Double-Stranded DNA and NETs Components in Relation to Clinical Outcome After ST-Elevation Myocardial Infarction.

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 (rs = 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.

Markers of Thrombin Generation Are Associated With Long-Term Clinical Outcome in Patients With ST-Segment Elevation Myocardial Infarction.

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.

Monocyte-derived circulating microparticles (CD14+, CD14+/CD11b+ and CD14+/CD142+) are related to long-term prognosis for cardiovascular mortality in STEMI patients.

BACKGROUND: Circulating microparticles (cMPs) have been proposed as novel biomarkers of cardiovascular disease (CVD). We aimed to investigate the prognostic relevance of cMPs for future major adverse cardiovascular events (MACE) in STEMI patients. METHODS: We included 200 STEMI patients treated with percutaneous coronary intervention (PCI). One hundred patients with a primary composite end point (recurrent nonfatal acute MI, rehospitalization for heart failure, unscheduled PCI or death because of CV causes) were case-matched for sex, age, and CVD risk factors to 100 patients without a primary endpoint at the end of study follow-up (4.4 (1.4) years). cMPs from vascular cells were measured by flow cytometer at a mean of 28h after onset of symptoms. RESULTS: No differences were observed in MP shedding between patients with or without a MACE at the end of the study follow-up. However, compared to patients who survived during follow-up, patients who died because of CV causes (n=24) presented with increased total cMPs (Annexin V-AV-+), cMPs carrying tissue factor, and increased MP shedding from platelets, lymphocytes, monocytes, and activated leukocytes, and ~10% lower left ventricular ejection fraction (LVEF). ROC-curve analyses showed that monocyte-derived cMPs (CD14+/AV+, CD11b+/CD14+/AV+ and CD142+/CD14+/AV+) considered together with LVEF best predicted cardiovascular mortality. CONCLUSIONS: 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.

Evaluation of circulating levels of CCN2/connective tissue growth factor in patients with ST-elevation myocardial infarction.

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.

Circulating Levels of IL-6 Receptor and gp130 and Long-Term Clinical Outcomes in ST-Elevation Myocardial Infarction.

BACKGROUND: Reports 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 RESULTS: Circulating 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. CONCLUSION: High 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.

Increased expression of NAMPT in PBMC from patients with acute coronary syndrome and in inflammatory M1 macrophages.

AIM: The aim of the present study were to elucidate the role of NAMPT in atherosclerosis, by examine NAMPT expression in peripheral blood mononuclear cells (PBMC) in patients with coronary artery disease (CAD) and healthy controls and by examining the regulation and effect of NAMPT on macrophage polarization, hypothesizing that it could influence the polarization to inflammatory and resolving macrophages. METHOD AND RESULTS: We analyzed RNA levels of NAMPT in PBMC from CAD and healthy controls and found NAMPT to be increased in PBMC from patients with acute coronary syndrome (n = 39) compared to healthy controls (n = 20) and patients with stable CAD (n = 22). Within the PBMC NAMPT was correlated to several inflammatory cytokines and the antioxidant enzyme superoxide dismutase 2. In vitro cell experiments revealed that NAMPT is increased both intracellular and extracellular in inflammatory M1 macrophages compared to in anti-inflammatory M2 macrophages. In addition, inhibiting NAMPT enzymatic activity inhibited M1 polarization in macrophages. CONCLUSION: 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.

IL-6 signalling in patients with acute ST-elevation myocardial infarction.

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.