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Background: We aimed to evaluate the diagnostic sensitivity for myocardial infarction (MI) when using an undetectable level of high-sensitivity cardiac troponin T (hs-cTnT < 5 ng/L) at presentation combined with a non-ischemic electrocardiogram (ECG), to rule out MI in a non-ST-segment elevation MI (NSTEMI) cohort presenting ≤2 h from symptom onset. We also aimed to compare baseline characteristics and 30-day outcome in NSTEMI patients presenting with and without hs-cTnT < 5 ng/L., Methods: All patients admitted to five centers in Sweden 2011-2015, after the introduction of hs-cTnT, who presented ≤2 h from symptom onset and received a final diagnosis of NSTEMI, were identified through the SWEDEHEART registry. These data and data of hs-cTnT levels were verified in the hospitals' medical records. The registry provided baseline and outcome data., Results: Twenty-four (2.6%) of 911 NSTEMI patients presented with hs-cTnT < 5 ng/L. In patients presenting >1-≤2 h from symptom onset the sensitivity for MI when combining hs-cTnT and ECG was 99.4% (95% CI 98.4%-99.8%). In patients presenting ≤1 h, and in patients aged ≤65 years without prior MI, the sensitivity was insufficient. NSTEMI patients presenting with hs-cTnT < 5 ng/L were younger and had less often a prior MI. A total of 62.5 vs. 63.5% of the NSTEMI patients presenting with and without hs-cTnT < 5 ng/L underwent revascularization within 30 days and 4.5 and 3.2% died respectively., Conclusions: Hs-cTnT < 5 ng/L at presentation combined with a non-ischemic ECG may be used to rule out MI in patients presenting as early as >1 h from symptom onset with a sufficient sensitivity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Troponin is the gold-standard for diagnostic evaluation of patients with suspected myocardial infarction (MI). We aimed to evaluate the diagnostic and prognostic performance of a new ultra-sensitivity troponin I (us-TnI) assay in patients with suspected MI., Methods and Results: 1534 patients with suspected MI were included. Us-TnI measurements were performed directly on admission and after one hour. One-year rates of mortality and incident MI were assessed. For diagnostic evaluation the negative and positive predictive value (NPV/PPV) using admission us-TnI concentrations and 0/1h delta were calculated. For rule-out an NPV > 99.5% (100% for single-admission-value) and for rule-in a PPV > 80% was targeted. Internal derivation/validation was used. In the derivation dataset 155/767 (20.2%) patients were diagnosed with having non-ST-elevation MI (NSTEMI). For rule-out of NSTEMI an us-TnI < 1 ng/L directly on admission resulted in an NPV of 100.0% (CI 98.2-100.0). Using serial sampling an admission us-TnI < 2 ng/L and a 0/1h delta < 1 ng/L resulted in an NPV of 99.7% (CI 98.4-100.0) and ruled-out NSTEMI in 46.8% of all patients. The respective one-year rate of death or MI was 0.6%. For rule-in of NSTEMI an us-TnI ≥ 25 ng/L on admission or a 0/1h delta ≥ 6 ng/L resulted in a PPV of 81.3% (CI 73.7-87.5) and ruled-in NSTEMI in 18.5% of all patients. The one-year event rate was 12.7%. Results were similar in 767 patients from the validation cohort., Conclusion: Application of an us-TnI assay allows the accurate triage of a large proportion of patients with suspected MI using a 0/1h algorithm., Trial Registration: www.clinicaltrials.gov (NCT02355457)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Sex- and age-specific high-sensitivity Troponin T (hs-cTnT) cutpoints for the diagnosis and prognosis in acute coronary syndromes are not well established. We evaluated the use of such dichotomous thresholds for calculation of the GRACE score., Methods: We analyzed a retrospective cohort study of 1146 patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). Sex-dependent hs-cTnT cutpoints comprised 15.5 ng/L for men and 9.0 ng/L for women, while the sex-/age-specific cutpoints comprised 17 ng/L for 50-64-year-old men and ≥65-year-old women, 31 ng/L for ≥65-year-old men and 14 ng/L for the remainder of patients., Results: For the diagnosis of NSTEMI using sex-specific hs-cTnT cutpoints, in women, the positive likelihood ratio (LR+) was 2.04 (1.68-2.47) while in men, the negative likelihood ratio (LR-) was 0.05 (0.04-0.07). Using sex-/age-specific hs-cTnT cutpoints, in ≥65-year-old women the LR- was 0.09 (0.06-0.15), in 50 to 64-year-old men the LR- was 0.08 (0.04-0.13) while in ≥65-year-old men the LR- was 0.32 (0.28-0.37). Sex-specific hs-cTnT cutpoints achieved an NRI of -0.020 (95% CI, -0.101-0.118) for women and 0.030 (95% CI, -0.013-0.079) for men, and the sex-/age-specific hs-cTnT cutpoints achieved an NRI of 0.061 (95% CI, -0.019-0.132) for women and 0.021 (95% CI, -0.062-0.108) for men, while net benefit and clinical utility were highest for women using the sex-/age-specific hs-cTnT cutpoints., Conclusions: Sex-dependent hs-cTNT cutpoints imply increasing diagnostic sensitivity for women at the cost of specificity. Considering age for hs-cTNT cutoffs slightly improves risk reclassification, although the overall gain in terms of the clinical management appears negligible., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The IL-6 receptor antagonist tocilizumab has been shown to attenuate the proatherogenic lipoprotein a [Lp(a)] in rheumatoid arthritis. We evaluated if a single dose of tocilizumab reduced Lp(a) in patients with non-ST-elevation myocardial infarction (NSTEMI)., Methods: Lp(a) was assessed by immunoassay (n = 117 patients) at 7 consecutive time-points between day 1 and 3 and at 3 and 6 months follow-up., Results: Tocilizumab did not affect Lp(a) at any time-point during the study and was not associated with cardiovascular risk factors., Conclusions: Short-time inhibition of IL-6 with tocilizumab in patients with NSTEMI did not influence Lp(a) levels., (Copyright © 2018. Published by Elsevier B.V.)

Aim: To evaluate the effect of interleukin-6 inhibition with tocilizumab on the cytokine network in patients with acute non-ST-elevation myocardial infarction (NSTEMI)., Methods: 117 patients with acute NSTEMI were randomised to an intravenous infusion of 280 mg tocilizumab or placebo prior to coronary angiography. Blood samples were obtained at baseline, at 6 consecutive points in time during hospitalisation, and at follow-up after 3 and 6 months. Cytokines (n = 27) were analysed with a multiplex cytokine assay., Results: Using a mixed between-within subjects analysis of variance, we observed a significant (p < 0.001) between-group difference in changes for interferon gamma-inducible protein (IP-10) and macrophage inflammatory protein-1β (MIP-1β), due to significant increases in the tocilizumab group during hospitalisation (i.e., IP-10 median change from baseline during hospitalisation (m Δ ), placebo: 3 (-60, 68) pg/ml vs tocilizumab: 209 (69, 335) pg/ml; MIP-1β m Δ , placebo: 5 (-2, 12) pg/ml vs tocilizumab: 39 (24, 63) pg/ml). MIP-1β was inversely correlated to troponin T (r = -0.28, p < 0.05) and neutrophils (r = -0.32, p < 0.05) in the tocilizumab group. In contrast, tocilizumab had only modest or no effects on the other examined cytokines., Conclusions: Tocilizumab led to a selective and substantial increase in IP-10 and MIP-1β during the acute phase of NSTEMI, with no or only minor effects on the other measured cytokines. ClinicalTrials.gov, NCT01491074., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Elderly treated with dual antiplatelet therapy after percutaneous coronary intervention (PCI) represent a challenging population because of increased risk of both ischemic and bleeding events. We aimed to investigate the association between high on-treatment platelet reactivity (HPR) and long-term outcome in elderly with non-ST-elevated acute coronary syndromes (NSTE-ACS) undergoing PCI., Methods: Platelet reactivity was measured by vasodilator-stimulated phosphoprotein (VASP) assay at three time-points (baseline, discharge, 1 month after PCI) in 1053 NSTE-ACS patients (311 elderly) treated with clopidogrel. Major adverse cardiac events (MACE) were assessed up to 1 year-follow-up., Results: Elderly with HPR at discharge showed a significantly higher incidence of overall MACE (13 vs 4%, p = .006), cardiac death (6 vs 0.7%, p = .020), myocardial infarction (MI, 12 vs 4%, p = .031) and a trend for higher stent-thrombosis (5 vs 0.7%, p = .068). Similarly, elderly with 1-month-HPR showed between 1 month and 1 year significantly higher incidence of MACE (10 vs 4%, p = .012), cardiac death (6 vs 0.7%, p = .019) and composite cardiac death/MI (11 vs 4%, p = .014). Up to 1 year, elderly with HPR showed a 4-fold increased risk of MACE compared to both elderly without HPR (for discharge-HPR: p = .005; for 1-month-HPR: p = .01) and non-elderly with HPR (for discharge-HPR: p < .001; for 1-month-HPR: p < .0001). At multivariable analysis, HPR could independently predict 1-year-MACE in elderly (for discharge-HPR: HR = 3.191, CI: 1.373-7.417, p = .007; for 1-month-HPR: HR = 3.542, CI: 1.373-9.137, p = .009)., Conclusions: In elderly with NSTE-ACS undergoing PCI and treated with clopidogrel, HPR was independently associated with an increased risk of MACE up to 1 year., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: A rapid rule-out or rule-in protocol based on the 0-hour/1-hour algorithm using high-sensitivity cardiac troponin T is recommended by the European Society of Cardiology. However, Asian data are not available., Methods: This prospective cohort study included 413 patients with suspected non-ST elevation myocardial infarction in 3 hospitals in Japan and Taiwan from November 2014 to April 2017. Patients were divided into 3groups-rule-out, observe, and rule-in-according to the algorithm. Major adverse cardiovascular events were evaluated at the 30-dayfollow-up., Results: The algorithm ruled out acute myocardial infarction (AMI) in 171 patients with a negative predictive value and sensitivity of 100% (95% confidential interval [CI], 96.8%-100%) and 100% (95% CI, 88.0%-100%), respectively, in the rule-out group. None of the patients were diagnosed with AMI. Among the 127 patients classified into the rule-in group, 47 were diagnosed as having AMI. The positive predictive value and specificity were 33.1% (95% CI, 25.1%-41.9%) and 66.3% (95% CI, 60.2%-72.0%), respectively. Elective catheter intervention was required in 13 patients (5 in the rule-out group, 8 in the observe group) by the 30-dayfollow-up. The Framingham Risk Score (FRS) identified moderate risk in 5 patients and high risk in 8, while the Global Registry of Acute Coronary Events (GRACE) 2.0 risk score identified low risk in 6 patients and moderate risk in 7., Conclusion: The ESC0-hour/1-hour algorithm could be sufficient in Asian patients. The combination with FRS may be more precise than that with the GRACE 2.0 risk score., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Non-ST-elevation Myocardial Infarction (NSTEMI) subgroup of ACS has wide variability in patient prognosis. Risk stratification in NSTE-ACS is essential for deciding about early management. Corrected QT interval estimation is one tool which has utility in bedside risk stratification. Whether it differentiates NSTEMI patients into different risk groups is the contention of this study., Objective: To assess (1) correlation between maximum corrected QT interval (QTc) and cardiac Troponin I (cTnI) levels; (2) if prolonged corrected QT interval is an independent predictor of higher MACE in NSTEMI patients., Methods: We prospectively studied 301 NSTEMI patients. cTnI level and QTc were measured at 0, 12, 24 and 48h post-admission. Patients were followed for 30days post-discharge for incidence of major adverse cardiac events (MACE) defined as composite of cardiac death, non-fatal MI and urgent revascularization. We assessed correlation between cTnI level and maximum QTc value. Regression analysis was performed to identify independent predictors of MACE., Results: We found a strong positive linear correlation between maximum QTc interval and cTnI level with a correlation coefficient of 0.637 (p<0.001). Cut-off value of QTc>468ms predicted poor prognosis in form of MACE with 72% sensitivity and 61% specificity. Multivariate analysis revealed that after adjusting for different prognostic variables, TIMI score>2 and QTc>468ms, were the only independent predictors of MACE., Conclusion: QTc-max interval has a strong positive linear correlation with cTnI level. Prolonged QTc has utility as an independent high risk predictor in NSTEMI population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: A point of care test (POCT) for troponin T (TnT) in the Emergency Department (ED) was compared to a high-sensitivity TnT (hsTnT) central laboratory test (CLT) to determine the influence of test system and different cut-off values on the diagnostic performance in patients with suspected acute coronary syndrome (ACS) under routine conditions., Methods: All patients with routine TnT testing in the ED were enrolled. Only internal medicine patients without STEMI and with both troponin values were analyzed. TnT was measured with a contemporary sensitive POCT assay in the ED and with a hs-assay in the central laboratory. The diagnostic performance was analyzed at two different cut-off points (99th percentile and conventional rule-in cut-offs). Primary endpoint was the diagnosis of NSTEMI., Results: Of all patients (n=3423), 3.6% had a diagnosis of NSTEMI (n=124). For the hsTnT assay, 28.4% of all values were at or below the lower limit of detection (LOD) as compared to 75.7% of the POC-TnT-values. The area under the receiver operating curves did not differ significantly between the assays (hsTnT: 0.912(95%-CI: 0.884-0.940); POC-TnT: 0.896(95%-CI: 0.859-0.933)). The diagnostic performance was very similar for both assays: the positive predictive value was below 50% for troponin values below 100ng/L and hardly increased for values between 100 and 600ng/L for hs and conventional assays., Conclusions: In our cohort of emergency patients, the diagnostic performance of conventional POC-testing was comparable to hsTnT. A 99th percentile cut-off may be useful for rule-out of NSTEMI, but seems limited for routine rule-in strategies., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Mean platelet volume to platelet count ratio (MPV/P ratio) has been demonstrated to be a predictor of adverse outcome in patients with non-ST-segment elevation myocardial infarction (NSTEMI). We aimed to assess whether MPV/P ratio is a useful marker to predict long-term prognosis in NSTEMI patients undergoing PCI. Moreover, the prognostic accuracy of MPV/P ratio was compared with MPV and GRACE score., Methods: In a retrospective cohort study, according to the baseline MPV/P values, 887 consecutive NSTEMI patients undergoing PCI were divided into two groups: the high MPV/P group (n=296, MPV/P ≥0.054) and the low MPV/P group (n=591, MPV/P<0.054). Clinical endpoints were all-cause mortality and all-cause mortality/nonfatal reinfarction., Results: Multivariate analysis showed that high MPV/P was an independent predictor of all-cause mortality [HRs: 1.973, 95% CI: 1.528-2.549, P<0.001], and all-cause mortality/nonfatal myocardial reinfarction [HRs: 1.289, 95% CI: 1.181-1.408, P<0.001]. MPV/P ratio has good accuracy for predicting clinical endpoints. The discriminatory performance of MPV/P ratio was similar to GRACE score but better than MPV (for all-cause mortality: MPV/P vs. GRACE: z=0.205, p=0.837; MPV/P vs. MPV: z=2.677, p=0.008; GRACE vs. MPV: z=3.017, p=0.003; for all-cause mortality/nonfatal myocardial: MPV/P vs. GRACE: z=1.098, p=0.272; MPV/P vs. MPV: z=4.026, p<0.001; GRACE vs. MPV: z=4.962, p<0.001)., Conclusions: MPV/P ratio was similar to GRACE score but better than MPV for predicting all-cause mortality and all-cause mortality/nonfatal myocardial reinfarction in NSTEMI patients undergoing PCI. However, MPV/P ratio is easier to calculate than GRACE score., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Chronic total occlusion (CTO) in a noninfarct-related artery (non-IRA) is an independent predictor of mortality in non-ST elevation myocardial infarction (NSTEMI). Mean platelet volume (MPV) is associated with cardiovascular events in NSTEMI. Little is known about the predictors of non-IRA-CTO in patients with NSTEMI. The purpose of this study was to evaluate the relationship between the presence of non-IRA-CTO with MPV level in patients with NSTEMI and multivessel coronary artery disease (MVCAD)., Methods: Data of consecutive patients with NSTEMI and MVCAD treated in high-volume PCI center between 2006 and 2012 and included in the prospective registry were divided according to the presence of CTO and analyzed., Results: In the group of 685 patients fulfilling the inclusion criteria, 308 (45%) patients had CTO (CTO+), and in 377 (55%) patients CTO was not observed (CTO-). The MPV level on admission was significantly higher in the CTO+ group than in the CTO- group (P<0.0001). In the multivariate analysis of the entire study population, independent predictors of occurrence of CTO were medium platelet volume (MPV; per 1fL more; odds ratio [OR] 1.34; 95% confidence interval [CI] 1.15-1.57; P=0.0002) together with left ventricular ejection fraction and prior MI., Conclusions: MPV at admission is independently associated with more frequent occurrence of non-IRA CTO in patients with NSTEMI and MVCAD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Relatively little is known about the role of phosphatidylserine (PS) in procoagulant activity (PCA) in patients with non-ST-elevated myocardial infarction (NSTEMI) after stent implantation. This study was designed to evaluate whether exposed PS on microparticles (MPs) and blood cells were involved in the hypercoagulable state in NSTEMI patients with stent implantation., Methods: NSTEMI patients (n=90) and healthy controls (n=20) were included in our study. PS exposure on MPs and blood cells was analyzed with flow cytometer and confocal microscope. PCA was evaluated by clotting time, purified coagulation complex assays and fibrin production assays., Results: Baseline levels of MPs and PS + blood cells were significantly higher (P<0.001) in the patients than in controls. After stent implantation, a remarkable increase was observed in both MPs and PS + blood cells. Specifically, PS + MPs, PS + platelets and erythrocytes peaked at 18h following stent implantation, while PS + leukocytes peaked on day 2. In addition, circulating MPs (mostly derived from platelets, leukocytes, erythrocytes and endothelial cells) cooperating with PS + blood cells, contributed to markedly shortened coagulation time and markedly increased FXa/thrombin/fibrin (all P<0.01) generation in patient group. Moreover, blockade of exposed PS on MPs and cells with lactadherin inhibited PCA by approximately 70%., Conclusions: Our results suggest that PS + MPs and blood cells play a procoagulant role in NSTEMI patients following stent implantation. Blockade of PS could become a novel therapeutic modality for the prevention of thrombosis in these patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Copeptin, a neuropeptide of unknown pathophysiological function that is stoichiometrically secreted with the antidiuretic hormone, is a non-specific marker of endogenous stress which has recently gained interest for its use within a dual-marker strategy in combination with cardiac troponin for the early rule-out of non-ST-elevation myocardial infarction (NSTEMI) in emergency department patients with suspected MI. Based on methodologically strong and consistent evidence from large diagnostic studies and even one randomized intervention study, current European Society of Cardiology Guidelines recommend copeptin and the dual-marker strategy for the early rule-out of MI when high-sensitivity cardiac troponin (hs-cTn) assays are not available. When used with conventional cTn assays, the incremental value of copeptin is large. When used with hs-cTn, the incremental value is very small and does not justify routine clinical use. This review aims to describe the structure, function, and release mechanism of copeptin; as well as to provide an explanation on why this biomarker should be used in the rule-out, and not in the rule-in, of NSTEMI., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)