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Background: Biomarkers simplifying the diagnostic workup by discriminating between non-ST-segment-elevation myocardial infarction (NSTEMI) and infarct-like myocarditis are an unmet clinical need., Methods and Results: A total of 105 subjects were categorized into groups as follows: ST-segment-elevation myocardial infarction (n=36), NSTEMI (n=22), infarct-like myocarditis (n=19), cardiomyopathy-like myocarditis (n=18), and healthy control (n=10). All subjects underwent cardiac magnetic resonance imaging, and serum concentrations of matrix metalloproteinase-1 (MMP-1) and procollagen type I carboxy terminal propeptide (PICP) were measured. Biomarker concentrations in subjects presenting with acute coronary syndrome and non-ST-segment-elevation, for example NSTEMI or infarct-like myocarditis, categorized as the non-ST-segment-elevation acute coronary syndrome-like cohort, were of particular interest for this study. Compared with healthy controls, subjects with myocarditis had higher serum concentrations of MMP-1 and PICP, while no difference was observed in individuals with myocardial infarction. In the non-ST-segment-elevation acute coronary syndrome-like cohort, MMP-1 concentrations discriminated infarct-like myocarditis and NSTEMI with an area under the receiver operating characteristic curve (AUC) of 0.95 (95% CI, 0.89-1.00), whereas high-sensitivity cardiac troponin T performed inferiorly (AUC, 0.74 [95% CI, 0.58-0.90]; P =0.012). Application of an optimal MMP-1 cutoff had 94.4% sensitivity (95% CI, 72.7%-99.9%) and 90.9% specificity (95% CI, 70.8%-98.9%) for the diagnosis of infarct-like myocarditis in this cohort. The AUC of PICP in this context was 0.82 (95% CI, 0.68-0.97). As assessed by likelihood ratio tests, incorporating MMP-1 or PICP with age and C-reactive protein into composite prediction models enhanced their diagnostic performance., Conclusions: MMP-1 and PICP could potentially be useful biomarkers for differentiating between NSTEMI and infarct-like myocarditis in individuals with non-ST-segment-elevation acute coronary syndrome-like presentation, though further research is needed to validate their clinical applicability.

Background Cardiac troponin (cTn) permits early rule-out/rule-in of patients admitted with possible non-ST-segment-elevation myocardial infarction. In this study, we developed an admission and a 0/1 hour rule-out/rule-in algorithm for a troponin assay with measurable results in >99% of healthy individuals. We then compared its diagnostic and long-term prognostic properties with other protocols. Methods and Results Blood samples were collected at 0, 1, 3, and 8 to 12 hours from patients admitted with possible non-ST-segment-elevation myocardial infarction. cTnT (Roche Diagnostics), cTnI (Abbott) (Abbott Diagnostics), and cTnI (sgx) (Singulex Clarity System) were measured in 971 admission and 465 1-hour samples. An admission and a 0/1 hour rule-out/rule-in algorithm were developed for the cTnI (sgx) assay and its diagnostic properties were compared with cTnT ESC (European Society of Cardiology), cTnI (Abbott)ESC , and 2 earlier cTnI (sgx) algorithms. The prognostic composite end point was all-cause mortality and future nonfatal myocardial infarction during a median follow-up of 723 days. non-ST-segment-elevation myocardial infarction prevalence was 13%. The novel cTnI (sgx) algorithms showed similar performance regardless of time from symptom onset, and area under the curve was significantly better than comparators. The cTnI (sgx)0/1 hour algorithm classified 92% of patients to rule-in or rule-out compared with ≤78% of comparators. Patients allocated to rule-out by the prior published 0/1 hour algorithms had significantly fewer long-term events compared with the rule-in and observation groups. The novel cTnI (sgx)0/1 hour algorithm used a higher troponin baseline concentration for rule-out and did not allow for prognostication. Conclusions Increasingly sensitive troponin assays may improve identification of non-ST-segment-elevation myocardial infarction but could rule-out patients with subclinical chronic myocardial injury. Separate protocols for diagnosis and risk prediction seem appropriate.

Background Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non-ST-segment-elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction, concentration of both C-reactive protein and troponin T were reduced in the active treatment arm. In this follow-up study, an aptamer-based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. Methods and Results Plasma from percutaneous coronary intervention-treated patients, 24 in the active intervention and 24 in the placebo-control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMAscan assay. Employing slow off-rate aptamers, the relative abundance of 1074 circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1-3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMAscan assay, and subsequently confirmed by enzyme immunoassay, were significantly altered by tocilizumab administration. The acute-phase proteins lipopolysaccharide-binding protein, hepcidin, and insulin-like growth factor-binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C-C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. Conclusions Employing the SOMAscan aptamer-based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non-ST-segment-elevation myocardial infarction.

Background Cardiac troponin T ( cTnT ) is seen in many other conditions besides myocardial infarction, and recent studies demonstrated distinct forms of cTnT . At present, the in vivo formation of these different cTnT forms is incompletely understood. We therefore performed a study on the composition of cTnT during the course of myocardial infarction, including coronary venous system sampling, close to its site of release. Methods and Results Baseline samples were obtained from multiple coronary venous system locations, and a peripheral artery and vein in 71 non- ST -segment-elevation myocardial infarction patients. Additionally, peripheral blood was drawn at 6- and 12-hours postcatheterization. cTnT concentrations were measured using the high-sensitivity- cTnT immunoassay. The cTnT composition was determined via gel filtration chromatography and Western blotting in an early and late presenting patient. High-sensitivity - cTnT concentrations were 28% higher in the coronary venous system than peripherally (n=71, P<0.001). Coronary venous system samples demonstrated cT n T-I-C complex, free intact cTnT , and 29 kD a and 15 to 18 kD a cTnT fragments, all in higher concentrations than in simultaneously obtained peripheral samples. While cT n T-I-C complex proportionally decreased, and disappeared over time, 15 to 18 kD a cTnT fragments increased. Moreover, cT n T-I-C complex was more prominent in the early than in the late presenting patient. Conclusions This explorative study in non- ST -segment-elevation myocardial infarction shows that cTnT is released from cardiomyocytes as a combination of cT n T-I-C complex, free intact cTnT , and multiple cTnT fragments indicating intracellular cTnT degradation. Over time, the cT n T-I-C complex disappeared because of in vivo degradation. These insights might serve as a stepping stone toward a high-sensitivity- cTnT immunoassay more specific for myocardial infarction.

Background Although acute coronary syndromes (ACS) are a major cause of morbidity and mortality, relationships with biologically active lipid species potentially associated with plaque disruption/erosion in the context of their lipoprotein carriers are indeterminate. The aim was to characterize lipid species within lipoprotein particles which differentiate ACS from stable coronary artery disease. Methods and Results Venous blood was obtained from 130 individuals with de novo presentation of an ACS (n=47) or stable coronary artery disease (n=83) before coronary catheterization. Lipidomic measurements (533 lipid species; liquid chromatography electrospray ionization/tandem mass spectrometry) were performed on whole plasma as well as 2 lipoprotein subfractions: apolipoprotein A1 (apolipoprotein A, high-density lipoprotein) and apolipoprotein B. Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high-density lipoprotein (high-density lipoprotein, 113 lipids; plasma, 73 lipids). Models including plasma lipid species alone improved discrimination between the stable and ACS groups by 0.16 (C-statistic) compared with conventional risk factors. Models utilizing lipid species either in plasma or within lipoprotein fractions had a similar ability to discriminate groups, though the C-statistic was highest for plasma lipid species (0.80; 95% CI, 0.75-0.86). Conclusions Multiple lysophospholipids, but not cholesterol, featured among the lipids which were present at low concentration within high-density lipoprotein of those presenting with ACS. Lipidomics, when applied to either whole plasma or lipoprotein fractions, was superior to conventional risk factors in discriminating ACS from stable coronary artery disease. These associative mechanistic insights elucidate potential new preventive, prognostic, and therapeutic avenues for ACS which require investigation in prospective analyses.

Background Small studies have suggested an association between markers of collagen turnover and adverse outcomes in heart failure ( HF ). We examined C-terminal telopeptide (beta- CT x) and the risk of cardiovascular death or new or worsening HF in non- ST -elevation acute coronary syndrome. Methods and Results We measured baseline serum beta- CT x, NT -pro BNP (N-terminal pro-B-type natriuretic peptide), hsTnT (high-sensitivity cardiac troponin T) and hs CRP (high-sensitivity C-reactive protein) (Roche Diagnostics) in a nested biomarker analysis (n=4094) from a study of patients with non- ST -elevation acute coronary syndrome. The relationship between quartiles of beta- CT x and cardiovascular death or HF over a median follow-up time of 12 months was analyzed using adjusted Cox models. Higher beta- CT x levels identified a significantly higher risk of cardiovascular death/ HF (Q4 10.9% versus Q1 3.8%, Logrank P<0.001). After multivariable adjustment, beta- CT x in the top quartile (Q4) was associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 2.22 [1.50-3.27]) and its components (Q4 versus Q1: cardiovascular death: adjusted hazard ratio 2.48 [1.46-4.21]; HF : adjusted hazard ratio 2.04 [1.26-3.30]). In an adjusted multimarker model including NT -pro BNP , hsTnT, and hs CRP , beta- CT x remained independently associated with cardiovascular death/ HF (Q4 versus Q1: adjusted hazard ratio 1.98 [1.34-2.93]) and its components. Beta- CT x correlated weakly with NT -pro BNP ( r=0.17, P<0.001) and left ventricular ejection fraction ( r=-0.05, P=0.008) and did not correlate with hsTnT ( r=0.02, P=0.20), or hs CRP ( r=-0.03, P=0.09). Conclusions Levels of beta- CT x, a biomarker of collagen turnover, were associated with cardiovascular death and HF in patients with non- ST -elevation acute coronary syndrome. This biomarker, which correlated only weakly or not significantly with traditional biomarkers of cardiovascular death and HF , may provide complementary pathobiological insight and risk stratification in these patients.

Background: Triggering receptor expressed on myeloid cells-1 (TREM-1) is thought to be critical for inflammatory signal amplification and involved in the development of atherosclerosis. TREM-1 is significantly increased in patients with myocardial infarction. The aim of this study was to investigate the association between soluble TREM-1 (sTREM-1) and mortality and cardiovascular events in patients with acute myocardial infarction., Methods and Results: We included 838 consecutive patients with acute myocardial infarction from October 7, 2012 to December 5, 2014. Blood samples were collected from patients with acute myocardial infarction immediately after diagnosis. During follow-up, 88 patients died, and 180 patients reached the combined end points of major adverse cardiovascular event (MACE). Patients with high sTREM-1 (higher than the median) had increased risk of all-cause mortality and MACE compared with those with low sTREM-1 (log-rank test, P <0.001). After adjustment for confounding risk factors by Cox regression analysis, high sTREM-1 remained an independent predictor of all-cause mortality (hazard ratio, 1.978; 95% confidence interval, 1.462-2.675; P <0.001) and MACE (hazard ratio, 2.413; 95% confidence interval, 2.022-2.879; P <0.001). After the addition of sTREM-1 to the reference model, the C-statistic for all-cause mortality increased from 0.86 to 0.89, and the difference was 0.023 (95% confidence interval, 0.0009-0.0477), and the C-statistic for MACE increased from 0.71 to 0.80, and the difference was 0.087 (95% confidence interval, 0.053-0.122). sTREM-1 levels were consistently positively associated with risks of all-cause mortality and MACE in various subpopulations, and there was no significant interaction among prespecified subgroups., Conclusions: sTREM-1 was significantly associated with all-cause mortality and MACE, independent of established conventional risk factors in patients with acute myocardial infarction., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Current American Heart Association/American College of Cardiology guidelines recommend the GRACE (Global Registry of Acute Coronary Events) and TIMI (Thrombolysis in Myocardial Infarction) scores to assess myocardial infarction (MI) prognosis. Changes in the epidemiological characteristics of MI and the availability of new biomarkers warrant an assessment of the performance of these scores in contemporary practice. We assessed the following: (1) the performance of GRACE and TIMI to predict 1-year mortality in a cohort of patients stratified by ST-segment elevation MI (STEMI) and non-STEMI (NSTEMI) and (2) the incremental discriminatory power of soluble suppression of tumorigenicity-2, a myocardial fibrosis biomarker., Methods and Results: Olmsted County, Minnesota, residents with incident MI (N=1401) were recruited prospectively from November 1, 2002 to December 31, 2012 (mean age, 67 years; 61% men; 79% with NSTEMI). Baseline data were used to calculate risk scores; soluble suppression of tumorigenicity-2 was measured in stored plasma samples obtained at index MI. C -statistics adapted to survival data were used to assess the discriminatory power of the risk scores and the improvement gained by adding other markers. During the first year of follow-up, 190 patients (14%) died. The discriminatory performance to predict death was reasonable for GRACE and poor for TIMI, and was generally worse in those with NSTEMI versus those with STEMI. In people with NSTEMI, sequential addition of comorbidities and soluble suppression of tumorigenicity-2 substantially improved the c -statistic over GRACE (from 0.78 to 0.80 to 0.84) and TIMI (from 0.61 to 0.73 to 0.81), respectively (all P ≤0.05)., Conclusions: Guideline-recommended scores for risk assessment after MI underperform in contemporary community patients, particularly those with NSTEMI, which now represents most infarcts. Incorporating comorbidities and soluble suppression of tumorigenicity-2 substantially improves risk prediction, thereby delineating opportunities to improve clinical care., (© 2017 The Authors and Mayo Clinic. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Current guidelines recommend early P2Y 12 inhibitor administration in non-ST-elevation myocardial infarction, but it is unclear if precatheterization use is associated with longer delays to coronary artery bypass grafting (CABG) or higher risk of post-CABG bleeding and transfusion. This study examines the patterns and outcomes of precatheterization P2Y 12 inhibitor use in non-ST-elevation myocardial infarction patients who undergo CABG., Methods and Results: Retrospective analysis was done of 20 304 non-ST-elevation myocardial infarction patients in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry (2009-2014) who underwent catheterization within 24 hours of admission and CABG during the index hospitalization. Using inverse probability-weighted propensity adjustment, we compared time from catheterization to CABG, post-CABG bleeding, and transfusion rates between patients who did and did not receive precatheterization P2Y 12 inhibitors. Among study patients, 32.9% received a precatheterization P2Y 12 inhibitor (of these, 2.2% were given ticagrelor and 3.7% prasugrel). Time from catheterization to CABG was longer among patients who received precatheterization P2Y 12 inhibitor (median 69.9 hours [25th, 75th percentiles 28.2, 115.8] versus 43.5 hours [21.0, 71.8], P <0.0001), longer for patients treated with prasugrel (median 114.4 hours [66.5, 155.5]) or ticagrelor (90.4 hours [48.7, 124.5]) compared with clopidogrel (69.3 [27.5, 114.6], P <0.0001). Precatheterization P2Y 12 inhibitor use was associated with a higher risk of post-CABG major bleeding (75.7% versus 73.4%, adjusted odds ratio 1.33, 95% confidence interval 1.22-1.45, P <0.0001) and transfusion (47.6% versus 35.7%, adjusted odds ratio 1.51, 95% confidence interval 1.41-1.62, P <0001); these relationships did not differ among patients treated with clopidogrel, prasugrel, or ticagrelor., Conclusions: Precatheterization P2Y 12 inhibitor use occurs commonly among non-ST-elevation myocardial infarction patients who undergo early catheterization and in-hospital CABG. Despite longer delays to surgery, the majority of pretreated patients proceed to CABG <3 days postcatheterization. Precatheterization P2Y 12 inhibitor use is associated with higher risks of postoperative bleeding and transfusion., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The relationship between troponin level and outcomes among patients with non-ST-segment elevation ACS is established, but the relationship of troponin level with long-term outcomes among medically managed non-ST-segment elevation ACS patients receiving contemporary antiplatelet therapy is inadequately defined., Methods and Results: In 6763 medically managed non-ST-segment elevation ACS patients randomized in TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) (prasugrel versus clopidogrel), we examined relationships between categories of peak troponin/upper limit of normal (ULN) ratio within 48 hours of the index ACS event (≈4.5 days before randomization) and 30-month outcomes (cardiovascular death, myocardial infarction, or stroke; cardiovascular death or myocardial infarction; and all-cause death). Patients with peak troponin levels <1×ULN were younger, were more often women, and had lower GRACE risk scores than those in other troponin groups. Those with ratios ≥5×ULN were more frequently smokers but less often had prior myocardial infarction or percutaneous coronary intervention. Diabetes mellitus prevalence, body mass index, serum creatinine, and hemoglobin were similar across groups. For all end points, statistically significant differences in 30-month event rates were observed between peak troponin categories. The relationship was linear for 30-month mortality (<1×ULN, n=1849 [6.2%]; 1 to <3×ULN, n=1203 [9.6%]; 3 to <5×ULN, n=581 [10.8%]; and ≥5×ULN, n=3405 [12.8%]) but plateaued for composite end points beyond peak troponin values ≥3×ULN. There was no statistically significant heterogeneity in treatment effect by peak troponin ratio for any end point., Conclusions: Among medically managed non-ST-segment elevation ACS patients selected for medical management, there was a graded relationship between increasing peak troponin and long-term ischemic events but no heterogeneity of treatment effect for prasugrel versus clopidogrel according to peak troponin., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00699998., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)