AUC). Calibration was investigated graphically. The tool was validated in a single-center cohort of consecutive patients and in a multicenter cohort study from sites across Europe. RESULTS: There were 1,121, 250, and 253 patients in the derivation, single-center, and multicenter validation cohorts, with the primary outcome occurring in 27% (297 of 1,121), 26% (66 of 250), and 14% (35 of 253) of patients, respectively. The T2-risk score incorporating age, ischemic heart disease, heart failure, diabetes mellitus, myocardial ischemia on electrocardiogram, heart rate, anemia, estimated glomerular filtration rate, and maximal cardiac troponin concentration had good discrimination (AUC: 0.76; 95% CI: 0.73-0.79) for the primary outcome and was well calibrated. Discrimination was similar in the consecutive patient (AUC: 0.83; 95% CI: 0.77-0.88) and multicenter (AUC: 0.74; 95% CI: 0.64-0.83) cohorts. T2-risk provided improved discrimination over the Global Registry of Acute Coronary Events 2.0 risk score in all cohorts. CONCLUSIONS: The T2-risk score performed well in different health care settings and could help clinicians to prognosticate, as well as target investigation and preventative therapies more effectively. (High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome [High-STEACS]; NCT01852123).

Rapid In-Process Measurement of Live Virus Vaccine Potency Using Laser Force Cytology: Paving the Way for Rapid Vaccine Development.

Vaccinations to prevent infectious diseases are given to target the body's innate and adaptive immune systems. In most cases, the potency of a live virus vaccine (LVV) is the most critical measurement of efficacy, though in some cases the quantity of surface antigen on the virus is an equally critical quality attribute. Existing methods to measure the potency of viruses include plaque and TCID50 assays, both of which have very long lead times and cannot provide real time information on the quality of the vaccine during large-scale manufacturing. Here, we report the evaluation of LumaCyte's Radiance Laser Force Cytology platform as a new way to measure the potency of LVVs in upstream biomanufacturing process in real time and compare this to traditional TCID50 potency. We also assess this new platform as a way to detect adventitious agents, which is a regulatory expectation for the release of commercial vaccines. In both applications, we report the ability to obtain expedited and relevant potency information with strong correlation to release potency methods. Together, our data propose the application of Laser Force Cytology as a valuable process analytical technology (PAT) for the timely measurement of critical quality attributes of LVVs.

Influence of Age on the Diagnosis of Myocardial Infarction.

BACKGROUND: The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction. METHODS: In a secondary analysis of a multicenter trial of consecutive patients with suspected myocardial infarction, we assessed the diagnostic accuracy of high-sensitivity cardiac troponin I at presentation for the diagnosis of type 1, type 2, or type 4b myocardial infarction across 3 age groups (<50, 50-74, and ≥75 years) using guideline-recommended sex-specific and age-adjusted 99th centile thresholds. RESULTS: In 46 435 consecutive patients aged 18 to 108 years (mean, 61±17 years), 5216 (11%) had a diagnosis of myocardial infarction. In patients <50 (n=12 379), 50 to 74 (n=22 380), and ≥75 (n=11 676) years, the sensitivity of the guideline-recommended threshold was similar at 79.2% (95% CI, 75.5-82.9), 80.6% (95% CI, 79.2-82.1), and 81.6% (95% CI, 79.8-83.2), respectively. The specificity decreased with advancing age from 98.3% (95% CI, 98.1-98.5) to 95.5% (95% CI, 95.2-95.8), and 82.6% (95% CI, 81.9-83.4). The use of age-adjusted 99th centile thresholds improved the specificity (91.3% [90.8%-91.9%] versus 82.6% [95% CI, 81.9%-83.4%]) and positive predictive value (59.3% [57.0%-61.5%] versus 51.5% [49.9%-53.3%]) for myocardial infarction in patients ≥75 years but failed to prevent the decrease in either parameter with increasing age and resulted in a marked reduction in sensitivity compared with the use of the guideline-recommended threshold (55.9% [53.6%-57.9%] versus 81.6% [79.8%-83.3%]. CONCLUSIONS: Age alters the diagnostic performance of cardiac troponin, with reduced specificity and positive predictive value in older patients when applying the guideline-recommended or age-adjusted 99th centiles. Individualized diagnostic approaches rather than the adjustment of binary thresholds are needed in an aging population.

The Prognostic and Discriminatory Utility of the Clinical Frailty Scale and Modified Frailty Index Compared to Age.

Background: There is no consensus on the optimal method for the assessment of frailty. We compared the prognostic utility of two approaches (modified Frailty Index [mFI], Clinical Frailty Scale [CFS]) in older adults (≥65 years) hospitalised with COVID-19 versus age. Methods: We used a test and validation cohort that enrolled participants hospitalised with COVID-19 between 27 February and 30 June 2020. Multivariable mixed-effects logistic modelling was undertaken, with 28-day mortality as the primary outcome. Nested models were compared between a base model, age and frailty assessments using likelihood ratio testing (LRT) and an area under the receiver operating curves (AUROC). Results: The primary cohort enrolled 998 participants from 13 centres. The median age was 80 (range:65−101), 453 (45%) were female, and 377 (37.8%) died within 28 days. The sample was replicated in a validation cohort of two additional centres (n = 672) with similar characteristics. In the primary cohort, both mFI and CFS were associated with mortality in the base models. There was improved precision when fitting CFS to the base model +mFI (LRT = 25.87, p < 0.001); however, there was no improvement when fitting mFI to the base model +CFS (LRT = 1.99, p = 0.16). AUROC suggested increased discrimination when fitting CFS compared to age (p = 0.02) and age +mFI (p = 0.03). In contrast, the mFI offered no improved discrimination in any comparison (p > 0.05). Similar findings were seen in the validation cohort. Conclusions: These observations suggest the CFS has superior prognostic value to mFI in predicting mortality following COVID-19. Our data do not support the use of the mFI as a tool to aid clinical decision-making and prognosis.

Assessment of Oxygen Supply-Demand Imbalance and Outcomes Among Patients With Type 2 Myocardial Infarction: A Secondary Analysis of the High-STEACS Cluster Randomized Clinical Trial.

Importance: Type 2 myocardial infarction occurs owing to multiple factors associated with myocardial oxygen supply-demand imbalance, which may confer different risks of adverse outcomes. Objective: To evaluate the prevalence and outcomes of different factors associated with oxygen supply-demand imbalance among patients with type 2 myocardial infarction. Design, Setting, and Participants: In this secondary analysis of a stepped-wedge, cluster randomized clinical trial conducted at 10 secondary and tertiary care hospitals in Scotland, 6096 patients with an adjudicated diagnosis of type 1 or type 2 myocardial infarction from June 10, 2013, to March 3, 2016, were identified, and the findings were reported on August 28, 2018. The trial enrolled consecutive patients with suspected acute coronary syndrome. The diagnosis of myocardial infarction was adjudicated according to the Fourth Universal Definition of Myocardial Infarction and the primary factor associated with oxygen supply-demand imbalance in type 2 myocardial infarction was defined. This secondary analysis was not prespecified. Statistical analysis was performed from July 7 to 30, 2020. Intervention: Implementation of a high-sensitivity cardiac troponin I assay. Main Outcomes and Measures: All-cause death at 1 year according to the factors associated with oxygen supply-demand imbalance among patients with type 2 myocardial infarction. Results: Of 6096 patients (2602 women [43%]; median age, 70 years [IQR, 58-80 years]), 4981 patients had type 1 myocardial infarction, and 1115 patients had type 2 myocardial infarction. The most common factor associated with oxygen supply-demand imbalance was tachyarrhythmia (616 of 1115 [55%]), followed by hypoxemia (219 of 1115 [20%]), anemia (95 of 1115 [9%]), hypotension (89 of 1115 [8%]), severe hypertension (61 of 1115 [5%]), and coronary mechanisms (35 of 1115 [3%]). At 1 year, all-cause mortality occurred for 15% of patients (720 of 4981) with type 1 myocardial infarction and 23% of patients (285 of 1115) with type 2 myocardial infarction. Compared with patients with type 1 myocardial infarction, those with type 2 myocardial infarction owing to hypoxemia (adjusted odds ratio [aOR], 2.35; 95% CI, 1.72-3.18) and anemia (aOR, 1.83; 95% CI, 1.14-2.88) were at greatest risk of death, whereas those with type 2 myocardial infarction owing to tachyarrhythmia (aOR, 0.83; 95% CI, 0.65-1.06) or coronary mechanisms (aOR, 1.07; 95% CI, 0.17-3.86) were at similar risk of death as patients with type 1 myocardial infarction. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, mortality after type 2 myocardial infarction was associated with the underlying etiologic factor associated with oxygen supply-demand imbalance. Most type 2 myocardial infarctions were associated with tachyarrhythmia, with better prognosis, whereas hypoxemia and anemia accounted for one-third of cases, with double the mortality of type 1 myocardial infarction. These differential outcomes should be considered by clinicians when determining which cases need to be managed if patient outcomes are to improve. Trial Registration: ClinicalTrials.gov Identifier: NCT01852123.

Cardiac Troponin Thresholds and Kinetics to Differentiate Myocardial Injury and Myocardial Infarction.

BACKGROUND: Although the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It is unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice. METHODS: In a secondary analysis of a multicenter randomized controlled trial, we identified 46 092 consecutive patients presenting with suspected acute coronary syndrome without ST-segment-elevation myocardial infarction. High-sensitivity cardiac troponin I concentrations at presentation and on serial testing were compared between patients with myocardial injury and infarction. The positive predictive value and specificity were determined at the sex-specific 99th percentile upper reference limit and rule-in thresholds of 64 ng/L and 5-fold of the upper reference limit for a diagnosis of type 1 myocardial infarction. RESULTS: Troponin was above the 99th percentile in 8188 patients (18%). The diagnosis was type 1 or type 2 myocardial infarction in 50% and 14% and acute or chronic myocardial injury in 20% and 16%, respectively. Troponin concentrations were similar at presentation in type 1 (median [25th-75th percentile] 91 [30-493] ng/L) and type 2 (50 [22-147] ng/L) myocardial infarction and in acute (50 [26-134] ng/L) and chronic (51 [31-130] ng/L) myocardial injury. The 99th percentile and rule-in thresholds of 64 ng/L and 5-fold upper reference limit gave a positive predictive value of 57% (95% CI, 56%-58%), 59% (58%-61%), and 62% (60%-64%) and a specificity of 96% (96%-96%), 96% (96%-96%), and 98% (97%-98%), respectively. The absolute, relative, and rate of change in troponin concentration were highest in patients with type 1 myocardial infarction (P<0.001 for all). Discrimination improved when troponin concentration and change in troponin were combined compared with troponin concentration at presentation alone (area under the curve, 0.661 [0.642-0.680] versus 0.613 [0.594-0.633]). CONCLUSIONS: Although we observed important differences in the kinetics, cardiac troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction in practice and should not guide management decisions in isolation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01852123.

Hyperoxia-induced lung injury in gamma-glutamyl transferase deficiency is associated with alterations in nitrosative and nitrative stress.

gamma-Glutamyl transferase (GGT) regulates glutathione metabolism and cysteine supply. GGT inactivation in GGT(enu1) mice limits cysteine availability causing cellular glutathione deficiency. In lung, the resultant oxidant burden is associated with increased nitric oxide (NO) production, yet GGT(enu1) mice still exhibit higher mortality in hyperoxia. We hypothesized that NO metabolism is altered under severe oxidant stress and contributes to lung cellular injury and death. We compared lung injury, NO synthase (NOS) expression, nitrate/nitrite production, nitroso product formation, peroxynitrite accumulation, and cell death in wild-type and GGT(enu1) mice in normoxia and hyperoxia. The role of NOS activity in cell death was determined by NOS inhibition. Exposure of wild-type mice to hyperoxia caused increased lung injury, altered NO metabolism, and induction of cell death compared with normoxia, which was attenuated by NOS inhibition. Each of these lung injury indices were magnified in hyperoxia-exposed GGT(enu1) mice except nitrosation, which showed a diminished decrease compared with wild-type mice. NOS inhibition attenuated cell death only slightly, likely due to further exacerbation of oxidant stress. Taken together, these data suggest that apoptosis in hyperoxia is partially NO-dependent and reiterate the importance of cellular glutathione in lung antioxidant defense. Therefore, reduced denitrosylation of proteins, possibly resulting in impaired cellular repair, and excessive apoptotic cell death likely contribute to increased lung injury and mortality of GGT(enu1) mice in hyperoxia.

Lung lining fluid glutathione attenuates IL-13-induced asthma.

GGT(enu1) mice, deficient in gamma-glutamyl transferase and unable to metabolize extracellular glutathione, develop intracellular glutathione deficiency and oxidant stress. We used intratracheal IL-13 to induce airway inflammation and asthma in wild-type (WT) and GGT(enu1) mice to determine the effect of altered glutathione metabolism on bronchial asthma. WT and GGT(enu1) mice developed similar degrees of lung inflammation. In contrast, IL-13 induced airway epithelial cell mucous cell hyperplasia, mucin and mucin-related gene expression, epidermal growth factor receptor mRNA, and epidermal growth factor receptor activation along with airway hyperreactivity in WT mice but not in GGT(enu1) mice. Lung lining fluid (extracellular) glutathione was 10-fold greater in GGT(enu1) than in WT lungs, providing increased buffering of inflammation-associated reactive oxygen species. Pharmacologic inhibition of GGT in WT mice produced similar effects, suggesting that the lung lining fluid glutathione protects against epithelial cell induction of asthma. Inhibiting GGT activity in lung lining fluid may represent a novel therapeutic approach for preventing and treating asthma.