Cytokines of the IL-6 family have been related to infarct size and prognosis in patients with myocardial infarction. The aims of the present study were to elucidate possible associations between myocardial necrosis and left ventricular impairment and members of the IL-6 transsignalling system including soluble (s) IL-6R and (s) glycoprotein 130 (sgp130) in patients with ST-elevation myocardial infarction (STEMI) treated with primary PCI. In blood samples from 1028 STEMI patients, collected in-hosptial, we found significant correlations between peak TnT and IL-6 and CRP (p < 0.001, all) and between IL-6 and CRP and LV ejection fraction and NT-proBNP (p < 0.001, all). On the contrary, no significant associations were found between peak TnT and sgp130 or sIL-6R. Furthermore sgp130 was significantly elevated in diabetic patients and also associated with the glucometabolic state. In conclusion, circulating levels of IL-6 and CRP, but not the soluble forms of the receptor (sIL-6R) or the receptor signalling subunit (sgp130) were associated with the extent of myocardial necrosis. The biological importance of the IL-6/gp130-mediated signalling pathways in patients with acute myocardial infarction and dysglycemia should be further elucidated.

Neutrophil extracellular traps (NETs) have been implicated in atherothrombosis; however, their potential role as markers of risk is unclear. We investigated whether circulating NETs-related components associated with clinical outcome and hypercoagulability in St-elevation myocardial infarction (STEMI). In this observational cohort study, STEMI patients admitted for PCI (n = 956) were followed for median 4.6 years, recording 190 events (reinfarction, unscheduled revascularization, stroke, heart failure hospitalization, or death). Serum drawn median 18 hours post-PCI was used to quantify double-stranded DNA (dsDNA) and the more specific NETs markers myeloperoxidase-DNA and citrullinated histone 3. Levels of the NETs markers did not differ significantly between groups with/without a primary composite endpoint. However, patients who died (n = 76) had higher dsDNA compared to survivors (p < 0.001). Above-median dsDNA was associated with an increased number of deaths (54 vs. 22, p < 0.001). dsDNA in the upper quartiles (Q) was associated with increased mortality (Q3 vs. Q1 + 2 adjusted HR: 1.89 [95% CI 1.03 to 3.49], p = 0.041 and Q4 vs. Q1 + 2 adjusted HR: 2.28 [95% CI 1.19 to 4.36], p = 0.013). dsDNA was weakly correlated with D-dimer (r s = 0.17, p < 0.001). dsDNA levels associated with increased all-cause mortality, yet weakly with hypercoagulability in STEMI patients. The prognostic significance of potentially NETs-related markers requires further exploration. Acute coronary syndrome (ACS) often results from erosion or rupture of atherosclerotic plaques followed by thrombosis, ischemia, and myocardial injury. It has been suggested that the risk-stratification of ACS patients should be expanded to include new soluble biomarkers, which may help individualize treatment 1. Potential candidates include components of the innate immune response, widely accepted to be important in the immediate aftermath of ACS, yet still not completely understood. Neutrophil extracellular traps (NETs) were first described in 2004 by Brinkmann and colleagues, who documented the expulsion of extracellular webbed structures comprising deoxyribonucleic acid (DNA) and histones, studded with neutrophil granule proteins 2. The process of NETs release, or NETosis, is initiated by granular proteins such as myeloperoxidase (MPO), neutrophil elastase, and peptidylarginine deiminase 4 3. The latter mediates the citrullination of histone 3, inducing chromatin decondensation before extracellular release 3. Circulating NETs-associated components may contribute to endothelial dysfunction and plaque instability 4 , as well as coronary thrombus formation 5 by activating platelets, triggering the coagulation cascade, and trapping thrombus constituents 6,7. Nevertheless, it is not yet clear how NETs per se are implicated in the fine balance between beneficial and deleterious effects of inflammation after revascularization.

BackgroundReports on soluble interleukin‐6 (IL‐6) receptor (sIL‐6R) and glycoprotein 130 (sgp130) in ST‐elevation myocardial infarction (STEMI) are few and include a small number of patients. The aim of this study was to investigate the possible association between levels of these biomarkers in the acute phase of STEMI and future cardiovascular events.Methods and ResultsCirculating IL‐6, sgp130, sIL‐6R, and C‐reactive protein (CRP) were measured in 989 STEMI patients during 2007–2011, and cardiovascular events were recorded during follow‐up. The primary endpoint was composite of all‐cause mortality, myocardial infarction, stroke, unscheduled revascularization, or rehospitalization for heart failure. Cox regression models were used to estimate hazard ratios (HRs) for cardiovascular events in relation to biomarker levels. Median levels of sIL‐6R, sgp130, IL‐6, and CRP measured 24 hours (median) after symptom onset were 39.2 ng/mL, 240 ng/mL, 18.8 pg/mL, and 13.7 mg/L, respectively. During a median follow‐up time of 4.6 years, 200 patients (20.2%) experienced a primary endpoint, and 82 patients (8.3%) died. Patients with sIL‐6R levels in the upper quartile (>47.7 ng/mL) had significantly higher risk of future adverse events (primary endpoint) and mortality compared to patients with lower levels (adjusted HR, 1.54 [1.08, 2.21]; P=0.02 and 1.81 [1.04, 3.18]; P=0.04, respectively). Neither IL‐6 nor sgp130 levels were related to future events, but patients with CRP levels in the upper quartile (>31.5 mg/L) had higher risk of death.ConclusionHigh levels of sIL‐6R were associated with future cardiovascular events and mortality in STEMI patients, suggesting an important role of the IL‐6 signaling system.

Monocyte-derived cMPs assessed in the acute phase relate to the prognosis of CV death at the long term. These findings may be of clinical interest in the risk assessment of STEMI patients.

Based on our in vivo and in vitro findings we suggest that NAMPT could contribute to systemic and plaque inflammation in atherosclerotic disorders at least partly through effect on macrophages.

IntroductionPlatelet activation, thrombin generation and fibrin formation play important roles in intracoronary thrombus formation, which may lead to acute myocardial infarction.We investigated whether the prothrombotic markers D-dimer, pro-thrombin fragment 1 + 2 (F1 + 2) and endogenous thrombin potential (ETP) are associated with myocardial necrosis assessed by Troponin T (TnT), and left ventricular impairment assessed by left ventricular ejection fraction (LVEF) and N-terminal pro b-type natriuretic peptide (NT-proBNP).Materials/MethodsPatients (n = 987) with ST-elevation mycardial infarction (STEMI) were included. Blood samples were drawn at a median time of 24 h after onset of symptoms.ResultsStatistically significant correlations were found between both peak TnT and D-dimer (p < 0.001) and F1 + 2 (p < 0.001), and between NT-proBNP and D-dimer (p = 0.001) and F1 + 2 (p < 0.001). When dividing TnT and NT-proBNP levels into quartiles there were significant trends for increased levels of both markers across quartiles (all p < 0.001) D-dimer remained significantly associated with NT-proBNP after adjustments for covariates (p = 0.001) whereas the association between NTproBNP and F1 + 2 was no longer statistically significant (p = 0.324).A significant inverse correlation was found between LVEF and D-dimer (p < 0.001) and F1 + 2 (p = 0.013). When dichotomizing LVEF levels at 40 %, we observed significantly higher levels of both D-dimer (p < 0.001) and F1 + 2 (p = 0.016) in the group with low EF (n = 147).Summary/conclusionIn our cohort of STEMI patients we demonstrated that levels of D-dimer and F1 + 2 were significantly associated with myocardial necrosis as assessed by peak TnT. High levels of these coagulation markers in patients with low LVEF and high NTproBNP may indicate a hypercoagulable state in patients with impaired myocardial function.

Hypercoagulability in ST-segment elevation myocardial infarction (STEMI) as related to long-term clinical outcome is not clarified. We aimed to investigate whether prothrombin fragment 1+2 (F1+2), d-dimer, and endogenous thrombin potential (ETP) measured in the acute phase of STEMI were associated with outcome. Blood samples were drawn median 24 hours after symptom onset in 987 patients with STEMI. Median follow-up time was 4.6 years. Primary outcome was a composite of all-cause mortality, reinfarction, stroke, unscheduled revascularization, or rehospitalization for heart failure; secondary outcome was total mortality. The number of combined end points/total mortality was 195/79. Higher levels of d-dimer and F1+2 were observed with both end points (all P < .005), whereas ETP was significantly lower ( P < .01). Dichotomized at medians, increased risk was observed for levels above median for F1+2 and d-dimer (combined end point P = .020 and P = .010 and total mortality P < .001, both), while an inverse pattern was observed for ETP ( P < .02, both). Adjusting for covariates, d-dimer was still associated with reduced risk of total mortality ( P = .034) and receiver operating characteristic curve analyses showed area under the curve of 0.700 (95% confidence interval, 0.640-0.758). The hypercoagulable state in acute STEMI seems to be of importance for clinical outcome.

CCN2/Connective tissue growth factor seems to be involved in development of cardiac hypertrophy and fibrosis, but a possible cardioprotective role in left ventricular (LV) remodelling following myocardial infarction has also been suggested. The main objectives of the study were therefore to investigate whether circulating CCN2 levels were associated with infarct size, LV function, adverse remodelling or clinical outcome in two cohorts of patients with ST-elevation myocardial infarction (STEMI). CCN2 was measured in 988 patients 18 hours after PCI and clinical events were recorded after 55 months in the BAMI cohort. In the POSTEMI trial, serial measurements of CCN2 were performed in 258 STEMI patients during index hospitalisation and cardiac magnetic resonance imaging was performed in the acute phase and after 4 months. Clinical events were also recorded. There were no significant associations between levels of CCN2 and infarct size, LV ejection fraction, changes in LV end-diastolic or end-systolic volume, myocardial salvage or microvascular obstruction. There were no significant associations between CCN2 levels and clinical events including mortality, in either of the study cohorts. In conclusion, circulating levels of CCN2 measured in the acute phase of STEMI were not associated with final infarct size, left ventricular function or new clinical events.