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Endothelial dysfunction is an early consequence of vascular inflammation and a driver of coronary atherosclerotic disease leading to myocardial infarction. The red blood cells (RBCs) mediate endothelial dysfunction in patients at cardiovascular risk, but their role in patients with acute myocardial infarction is unknown. This study aimed to investigate if RBCs from patients with ST-elevation myocardial infarction (STEMI) induced endothelial dysfunction and the role of systemic inflammation in this effect. RBCs from patients with STEMI and aged-matched healthy controls were coincubated with rat aortic segments for 18 h followed by evaluation of endothelium-dependent (EDR) and endothelium-independent relaxation (EIDR). RBCs and aortic segments were also analyzed for arginase and oxidative stress. The patients were divided into groups depending on C-reactive protein (CRP) levels at admission. RBCs from patients with STEMI and CRP levels ≥2 mg/L induced impairment of EDR, but not EIDR, compared with RBCs from STEMI and CRP <2 mg/L and healthy controls. Aortic expression of arginase 1 was increased following incubation with RBCs from patients with STEMI and CRP ≥2, and arginase inhibition prevented the RBC-induced endothelial dysfunction. RBCs from patients with STEMI and CRP ≥2 had increased reactive oxygen species compared with RBCs from patients with CRP <2 and healthy controls. Vascular inhibition of NADPH oxidases and increased dismutation of superoxide improved EDR. RBCs from patients with STEMI and low-grade inflammation induce endothelial dysfunction through a mechanism involving arginase 1 as well as increased RBC and vascular superoxide by NADPH oxidases. NEW & NOTEWORTHY Red blood cells from patients with STEMI and systemic inflammation induce endothelial dysfunction ex vivo. The RBC-induced endothelial dysfunction is mediated through increased arginase 1 and a shift in the redox balance toward oxidative stress. Inhibition of arginase or free radicals attenuates the impairment of endothelial function. The study suggests that red blood cells deserve attention as a key player in systemic inflammation and STEMI.

Background: ST-elevation myocardial infarction (STEMI) and Takotsubo syndrome (TS) are two distinct cardiac conditions that both result in sudden loss of cardiac dysfunction and that are difficult to distinguish clinically. This study compared plasma protein changes in 24 women with STEMI and 12 women with TS in the acute phase (days 0-3 post symptom onset) and the stabilization phase (days 7, 14, and 30) to examine the molecular differences between these conditions., Methods: Plasma proteins from STEMI and TS patients were extracted during the acute and stabilization phases and analyzed via quantitative proteomics. Differential expression and functional significance were assessed. Data are accessible on ProteomeXchange, ID PXD051367., Results: During the acute phase, STEMI patients showed higher levels of myocardial inflammation and tissue damage proteins compared to TS patients, along with reduced tissue repair and anti-inflammatory proteins. In the stabilization phase, STEMI patients exhibited ongoing inflammation and disrupted lipid metabolism. Notably, ADIPOQ was consistently downregulated in STEMI patients in both phases. When comparing the acute to the stabilization phase, STEMI patients showed increased inflammatory proteins and decreased structural proteins. Conversely, TS patients showed increased proteins involved in inflammation and the regulatory response to counter excessive inflammation. Consistent protein changes between the acute and stabilization phases in both conditions, such as SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE, suggest shared underlying pathophysiological mechanisms., Conclusions: This study presents protein changes in women with STEMI or TS and identifies ADIPOQ, SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE as candidates for further exploration in both therapeutic and diagnostic contexts.

Myocardial infarction is a major cause of morbidity and mortality worldwide. Metabolomic investigations may be useful for understanding the pathogenesis of ST-segment elevation myocardial infarction (STEMI). STEMI patients were comprehensively examined via targeted metabolomic profiling, machine learning and weighted correlation network analysis. A total of 195 subjects, including 68 STEMI patients, 84 patients with stable angina pectoris (SAP) and 43 non-CVD patients, were enrolled in the study. Metabolomic profiling involving the quantitative analysis of 87 endogenous metabolites in plasma was conducted. This study is the first to perform targeted metabolomic profiling in patients with STEMI. We identified 36 significantly altered metabolites in STEMI patients. Increased levels of four amino acids, eight acylcarnitines, six metabolites of the NO-urea cycle and neurotransmitters, and three intermediates of tryptophan metabolism were detected. The following metabolites exhibited decreased levels: six amino acids, three acylcarnitines, three components of the NO-urea cycle and neurotransmitters, and three intermediates of tryptophan metabolism. We found that the significant changes in tryptophan metabolism observed in STEMI patients-the increase in anthranilic acid and tryptophol and decrease in xanthurenic acid and 3-OH-kynurenine-may play important roles in STEMI pathogenesis. On the basis of the differences in the constructed weighted correlation networks, new significant metabolite ratios were identified. Among the 22 significantly altered metabolite ratios identified, 13 were between STEMI patients and non-CVD patients, and 17 were between STEMI patients and SAP patients. Seven of these ratios were common to both comparisons (STEMI patients vs. non-CVD patients and STEMI patients vs. SAP patients). Additionally, two ratios were consistently observed among the STEMI, SAP and non-CVD groups (anthranilic acid: aspartic acid and GSG (glutamine: serine + glycine)). These findings provide new insight into the diagnosis and pathogenesis of STEMI., (© 2024. The Author(s).)

Background: Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship., Methods: Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation., Results: The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation., Conclusions: Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury., (© 2024. The Author(s).)

Coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-β1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-β1 after MI. In patients with STEMI, there was a significant correlation (P = 0.003) between higher circulating TGF-β1 levels at 24 hours after MI and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-β1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-β1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of inflammatory cytokines IL-1β and chemokine (C-C motif) ligand 2 (>50% reduction, P = 0.038 and 0.0004, respectively) at 24 hours, and reduced scar size at 4 weeks (21% reduction, P = 0.015) after reperfusion. Furthermore, a low-fibrogenic mimic of TGF-β1, secreted by the helminth parasite Heligmosomoides polygyrus, had an almost identical protective effect on injured mouse hearts. Finally, genetic studies indicated that this benefit was mediated by TGF-β signaling in the vascular endothelium., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the correlation between serum growth differentiation factor 11 (GDF11) level and coronary artery lesions in patients with ST-segment elevation myocardial infarction (STEMI), and the predictive efficacy of nomogram risk prediction model based on GDF11 combined with traditional risk factors on the occurrence of STEMI. Methods: This study was a retrospective cross-sectional study. Patients hospitalized in the Department of Cardiology of the 904th Hospital of Joint Logistic Support Force of People's Liberation Army of China from 2016 to 2018 were selected and divided into control group and STEMI group. The demographic data, blood lipid level, laboratory indicators of blood and GDF11 level were collected. Logistic regression analysis screened out independent correlated factors for the occurrence of STEMI. Spearman correlation analysis clarified the correlation of each indicator with the SYNTAX or Gensini scores. A nomogram risk prediction model for the risk of STEMI occurrence and the receiver operating characteristic curve was used to compare the prediction efficiency of each model. Results: A total of 367 patients were enrolled, divided into control group ( n =172) and STEMI group ( n =195), age (66.5±11.8), male 222 (60.49%). The serum GDF11 level of STEMI group was significantly lower than that of the control group (36.20 (16.60, 70.75) μg/L vs. 85.00 (53.93, 117.10) μg/L, P <0.001). The results of multivariate logistic regression analysis showed serum GDF11( OR= 0.98, 95% CI : 0.97-0.99) and traditional independent risk factors such as smoking, diabetes, C-reactive protein, homocysteine, lipoprotein (a) and apolipoprotein A1/B were independent correlate factors for the occurrence of STEMI ( P <0.05). Spearman correlation analysis showed that serum GDF11 was negatively correlated with SYNTAX score and Gensini score ( P <0.05). The nomogram model constructed by serum GDF11 combined with traditional independent risk factors (AUC=0.85, 95% CI : 0.81-0.89) had better predictive value for the occurrence of STEMI than the traditional nomogram model constructed by independent risk factors(AUC=0.80, 95% CI :0.75-0.84) or serum GDF11 (AUC=0.76, 95% CI : 0.72-0.81), all P <0.01. Conclusions: Serum GDF11 is an independent correlate factor in the occurrence of STEMI and is negatively correlated with the severity of coronary artery lesions in patients with STEMI. The nomogram model constructed based on GDF11 combined with traditional risk factors can be a good predictor for the occurrence of STEMI.

Ischemia/reperfusion (I/R) injury after revascularization contributes ∼50% of infarct size and causes heart failure, for which no established clinical treatment exists. β-hydroxybutyrate (β-OHB), which serves as both an energy source and a signaling molecule, has recently been reported to be cardioprotective when administered immediately before I/R and continuously after reperfusion. This study aims to determine whether administering β-OHB at the time of reperfusion with a single dose can alleviate I/R injury and, if so, to define the mechanisms involved. We found plasma β-OHB levels were elevated during ischemia in STEMI patients, albeit not to myocardial protection level, and decreased after revascularization. In mice, compared with normal saline, β-OHB administrated at reperfusion reduced infarct size (by 50%) and preserved cardiac function, as well as activated autophagy and preserved mtDNA levels in the border zone. Our treatment with one dose β-OHB reached a level achievable with fasting and strenuous physical activity. In neonatal rat ventricular myocytes (NRVMs) subjected to I/R, β-OHB at physiologic level reduced cell death, increased autophagy, preserved mitochondrial mass, function, and membrane potential, in addition to attenuating reactive oxygen species (ROS) levels. ATG7 knockdown/knockout abolished the protective effects of β-OHB observed both in vitro and in vivo. Mechanistically, β-OHB's cardioprotective effects were associated with inhibition of mTOR signaling. In conclusion, β-OHB, when administered at reperfusion, reduces infarct size and maintains mitochondrial homeostasis by increasing autophagic flux (potentially through mTOR inhibition). Since β-OHB has been safely tested in heart failure patients, it may be a viable therapeutic to reduce infarct size in STEMI patients., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Acute ST-elevation myocardial infarction (STEMI) leads to myocardial injury or necrosis, and M1 macrophages play an important role in the inflammatory response. Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are capable of modulating macrophage plasticity, principally due to their immunoregulatory capacity. In the present study, we analyzed the capacity of MSCs to modulate macrophages derived from monocytes from patients with STEMI. We analyzed the circulating levels of cytokines associated with M1 and M2 macrophages in patients with STEMI, and the levels of cytokines associated with M1 macrophages were significantly higher in patients with STEMI than in controls. BM-MSCs facilitate the generation of M1 and M2 macrophages. M1 macrophages cocultured with MSCs did not have decreased M1 marker expression, but these macrophages had an increased expression of markers of the M2 macrophage phenotype (CD14, CD163 and CD206) and IL-10 and IL-1Ra signaling-induced regulatory T cells (Tregs). M2 macrophages from patients with STEMI had an increased expression of M2 phenotypic markers in coculture with BM-MSCs, as well as an increased secretion of anti-inflammatory cytokines and an increased generation of Tregs. The findings in this study indicate that BM-MSCs have the ability to modulate the M1 macrophage response, which could improve cardiac tissue damage in patients with STEMI.

Aims: Variants of the junctional cadherin 5 associated (JCAD) locus associate with acute coronary syndromes. JCAD promotes experimental atherosclerosis through the large tumor suppressor kinase 2 (LATS2)/Hippo pathway. This study investigates the role of JCAD in arterial thrombosis., Methods and Results: JCAD knockout (Jcad-/-) mice underwent photochemically induced endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with JCAD small interfering RNA (siJCAD), LATS2 small interfering RNA (siLATS2) or control siRNA (siSCR) were employed for in vitro assays. Plasma JCAD was measured in patients with chronic coronary syndrome or ST-elevation myocardial infarction (STEMI). Jcad-/- mice displayed reduced thrombogenicity as reflected by delayed time to carotid occlusion. Mechanisms include reduced activation of the coagulation cascade [reduced tissue factor (TF) expression and activity] and increased fibrinolysis [higher thrombus embolization episodes and D-dimer levels, reduced vascular plasminogen activator inhibitor (PAI)-1 expression]. In vitro, JCAD silencing inhibited TF and PAI-1 expression in HAECs. JCAD-silenced HAECs (siJCAD) displayed increased levels of LATS2 kinase. Yet, double JCAD and LATS2 silencing did not restore the control phenotype. si-JCAD HAECs showed increased levels of phosphoinositide 3-kinases (PI3K)/ proteinkinase B (Akt) activation, known to downregulate procoagulant expression. The PI3K/Akt pathway inhibitor-wortmannin-prevented the effect of JCAD silencing on TF and PAI-1, indicating a causative role. Also, co-immunoprecipitation unveiled a direct interaction between JCAD and Akt. Confirming in vitro findings, PI3K/Akt and P-yes-associated protein levels were higher in Jcad-/- animals. Lastly, as compared with chronic coronary syndrome, STEMI patients showed higher plasma JCAD, which notably correlated positively with both TF and PAI-1 levels., Conclusions: JCAD promotes arterial thrombosis by modulating coagulation and fibrinolysis. Herein, reported translational data suggest JCAD as a potential therapeutic target for atherothrombosis., Competing Interests: Conflict of interest: L.L. and G.G.C. are coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida solutions limited. T.F.L. has no conflicts related to this manuscript. Outside the work he received unrestricted research and education grants from Abbott, Amgen, Boehringer Ingelheim, Daichi-Sankyo, Novartis, Roche Diagnostics, Sanofi, Servier and Vifor. L.L. reports speaker fees outside of this work from Daichi-Sankyo. G.L. reports Consulting fees and Payment or honoraria for lectures: Novo Nordisk, Novartis, Sanofi, AstraZeneca, Boehringer, Bayer. F.C. reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. The other authors report no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Frailty and ST-Elevation Myocardial Infarction (STEMI) share similar molecular pathways. Specific biomarkers, such as microRNAs (miRNAs), may provide insights into the molecular mechanisms that cause the relationship between frailty and STEMI., Objective: Our aim was to identify and compare circulating miRNA levels between frail and non-frail older adults following STEMI and comprehend the regulatory miRNA-gene networks and pathways involved in this condition., Methods: This exploratory study is a subanalysis of a larger observational study. In this study, we selected patients ≥ 65 years old, following STEMI, with pre-frail/frail (n=5) and non-frail (n=4) phenotype evaluated using the Clinical Frailty Scale and serum circulating miRNA levels were analyzed., Results: Pre-frail/frail patients had greater serum levels of 53 miRNAs, compared with non-frail patients. Notably, miR-103a-3p, miR-598-3p, and miR-130a-3p were the top three significantly deregulated miRNAs predicted to modulate gene expression associated with aging. Additional computational analyses showed 7,420 predicted miRNA gene targets, which were regulated by at least two of the 53 identified miRNAs. Pathway enrichment analysis showed that axon guidance and MAPK signaling were among pathways regulated by miRNA target genes., Conclusions: These novel findings suggest a correlation between the identified miRNAs, target genes, and pathways in pre-frail and frail patients with myocardial infarction., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has shown to methylate and alter the function of a variety of proteins in vitro; however, its function in the heart is poorly understood. The present study investigates the role of SETD7 in myocardial ischaemic injury., Methods and Results: Experiments were performed in neonatal rat ventricular myocytes (NRVMs), SETD7 knockout mice (SETD7-/-) undergoing myocardial ischaemia/reperfusion (I/R) injury, left ventricular (LV) myocardial samples from patients with ischaemic cardiomyopathy (ICM), and peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). We show that SETD7 is activated upon energy deprivation in cultured NRVMs and methylates the Hippo pathway effector YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes manganese superoxide dismutase (MnSOD) and catalase (CAT). Such impairment of antioxidant defence was associated with mitochondrial reactive oxygen species (mtROS), organelle swelling, and apoptosis. Selective pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization, thus preventing mtROS, mitochondrial damage, and apoptosis in NRVMs. In mice, genetic deletion of SETD7 attenuated myocardial I/R injury, mtROS, and LV dysfunction by restoring YAP-dependent transcription of MnSOD and CAT. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R)-PFI-2 prevented mtROS accumulation, while improving Ca2+-activated tension. Finally, SETD7 was up-regulated in PBMCs from STEMI patients and negatively correlated with MnSOD and CAT., Conclusion: We show a methylation-dependent checkpoint regulating oxidative stress during myocardial ischaemia. SETD7 inhibition may represent a valid therapeutic strategy in this setting., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Serum ACE2 level in the acute phase of ST-segment elevation myocardial infarction may be an indicator of heart failure, however, limited studies have reported conflicting results. Therefore, in our study, we aimed to evaluate the relationship between serum ACE2 level and infarct size in the acute phase of ST-segment elevation myocardial infarction and compare the predictive value of ACE2 level with classical biomarkers., Patients and Methods: Sixty-six patients after the primary percutaneous coronary intervention were included in the study. For the measurement of serum ACE2 levels, blood samples were taken twice from the patients: in the first 24 hours and on the 5th day of the infarction, and once from 30 healthy volunteers. hs-cTnT, BNP, and CRP levels were measured daily, and their peak values were taken. On the 7th day of ST-segment elevation myocardial infarction, gSPECT was used with the 99mTc-MIBI method for assessment of infarct size., Results: Baseline ACE2 values were found to be higher in patients compared to controls, and ACE2 values obtained on the 5th day were found to be higher than the baseline values in the patients. There was no significant correlation between serum ACE2 levels and the RSS (%), while peak levels of hs-cTnT, BNP, and CRP were assessed as predictive factors for the RSS (%)., Conclusions: Although serum ACE2 levels increased in the acute phase of ST-segment elevation myocardial infarction, this increase was not associated with infarct size. Serum ACE2 level did not provide additional benefit to classical biomarkers for infarct size-related prognosis prediction.

Red blood cells (RBCs) are suggested to play a role in cardiovascular regulation by exporting nitric oxide (NO) bioactivity and ATP under hypoxia. It remains unknown whether such beneficial effects of RBCs are protective in patients with acute myocardial infarction. We investigated whether RBCs from patients with ST-elevation myocardial infarction (STEMI) protect against myocardial ischemia-reperfusion injury and whether such effect involves NO and purinergic signaling in the RBCs. RBCs from patients with STEMI undergoing primary coronary intervention and healthy controls were administered to isolated rat hearts subjected to global ischemia and reperfusion. Compared to RBCs from healthy controls, RBCs from STEMI patients reduced myocardial infarct size (30 ± 12% RBC healthy vs. 11 ± 5% RBC STEMI patients, P < 0.001), improved recovery of left-ventricular developed pressure and dP/dt and reduced left-ventricular end-diastolic pressure in hearts subjected to ischemia-reperfusion. Inhibition of RBC NO synthase with L-NAME or soluble guanylyl cyclase (sGC) with ODQ, and inhibition of cardiac protein kinase G (PKG) abolished the cardioprotective effect. Furthermore, the non-selective purinergic P2 receptor antagonist PPADS but not the P1 receptor antagonist 8PT attenuated the cardioprotection induced by RBCs from STEMI patients. The P2Y 13 receptor was expressed in RBCs and the cardioprotection was abolished by the P2Y 13 receptor antagonist MRS2211. By contrast, perfusion with PPADS, L-NAME, or ODQ prior to RBCs administration failed to block the cardioprotection induced by RBCs from STEMI patients. Administration of RBCs from healthy subjects following pre-incubation with an ATP analog reduced infarct size from 20 ± 6 to 7 ± 2% (P < 0.001), and this effect was abolished by ODQ and MRS2211. This study demonstrates a novel function of RBCs in STEMI patients providing protection against myocardial ischemia-reperfusion injury through the P2Y 13 receptor and the NO-sGC-PKG pathway., (© 2022. The Author(s).)

Introduction and Objectives: Microvascular obstruction (MVO) is negatively associated with cardiac structure and worse prognosis after ST-segment elevation myocardial infarction (STEMI). Epithelial cell adhesion molecule (EpCAM), involved in epithelium adhesion, is an understudied area in the MVO setting. We aimed to determine whether EpCAM is associated with the appearance of cardiac magnetic resonance (CMR)-derived MVO and long-term systolic function in reperfused STEMI., Methods: We prospectively included 106 patients with a first STEMI treated with percutaneous coronary intervention, quantifying serum levels of EpCAM 24hours postreperfusion. All patients underwent CMR imaging 1 week and 6 months post-STEMI. The independent correlation of EpCAM with MVO, systolic volume indices, and left ventricular ejection fraction was evaluated., Results: The mean age of the sample was 59±13 years and 76% were male. Patients were dichotomized according to median EpCAM (4.48 pg/mL). At 1-week CMR, lower EpCAM was related to extensive MVO (P=.021) and larger infarct size (P=.019). At presentation, EpCAM values were significantly associated with the presence of MVO in univariate (OR, 0.58; 95%CI, 0.38-0.88; P=.011) and multivariate logistic regression models (OR, 0.55; 95%CI, 0.35-0.87; P=.010). Although MVO tends to resolve at chronic phases, decreased EpCAM was associated with worse systolic function: reduced left ventricular ejection fraction (P=.009) and higher left ventricular end-systolic volume (P=.043)., Conclusions: EpCAM is associated with the occurrence of CMR-derived MVO at acute phases and long-term adverse ventricular remodeling post-STEMI., (Copyright © 2021. Published by Elsevier España, S.L.U.)

Several contributions of circulating microvesicles (MVs) to the endothelial dysfunction have been reported in the past; a head-to-head comparison of platelet- and monocyte-derived MVs has however never been performed. To this aim, we assessed the involvement of these MVs in vessel damage related processes, i.e., oxidative stress, inflammation, and leukocyte-endothelial adhesion. Platelets and monocytes isolated from healthy subjects (HS, n = 15) were stimulated with TRAP-6 and LPS to release MVs that were added to human vascular endothelial cell (hECV) culture to evaluate superoxide anion production, inflammatory markers (IL-6, TNF α , NF-κB mRNA expression), and hECV adhesiveness. The effects of the MVs-induced from HS were compared to those induced by MVs spontaneously released from cells of patients with ST-segment elevation myocardial infarction (STEMI, n = 7). MVs released by HS-activated cells triggered a threefold increase in oxidative burst in a concentration-dependent manner. Only MVs released from monocytes doubled IL-6, TNF α , and NF-κB mRNA expression and monocyte-endothelial adhesion. Interestingly, the effects of the MVs isolated from STEMI-monocytes were not superimposable to previous ones except for adhesion to hECV. Conversely, MVs released from STEMI-platelets sustained both redox state and inflammatory phenotype. These data provide evidence that MVs released from activated and/or pathologic platelets and monocytes differently affect endothelial behavior, highlighting platelet-MVs as causative factors of impaired endothelial function in the acute phase of STEMI.

Increasing evidence indicates that microRNA (miRNA) regulated mechanisms in myocardial healing and ventricular remodeling following acute myocardial infarction (AMI). We aim to comprehensively investigate changes of exosomal miRNA profile during the post-MI period and determine potential miRNAs associated to adverse left ventricular remodeling (ALVR). We prospectively evaluated ST-elevated MI patients with cardiac magnetic resonance imaging at the 2 weeks and 6 months after AMI (n = 10). ALVR was defined as an increase in LV end-diastolic and end-systolic volume > 13%. The blood samples were taken for miRNA measurements at the baseline, 2 and 6 weeks after AMI. In the miRNA profile assessment, 8 miRNAs were identified that were associated ALVR (miR-199a-5p, miR-23b-3p, miR-26b-5p, miR-301a-3p, miR-374a-5p, miR-423-5p, miR-483-5p and miR-652-3p). Three of them (miR-301a-3p, miR-374a-5p and miR-423-5p) differed significantly between patients with and without ALVR during follow-up period and the rest of them during the acute phase of AMI. The detection of these miRNAs, which have different role in various pathways, necessitate future mechanistic studies unravel the complex remodeling process after AMI., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Atrial natriuretic peptide (ANP) is secreted in response to the stretching of the atrial wall. Atrial ischemia most likely impairs the ability of atrial myocytes to produce ANP. Atrial infarction (AI) is rarely diagnosed but not infrequently associated with myocardial infarction (MI). The aim of the study was to assess the association between AI and the prognostic value of N-terminal proANP (NT-proANP) in patients with MI treated with primary percutaneous coronary intervention (PCI). We evaluated data of 100 consecutive patients. Plasma levels of NT-proANP were measured by the ELISA method. ECG recordings were interpreted to diagnose AI according to Liu's criteria. All patients were followed-up prospectively for 12 months for the manifestation of major adverse cardiovascular events (MACE), defined as unplanned coronary revascularization, stroke, reinfarction or all-cause death. AI was diagnosed in 36 patients. 14% of patients developed MACE. AI did not affect the incidence of MACE or any of its components, nor the patients' prognosis. NT-proANP revealed to be a strong predictor of death but was not associated with other adverse events. Conclusions: AI in patients with MI treated with primary PCI is not connected with their prognosis nor affects the usefulness of NT-proANP in predicting death during the 12-month follow-up.

For cardiovascular disease prevention, statins alone or combined with ezetimibe have been recommended to achieve low-density lipoprotein cholesterol targets, but their effects on other lipids are less reported. This study was designed to examine lipid changes in subjects with ST-segment elevation myocardial infarction (STEMI) after two highly effective lipid-lowering therapies. Twenty patients with STEMI were randomized to be treated with rosuvastatin 20 mg QD or simvastatin 40 mg combined with ezetimibe 10 mg QD for 30 days. Fasting blood samples were collected on the first day (D1) and after 30 days (D30). Lipidomic analysis was performed using the Lipidyzer platform. Similar classic lipid profile was obtained in both groups of lipid-lowering therapies. However, differences with the lipidomic analysis were observed between D30 and D1 for most of the analyzed classes. Differences were noted with lipid-lowering therapies for lipids such as FA, LPC, PC, PE, CE, Cer, and SM, notably in patients treated with rosuvastatin. Correlation studies between classic lipid profiles and lipidomic results showed different information. These findings seem relevant, due to the involvement of these lipid classes in crucial mechanisms of atherosclerosis, and may account for residual cardiovascular risk.Randomized clinical trial: ClinicalTrials.gov, NCT02428374, registered on 28/09/2014., (© 2021. The Author(s).)

[Figure: see text].

Background: Myocardial infarction (MI) contributes to high mortality and morbidity and can also accelerate atherosclerosis, thus inducing recurrent event due to status changing of coronary artery walls or plaques. The research aimed to investigate the differentially expressed genes (DEGs), which may be potential therapeutic targets for plaques progression in stable coronary artery disease (CAD) and ST-elevated MI (STEMI)., Methods: Two human datasets (GSE56885 and GSE59867) were analyzed by GEO2R and enrichment analysis was applied through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. To explore the seed genes, the protein-protein interaction (PPI) network was constructed and seed genes, as well as top30 ranking neighbours were screened out. To validate these findings, one human dataset GSE120521 was analyzed. Linear regression analysis and ROC curve were also performed to determine which seed genes above mentioned could be independent factors for plaques progression. Mice MI model and ELISA of seed genes were applied and ROC curve was also performed for in vivo validation., Results: 169 DEGs and 573 DEGs were screened out in GSE56885 and GSE59867, respectively. Utilizing GO and KEGG analysis, these DEGs mainly enriched in immune system response and cytokines interaction. PPI network analysis was carried out and 19 seed genes were screened out. To validate these findings, GSE120521 was analyzed and three genes were demonstrated to be targets for plaques progression and stable CAD progression, including KLRD1, FOSL2 and LILRB3. KLRD1 and LILRB3 were demonstrated to be high-expressed at 1d after MI compared to SHAM group and FOSL2 expression was low-expressed at 1d and 1w. To investigate the diagnostic abilities of seed genes, ROC analysis was applied and the AUCs of KLRD1, FOSL2 and LILRB3, were 0.771, 0.938 and 0.972, respectively., Conclusion: This study provided the screened seed genes, KLRD1, FOSL2 and LILRB3, as credible molecular biomarkers for plaques status changing in CAD progression and MI recurrence. Other seed genes, such as FOS, SOCS3 and MCL1, may also be potential targets for treatment due to their special clinical value in cardiovascular diseases., (© 2021. The Author(s).)

This study aimed to investigate the impact of high-sensitivity C-reactive protein (hsCRP) on Lipoprotein(a) [Lp(a)] associated cardiovascular risk in patients with ST-segment elevation myocardial infarction (STEMI) underwent percutaneous coronary intervention (PCI). A total of 2318 STEMI-PCI patients were retrospectively recruited, and further stratified based on postprocedural hsCRP levels (≥ 2 vs < 2 mg/L). Major adverse cardiac events (MACE) were defined as all-cause death, myocardial infarction and stroke. During a mean follow-up of 2.5 years, MACE occurred in 159 (6.9%) patients. In the setting of hsCRP ≥ 2mg/L, per unit increase of Lp(a) was associated with a 28% increase of MACE risk (HR: 1.28, 95% CI: 1.09 to 1.49, p = 0.002; p = 0.031 for interaction); increasing tertiles of Lp(a) were significantly related to greater rates of MACE (p = 0.011 for interaction; p = 0.005 for trend across tertiles). Patients with upper tertile of Lp(a) had a significant lower event-free survival (p = 0.034) when hsCRP ≥ 2mg/L. No similar association between Lp(a) and MACE was noted when hsCRP < 2mg/L. In conclusion, high Lp(a) levels were associated with poor prognosis when hsCRP ≥ 2mg/L, implying systemic inflammation can modulate Lp(a)-associated MACE risk in STEMI-PCI patients. Measurement of Lp(a) in patients with high inflammation risk may identify individuals at high cardiovascular risk., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Knowledge of the long-term prognosis (>10 years) and mortality predictors of ST-elevation myocardial infarction (STEMI) patients who have undergone primary percutaneous coronary intervention (p-PCI) is scarce. Therefore, this study evaluated the long-term prognosis and determined the predictors of long-term outcomes for STEMI patients after p-PCI. Between January, 2006 and December, 2010, we collected data and analyzed 459 consecutive patients with acute STEMI who underwent p-PCI and were discharged from the hospital (mean age, 66.8 years; male, 75.2%; peak creatine phosphokinase level, 2,292.5 IU/L). The primary endpoint was 10-year all-cause mortality. The cumulative 10-year incidence of all-cause death was 23.8%. The Cox multivariate regression analysis identified age ≥ 65 years (adjusted hazard ratio [aHR], p <0.001), body mass index (aHR, 0.93, p = 0.033), presence of atrial fibrillation (aHR, 1.69, p = 0.038), mineralocorticoid receptor antagonist use (aHR, 1.95, p = 0.008), ejection fraction <40% (aHR, 2.14, p = 0.005), and albumin <3.5 g/dL (aHR, 2.01, p = 0.005) as independent predictors of all-cause mortality. In conclusion, a post-discharge 10-year survival rate of 76.2% was identified for STEMI patients who underwent p-PCI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The Nod-Like-Receptor-Protein-3 (NLRP3) inflammasome and the Interleukin-6 (IL-6) pathways are central mechanisms of the inflammatory response in myocardial reperfusion injury. Expanding our knowledge about the inflammasome signaling axis is important to improve treatment options. In a cross-sectional study, we aimed to study presence, localization, and genetic expression of inflammasome- and IL-6- signaling-related proteins in coronary thrombi and circulating leukocytes from ST-elevation myocardial infarction (STEMI) patients, with relation to myocardial injury and time from symptoms to PCI., Methods: Intracoronary thrombi were aspirated from 33 STEMI patients. Blood samples were drawn. mRNA of Toll-Like-Receptor-4 (TLR4), NLRP3, caspase 1, Interleukin-1 β (IL1- β ), Interleukin-18 (IL-18), IL-6, IL-6-receptor (IL-6R), and glycoprotein 130 (gp130) were isolated from thrombi and circulating leukocytes and relatively quantified by RT-PCR. A part of each thrombus was embedded in paraffin for histology and immunohistochemistry analyses., Results: Genes encoding the 8 markers were present in 76-100% of thrombi. Expression of TLR4 in thrombi significantly correlated to troponin T ( r = 0.455, p = 0.013), as did NLRP3 ( r = 0.468, p = 0.024). Troponin T correlated with expression in circulating leukocytes of TLR4 ( r = 0.438, p = 0.011), NLRP3 ( r = 0.420, p = 0.0149), and IL-1 β ( r = 0.394, p = 0.023). IL-6R expression in thrombi correlated significantly to troponin T ( r = 0.434, p = 0.019), whereas gp130 was inversely correlated ( r = -0.398, p = 0.050). IL-6 in circulating leukocytes correlated inversely to troponin T ( r = -0.421, p = 0.015). There were no significant correlations between genes expressed in thrombi and time from symptom to PCI., Conclusions: The inflammasome signaling pathway was actively regulated in coronary thrombi and in circulating leukocytes from patients with STEMI, in association with myocardial damage measured by troponin T. This supports the strategy of medically targeting this pathway in treating myocardial infarction and contributes to sort out optimal timing and targets for anti-inflammatory treatment. The study is registered at clinicaltrials.gov with identification number NCT02746822., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Jostein Nordeng et al.)

Angiogenesis accelerates tissue regeneration in a variety of ischemic conditions including myocardial infarction (MI). Here we tested the hypothesis that angiogenesis induced by α7-nicotinic acetylcholine receptors (α7-nAChRs) mitigates histopathological, electrocardiographic, and molecular consequences of MI in rats. These profiles were evaluated in the isoprenaline (85 mg/kg/day i. p. For 2 days) MI rat model treated with or without nicotine or PHA-543613 (PHA, selective α7-nAChR agonist). Isoprenaline-insulted rats showed (i) ECG signs of MI such as significant ST-segment elevations and prolonged QT-intervals, (ii) deteriorated left ventricular histopathological scoring and elevated inflammatory cell infiltration, (iii) reduced immunohistochemical expression of cardiac CD34, a surrogate marker of capillary density, (iv) decreased cardiac expression of iNOS and α7-nAChRs, and (v) adaptive increases in cardiac HO-1 expression and plasma angiogenic markers such as vascular endothelial growth factor (VEGF) and nitric oxide (NO). These effects of isoprenaline, except cardiac iNOS and α7-nAChRs downregulation, were ameliorated in rats treated with a low dose (20 μg/kg/day s. c. For 16 days) of nicotine or PHA. We also show that concurrent α7-nAChR blockade by methyllycaconitine (MLA, 40 μg/kg/day, for 16 days) reversed the ECG, histopathological, and capillary density effects of nicotine, thereby reinforcing the advantageous cardioprotective and anti-ischemic roles of α7-nAChRs in this setting. The observed results showed promising effects on isoprenaline induced myocardial damage. In conclusion, the activation of α7-nAChRs by doses of nicotine or PHA in the microgram scale promotes neovascularization and offers a promising therapeutic strategy for MI. CATEGORY: Cardiovascular Pharmacology., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Upon activation, neutrophils release neutrophil extracellular traps (NETs), which contribute to circulating DNA burden and thrombosis, including ST-segment elevation myocardial infarction (STEMI). Deoxyribonuclease (DNase) 1 degrades circulating DNA and NETs. Lower DNase activity correlates with NET burden and infarct size. The DNase 1 Q222R single nucleotide polymorphism (SNP), impairing DNase 1 function, is linked with myocardial infarction. We assessed whether the Q222R SNP is connected to increased NET burden in STEMI and influences long-term outcomes. We enrolled 711 STEMI patients undergoing primary percutaneous coronary intervention (pPCI), and 1422 controls. Genotyping was performed for DNase 1 Q222R SNP. DNase activity, double-stranded (ds)DNA and citrullinated histone H3 were determined in culprit site and peripheral plasma during pPCI. The association of the Q222R variant on cardiovascular and all-cause mortality was assessed by multivariable Cox regression adjusted for cardiovascular risk factors. Homozygous Q222R DNase 1 variant was present in 64 (9.0%) STEMI patients, at the same frequency as in controls. Patients homozygous for Q222R displayed less DNase activity and increased circulating DNA burden. In overall patients, median survival was 60 months. Homozygous Q222R variant was independently associated with cardiovascular and all-cause mortality after STEMI. dsDNA/DNase ratio independently predicted cardiovascular and all-cause mortality. These findings highlight that the Q222R DNase 1 SNP is associated with increased NET burden and decreased compensatory DNase activity, and may serve as an independent risk factor for poor outcome after STEMI.

Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca 2+ ) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1 G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI., Competing Interests: Declaration of interests There are no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Association between receptor for advanced glycation end products (RAGE) and postmyocardial infarction (MI) ventricular arrhythmias (VAs) in diabetes was investigated. Correlation between premature ventricular contractions (PVCs) and serum advanced glycation end products (AGEs) content was analyzed in a cohort consisting of 101 patients with ST-segment elevated MI (STEMI). MI diabetic rats were treated with anti-receptor for AGE (RAGE) antibody. Electrocardiography was used to record VAs. Myocytes were isolated from adjacent area around infracted region. Immunofluorescent stains were used to evaluate the association between FKBP12.6 (FK506-bindingprotein 12.6) and ryanodine receptor 2 (RyR2). Calcium sparks were evaluated by confocal microscope. Protein expression and phosphorylation were assessed by Western blotting. Calcineurin (CaN) enzymatic activity and RyR2 channel activity were also determined. In the cohort study, significantly increased amount of PVC was found in STEMI patients with diabetes ( P < 0.05). Serum AGE concentration was significantly positively correlated with PVC amount in patients with STEMI ( r  = 0.416, P < 0.001). Multivariate analysis showed that serum AGE concentration was independently and positively related to frequent PVCs (adjusted hazard ratio, 1.86; 95% CI, 1.09-3.18, P = 0.022). In the animal study, increased glucose-regulated protein 78 (GRP78) expression, protein kinase RNA-like ER kinase (PERK) phosphorylation, CaN enzymatic activity, FKBP12.6-RyR2 disassociation, RyR2 channel opening, and endoplasmic reticulum (ER) calcium releasing were found in diabetic MI animals, which were attenuated by anti-RAGE antibody treatment. This RAGE blocking also significantly lowered the VA amount in diabetic MI animals. Activation of RAGE-dependent ER stress-mediated PERK/CaN/RyR2 signaling participated in post-MI VAs in diabetes. NEW & NOTEWORTHY In this study, we proposed a possible mechanism interpreting the clinical scenario that after myocardial infarction (MI) patients were more vulnerable to ventricular arrhythmias (VAs) when complicated with diabetes. A cohort study revealed that advanced glycation end products (AGEs) accumulated in patients with diabetes and closely associated post-MI VAs. In vivo and in vitro studies indicated that receptor for AGEs (RAGE)-dependent endoplasmic reticulum (ER) stress protein kinase RNA-like ER kinase (PERK) pathway triggered VAs, via ER calcium releasing, through calcineurin/RyR2 mechanism.

Abstract: A specific anti-miR-21 has emerged as an effective treatment for ischemia/reperfusion injury in a pig model of myocardial infarction (MI), but the perspectives for clinical translation are limited. Anti-miR-21 blunts profibrotic pathways, whose excessive activation is detrimental in the post-MI setting. Repurposing antifibrotic drugs approved for other indications is a possible strategy. We compared the molecular effects of anti-miR-21 and the 2 drugs approved for idiopathic pulmonary fibrosis (nintedanib and pirfenidone) through a bioinformatic approach. We report that nintedanib and anti-miR-21 share many targets, including the proto-oncogene Rous sarcoma oncogene cellular homolog. Conversely, pirfenidone and anti-miR-21 do not have common mechanisms of action. In summary, the molecular mechanisms activated by nintedanib are partially overlapping with those elicited by anti-miR-21. Nintedanib could be evaluated in animal studies or clinical trials on MI., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Antithrombotic therapy is a critical component of the management of ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). Rapid and profound inhibition of platelet reactivity has been shown to mitigate the ischemic risks and improve myocardial salvage. High residual platelet reactivity (HRPR) has been reported up to 4 or 6 h after loading dose of prasugrel or ticagrelor; therefore, multiple alternative strategies, including crushed or chewed oral tables or intravenous agents, have been investigated to provide a more rapid and sustained inhibition of platelet function and bridge the initial treatment gap. The FABOLUS FASTER is the first investigator-initiated, multicentre, open-label, prospective, randomized study to directly compare the pharmacodynamics effects of cangrelor, tirofiban, chewed or integer prasugrel. This study will add new insights in the management of antiplatelet therapy in patients with STEMI undergoing primary PCI and might be hypothesis-generating for future clinical trials in this field. The trial is registered on clinicaltrials.gov NCT02978040, and EudraCT 2017-001065-24.

Coronary heart disease (CHD) is a cardiovascular disease with high mortality and disability worldwide. The main pathological manifestation of CHD is myocardial injury due to ischaemia-reperfusion, resulting in the death of cardiomyocytes (apoptosis and necrosis) and the occurrence of cardiac failure. Morphine is a nonselective opioid receptor agonist that has been commonly used for analgesia and to treat ischaemic heart disease. The present review focused on morphine-induced protection in an animal model of myocardial ischaemia-reperfusion and chronic heart failure and the effects of morphine on ST segment elevation myocardial infarction (STEMI) patients who underwent pre-primary percutaneous coronary intervention (pre-PPCI) or PPCI. The signalling pathways involved are also briefly described., (Copyright © 2020. Published by Elsevier B.V.)

The arginine metabolism as a target for cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI) remains insufficiently understood. Arginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA) and proline plasma levels were measured using liquid chromatography and tandem mass spectrometry in 70 consecutive STEMI patients upon admission and at 6-month follow-up and were compared with left ventricular function, volumes, and infarct characteristics determined by cardiac magnetic resonance imaging, and with 5-year clinical outcomes. Baseline median concentration of arginine was higher by 49% (P = 0.002) when compared to 6-month measurements and was correlated with an ischemia risk area (R = 0.34, P = 0.004) and infarct size (R = 0.33, P = 0.006). Following ischemia median citrulline/arginine index decreased when compared with 6-month result (P = 0.002), while citrulline/ornithine and arginine/ADMA ratios maintained unchanged indicating a shift of arginine metabolism from nitric oxide synthase (NOS) towards arginase. The 6-month arginine concentration reached the area under the ROC curve of 0.67 (95% confidence interval 0.54-0.81) for prediction of death, myocardial infarction or heart failure hospitalization and its value of < 29 µM was associated with lower event free survival (P = 0.02). In STEMI patients, during ischemia conversion of elevated plasma arginine was shifted from NOS towards arginase. Decreased 6-month arginine concentrations were associated with worse long-term outcomes.

The aim of this study was to explore potential predictive biomarkers and therapeutic targets of post-infarct heart failure (HF) using bioinformatics analyses.CEL raw data of GSE59867 and GSE62646 were downloaded from the GEO database. Differentially expressed genes (DEGs) between patients with ST-segment elevation myocardial infarction (STEMI) and those with stable coronary artery disease (CAD) at admission and DEGs between admission and 6 months after myocardial infarction (MI) in patients with STEMI were analyzed. A gene ontology (GO) analysis and a gene set enrichment analysis (GSEA) were performed, and a protein-protein interaction network was constructed. Critical genes were further analyzed.In total, 147 DEGs were screened between STEMI and CAD at admission, and 62 DEGs were identified in patients with STEMI between admission and 6 months after MI. The results of GO and GSEA indicate that neutrophils, neutrophil-related immunity responses, and monocytes/macrophages play important roles in MI pathogenesis. SLED1 expression was higher in patients with HF than in those without HF at admission and 1 month after MI. GSEA indicates that mTORC1 activation, E2F targets, G2M checkpoint, and MYC targets v1 inhibition may play key roles in the development of post-infarct HF. Furthermore, SLED1 may be involved in the development of post-infarct HF by activating mTORC1 and inhibiting E2F targets, G2M checkpoint, and MYC targets v1.SLED1 may be a novel biomarker of post-infarct HF and may serve as a potential therapeutic target in this disease.

Objective: To investigate the relationship between Transient Receptor Potential Vanilloid 6 (TRPV6) and ST-elevation acute myocardial infarction (STEMI) patients., Methods: This observational research included a total of 221 patients with STEMI admitted during January 2017~August 2019. Additionally, 50 cases of non-ST-elevation acute myocardial infarction (NSTEMI) patients and 50 healthy individuals were enrolled as the control. Serum levels of TRPV6 were detected by ELISA method. The relationship between TRPV6, clinical characteristics, laboratory indices of CK-MB, TnI, NT-pro-B-type natriuretic peptide (NT-pro-BNP), C-reactive protein (CRP), and the left ventricular ejection fraction (LVEF%) was analyzed by statistical methods. K-M curve was performed for survival time., Results: Serum levels of TRPV6 were remarkably lower in STEMI and NSTEMI patients compared with the healthy control. Levels of NT-pro-BNP and CK-MB were significantly higher and serum levels of TRPV6 were dramatically lower in deceased STEMI patients in comparison with the surviving patients. The levels of TRPV6 were negatively correlated with CK-MB and NT-pro-BNP. Meanwhile, TRPV6 was negatively expressed in tissues of STEMI patients and positively expressed in normal tissues. Patients with lower TRPV6 levels had remarkably lower LVEF ratio, higher GRACE scores, higher CK-MB and NT-pro-BNP levels, as well as higher ratios of cardiovascular death, malignant arrhythmia, cumulative MACE, and shorter survival time than patients with higher TRPV6., Conclusion: The lower expression of TRPV6 was associated with poor clinical outcomes and prognosis of STEMI patients., (© 2020 by the Association of Clinical Scientists, Inc.)

Acute myocardium infarction (AMI) is one of the main causes of cardiovascular death, and timely intervention and diagnosis are essential. Owing to the irreversible apoptosis and death of myocardial cells, which ultimately causes heart failure, the problem of myocardial repair after myocardial infarction needs to be urgently addressed. Exosomes can act as messengers between cells, delivering large amounts of proteins, RNA, and lipids to receptor cells, and regulating target cell functions. Studies have shown that exosomes can repair infarcted myocardium. We aimed to investigate the relationship between long non-coding RNA NEAT1 in serum exosomes of patients and AMI and its underlying mechanism. Subjects were divided into control, UA, and STEMI groups. RNA was extracted from the serum exosomes, and the expressions of lncRNA NEAT1 and miR-204 were detected by qRT-PCR. MMP-9 was detected by western blot, Spearman test was used to analyze the correlation among the three. Logistic regression and Receiver-operating characteristic curve (ROC) were used to evaluate the prediction of acute myocardial infarction. The expressions of NEAT1 and MMP-9 in serum exosomes of patients with acute ST-segment elevation myocardial infarction were up-regulated and positively correlated, miR-204 expression was down-regulated, there were no correlations between miR-204 with NEAT1, or MMP-9. Exosomal NEAT1, miR-204, and MMP-9 displayed potent biomarkers for diagnosis of acute ST-segment elevation myocardial infarction., (© 2020 International Union of Biochemistry and Molecular Biology.)

Plasma concentrations of many cardiovascular and inflammatory proteins are altered after ST-elevation myocardial infarction (STEMI) and may provide prognostic information. We conducted a large-scale proteomic analysis in patients with STEMI, correlating protein levels to infarct size and left ventricular ejection fraction (LVEF) determined with cardiac magnetic resonance imaging. We analysed 131 cardiovascular and inflammatory proteins using a multiplex proximity extension assay and blood samples obtained at baseline, 6, 24, and 96 h from the randomised clinical trial CHILL-MI. Cardiac magnetic resonance imaging data at 4 ± 2 days and 6 months were available as per trial protocol. Using a linear regression model with bootstrap resampling and false discovery rate adjustment we identified five proteins (ST2, interleukin-6, pentraxin-3, interleukin-10, renin, and myoglobin) with elevated values corresponding to larger infarct size or worse LVEF and four proteins (TNF-related apoptosis-inducing ligand, TNF-related activation induced cytokine, interleukin-16, and cystatin B) with values inversely related to LVEF and infarct size, concluding that among 131 circulating inflammatory and cardiovascular proteins in the acute and sub-acute phase of STEMI, nine showed a relationship with infarct size and LVEF post-STEMI, with IL-6 and ST2 exhibiting the strongest association.

Objective: The role of neutrophil extracellular traps (NETs) in acute heart failure is unknown. We recently showed that interleukin 8, a putative NETs stimulator, was associated with myocardial recovery in acute heart failure complicating ST-elevation myocardial infarction (STEMI). In this exploratory post-hoc study, we aimed to investigate the role of NETs components in relation to myocardial function and interleukin 8 in STEMI patients with symptomatic acute heart failure., Methods: In 61 STEMI patients developing acute heart failure within 48 hours of successful revascularization, wall motion score index (WMSI), global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography at baseline and on day 5. Blood drawn at baseline and days 1, 2 and 5 was used to quantify double-stranded DNA (dsDNA), myeloperoxidase-DNA complexes (MPO-DNA) and citrullinated histone 3 (CitH3). The area under the curve (AUC) of each NETs marker and interleukin 8 was approximated for the first 5 days., Results: dsDNAAUC and MPO-DNAAUC correlated significantly with change in WMSI from baseline to day 5 (rs = 0.28 for both, p≤0.05), whereas NETs AUCs did not correlate with changes in GLS and LVEF. dsDNAAUC was significantly correlated with interleukin 8AUC (r = 0.40, p = 0.003). However, mixed model regression could not identify a significant effect of the NETs components on myocardial function parameters., Conclusions: In this cohort with acute heart failure complicating STEMI, NETs components were partly correlated with myocardial function and interleukin 8 levels, yet no causal relationship between NETs components and myocardial recovery could be established., Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT00324766., Competing Interests: The authors have declared that no competing interests exist.

Sudden myocardial ischaemia causes an acute coronary syndrome. In the case of ST-elevation myocardial infarction (STEMI), this is usually caused by the acute rupture of atherosclerotic plaque and obstruction of a coronary artery. Timely restoration of blood flow can reduce infarct size, but ischaemic regions of myocardium remain in up to two-thirds of patients due to microvascular obstruction (MVO). Experimentally, cardioprotective strategies can limit infarct size, but these are primarily intended to target reperfusion injury. Here, we address the question of whether it is possible to specifically prevent ischaemic injury, for example in models of chronic coronary artery occlusion. Two main types of intervention are identified: those that preserve ATP levels by reducing myocardial oxygen consumption, (e.g. hypothermia; cardiac unloading; a reduction in heart rate or contractility; or ischaemic preconditioning), and those that increase myocardial oxygen/blood supply (e.g. collateral vessel dilation). An important consideration in these studies is the method used to assess infarct size, which is not straightforward in the absence of reperfusion. After several hours, most of the ischaemic area is likely to become infarcted, unless it is supplied by pre-formed collateral vessels. Therefore, therapies that stimulate the formation of new collaterals can potentially limit injury during subsequent exposure to ischaemia. After a prolonged period of ischaemia, the heart undergoes a remodelling process. Interventions, such as those targeting inflammation, may prevent adverse remodelling. Finally, harnessing of the endogenous process of myocardial regeneration has the potential to restore cardiomyocytes lost during infarction.

Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling. Extracellular vesicles (EV) are lipid bilayer membrane nanoparticle and their lipid composition may be different from parental cells, with a significant enrichment in sphingolipid species, especially in pathological conditions. We aimed at optimizing EV isolation from plasma and describing the differential lipid content of EV, as compared to whole plasma. As pilot study, we evaluated the diagnostic potential of lipidomic signature of circulating EV in patients with a diagnosis of ST-segment-elevation myocardial infarction (STEMI). STEMI patients were evaluated before reperfusion and 24-h after primary percutaneous coronary intervention. Twenty sphingolipid species were quantified by liquid-chromatography tandem-mass-spectrometry. EV-ceramides, -dihydroceramides, and -sphingomyelins increased in STEMI vs. matched controls and decreased after reperfusion. Their levels correlated to hs-troponin, leucocyte count, and ejection fraction. Plasma sphingolipids levels were 500-to-700-fold higher as compared to EV content; nevertheless, only sphingomyelins differed in STEMI vs. control patients. Different sphingolipid species were enriched in EV and their linear combination by machine learning algorithms accurately classified STEMI patients at pre-PCI evaluation. In conclusion, EV lipid signature discriminates STEMI patients. These findings may contribute to the identification of novel biomarkers and signaling mechanisms related to cardiac ischemia.

Infarct size is a major prognostic factor in ST-segment elevation myocardial infarction (STEMI). It is often assessed using repeated blood sampling and the estimation of biomarker area under the concentration versus time curve (AUC) in translational research. We aimed at developing limited sampling strategies (LSS) to accurately estimate biomarker AUC using only a limited number of blood samples in STEMI patients. This retrospective study was carried out on pooled data from five clinical trials of STEMI patients (TIMI blood flow 0/1) studies where repeated blood samples were collected within 72 h after admission to assess creatine kinase (CK), cardiac troponin I (cTnI) and muscle-brain CK (CK-MB). Biomarker kinetics was assessed using previously described biomarker kinetic models. A number of LSS models including combinations of 1 to 3 samples were developed to identify sampling times leading to the best estimation of AUC. Patients were randomly assigned to either learning (2/3) or validation (1/3) subsets. Descriptive and predictive performances of LSS models were compared using learning and validation subsets, respectively. An external validation cohort was used to validate the model and its applicability to different cTnI assays, including high-sensitive (hs) cTnI. 132 patients had full CK and cTnI dataset, 49 patients had CK-MB. For each biomarker, 180 LSS models were tested. Best LSS models were obtained for the following sampling times: T4-16 for CK, T8-T20 for cTnI and T8-T16 for CK-MB for 2-sample LSS; and T4-T16-T24 for CK, T4-T12-T20 for cTnI and T8-T16-T20 for CK-MB for 3-sample LSS. External validation was achieved on 103 anterior STEMI patients (TIMI flow 0/1), and the cTnI model applicability to recommended hs cTnI confirmed. Biomarker kinetics can be assessed with a limited number of samples using kinetic modelling. This opens the way for substantial simplification of future cardioprotection studies, more acceptable for the patients.

ST elevation on an electrocardiogram is a hallmark of acute transmural ischemia. However, the underlying mechanism remains unclear. We hypothesized that high ischemic sensitivities of epicardial adenosine triphosphate-sensitive potassium (IK ATP ) and sodium (INa) currents play key roles in the genesis of ST elevation. Using a multi-scale heart simulation under moderately ischemic conditions, transmural heterogeneities of IK ATP and INa created a transmural gradient, opposite to that observed in subendocardial injury, leading to ST elevation. These heterogeneities also contributed to the genesis of hyper-acute T waves under mildly ischemic conditions. By contrast, under severely ischemic conditions, although action potentials were suppressed transmurally, the potential gradient at the boundary between the ischemic and normal regions caused ST elevation without a contribution from transmural heterogeneity. Thus, transmural heterogeneities of ion channel properties may contribute to the genesis of ST-T changes during mild or moderate transmural ischemia, while ST elevation may be induced without the contribution of heterogeneity under severe ischemic conditions.

Background: Recent studies emphasize the importance of HDL function over HDL cholesterol measurement, as an important risk for cardiovascular diseases (CVD). We compared the HDL function of patients with acute coronary syndrome (ACS) and healthy controls., Methods: We measured cholesterol efflux capacity of HDL using THP-1 macrophages labelled with fluorescently tagged (BODIPY) cholesterol. PON1 activities toward paraoxon and phenyl acetate were assessed by spectrophotometric methods., Results: We recruited 150 ACS patients and 110 controls. The HDL function of all patients during acute phase and at six month follow-up was measured. The mean age of the patients and controls was 51.7 and 43.6 years respectively. The mean HDL cholesterol/apolipoprotein A-I levels (ratio) of patients during acute phase, follow-up and of controls were 40.2 mg/dl/ 112.5 mg/dl (ratio = 0.36), 38.3 mg/dl/ 127.2 mg/dl (ratio = 0.30) and 45.4 mg/dl/ 142.1 mg/dl (ratio = 0.32) respectively. The cholesterol efflux capacity (CEC) of HDL was positively correlated with apolipoprotein A-I levels during acute phase (r = 0.19, p = 0.019), follow-up (r = 0.26, p = 0.007) and of controls (r = 0.3, p = 0.0012) but not with HDL-C levels (acute phase: r = 0.07, p = 0.47; follow-up: r = 0.1, p = 0.2; control: r = 0.02, p = 0.82). Higher levels of cholesterol efflux capacity, PON1 activity and apolipoprotein A-I were associated with lower odds of development of ACS. We also observed that low CEC is associated with higher odds of having ACS if PON1 activity of HDL is also low and vice versa., Conclusion: ACS is associated with reduced HDL functions which improves at follow-up. The predicted probability of ACS depends upon individual HDL functions and the interactions between them.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein released by renal tubular cells upon nephrotoxic or ischemic events and is considered an early marker of tubular damage. We aimed to demonstrate the presence of early renal injury detected by elevated NGAL levels taken before contrast administration in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI)., Patients and Methods: We prospectively included 88 patients with STEMI treated with PCI. Blood samples for plasma NGAL were drawn immediately before PCI (baseline NGAL; NGAL1) and 24 h after PCI (NGAL2). Abnormal elevations in NGAL levels were defined using the cardiac surgery associated NGAL score (NGAL score) with NGAL levels at least 100 ng/ml, suggesting renal tubular damage. Patients were also assessed for the dynamics between NGAL2 and NGAL1 levels., Results: The mean age of the patients was 62 ± 13 years and 78% were men. A total of 50/88 (56%) patients had baseline NGAL level of at least 100, suggesting possible tubular damage before PCI. Only 10 patients progressed to clinical acute kidney injury during hospitalization, all of whom had baseline NGAL level of at least 100 (P < 0.001). Among patients with baseline NGAL at least 100, 28/50 (56%) showed a decrease in the NGAL level within 24 h, whereas only 9/50 (18%) showed an elevation in the NGAL level. In contrast, only 7/38 (19%) patients with baseline NGAL level less than 100 showed an elevation in NGAL levels within 24 h., Conclusion: Elevated NGAL levels before primary PCI suggesting renal tubular damage are common among STEMI patients. Further trials are needed to assess the complex cardio-renal interactions.

ST segment elevation myocardial infarction (STEMI) is one of the most common global causes of cardiovascular disease-related death. Several metabolites may change during STEMI. Hence, analysis of metabolites in body fluid may be considered as a rapid and accurate test for initial diagnosis. This study has therefore attempted to determine the variation in metabolites identified in the serum of STEMI patients (n = 20) and 15 controls. Samples collected from the Cardiology Department, Medical Faculty, Ataturk University, were extracted by liquid-liquid extraction and analysed using liquid chromatography quadrupole time-of-flight mass spectrometry. The METLIN database was used for the identification and characterization of metabolites. According to Q-TOF/MS measurements, 231 m/z values, which were significantly different between groups (P < 0.01 and fold analysis >1.5) were detected. Metabolite identification was achieved via the Human Metabolome database. According to the multivariate data analysis, leucine, isoleucine, l-proline, l-alanine, glycine, fumaric acid, citrate, succinate and carnitine levels were decreased, whereas levels of propionic acid, maleic acid, butyric acid, urea, oleic acid, palmitic acid, lysoPC [18:2(9Z)], glycerol, phoshpatidylethanolamine, caffeine and l-lactic acid were increased in STEMI patients compared with controls. In conclusion, malonic acid, maleic acid, fumaric acid and palmitic acid can be used as biomarkers for early risk stratification of patients with STEMI., (© 2019 John Wiley & Sons, Ltd.)

Background The circulating level of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) is a valuable biomarker of acute myocardial infarction (AMI). The most electronegative low-density lipoprotein, L5, signals through LOX-1 to trigger atherogenesis. We examined the characteristics of LOX-1 and the role of L5 in aspirated coronary thrombi of AMI patients. Methods and Results Intracoronary thrombi were aspirated by performing interventional thrombosuction in patients with ST-segment-elevation myocardial infarction (STEMI; n=32) or non-ST-segment-elevation myocardial infarction (n=12). LOX-1 level and the ratio of sLOX-1 to membrane-bound LOX-1 were higher in thrombi of STEMI patients than in those of non-ST-segment-elevation myocardial infarction patients. In all aspirated thrombi, LOX-1 colocalized with apoB100. When we explored the role of L5 in AMI, deconvolution microscopy showed that particles of L5 but not L1 (the least electronegative low-density lipoprotein) quickly formed aggregates prone to retention in thrombi. Treating human monocytic THP-1 cells with L5 or L1 showed that L5 induced cellular adhesion and promoted the differentiation of monocytes into macrophages in a dose-dependent manner. In a second cohort of AMI patients, the L5 percentage and plasma concentration of sLOX-1 were higher in STEMI patients (n=33) than in non-ST-segment-elevation myocardial infarction patients (n=25), and sLOX-1 level positively correlated with L5 level in AMI patients. Conclusions The level of LOX-1 and the ratio of sLOX-1 to membrane-bound LOX-1 in aspirated thrombi, as well as the circulating level of sLOX-1 were higher in STEMI patients than in non-ST-segment-elevation myocardial infarction patients. L5 may play a role in releasing a high level of sLOX-1 into the circulation of STEMI patients.

The aim of the study was to evaluate the clinical significance of microRNA-375 in acute myocardial infarction patients and its mimic action in hypoxia/reoxygenation- (H/R-) induced ventricular cardiomyocyte H9c2 injury. In the current study, 90 ST-elevated acute MI patients (STEMI), 75 non-ST-elevated acute MI patients (NSTEMI), 90 healthy subjects, 14 weeks old mice, and ventricular cardiomyocyte H9c2 were included. The expressions of plasma microRNA-375 in patients with STEMI and NSTEMI and AMI mouse models were remarkably decreased than in controls ( P < 0.001). The areas under the curve (AUC) of plasma microRNA-375 were revealed 0.939 in STEMI and 0.935 in NSTEMI subjects. Moreover, microRNA-375 levels in H/R-exposed cardiac H9c2 cells were evidently downregulated and significantly increased apoptosis rate and caspase-3 activity levels, while overexpression of miR-375 remarkably reduced apoptosis percentage and caspase-3 levels as compared with normal cells. Furthermore, this study also demonstrated that Nemo-like kinase (NLK), NLK mRNA, and protein expression levels were significantly downregulated in H/R-injured H9c2 cells, on the contrary, H9c2 cells transfected with mimic-miR-375 greatly upregulated NLK mRNA and protein expression. Plasma microRNA-375 may serve as an essential clinical biomarker for diagnosis of early-stage AMI. Mimic expression of miR-375 significantly prevented H/R-induced cardiomyocyte injury by decreasing caspase-3 activity through upregulation of the NLK gene, recommended as a new therapeutic option for AMI patient., Competing Interests: There is no conflict of interest in this article., (Copyright © 2020 Md Sayed Ali Sheikh.)

Kindlins are important proteins for integrin signaling and regulation of the cytoskeleton, but we know little about their precise function and regulation in platelets during acute ischemic events. In this work, we investigated kindlin-3 protein levels in platelets isolated from patients with ST-elevation myocardial infarction (STEMI) compared to patients with non-ischemic chest pain. Platelets from twelve patients with STEMI and twelve patients with non-ischemic chest pain were isolated and analyzed for kindlin-3 protein levels and intracellular localization by immunoblotting and two-dimensional gel electrophoresis. Platelet proteome analysis by two-dimensional gel electrophoresis and protein sequencing identified kindlin-3 as a protein that is cleaved in platelets from patients with myocardial infarction. Kindlin-3 full-length protein was significantly decreased in patients with STEMI compared to patients with non-ischemic chest pain (1.0 ± 0.2 versus 0.28 ± 0.2, p < 0.05) by immunoblotting. Kindlin-3 showed a differential distribution and was primarily cleaved in the cytosolic and membrane compartment of platelets in myocardial infarction. Platelet activation with thrombin alone did not affect kindlin-3 protein levels. The present study demonstrates that kindlin-3 protein levels become significantly reduced in platelets of patients with myocardial infarction compared to controls. The results suggest that kindlin-3 cleavage in platelets is associated with the ischemic event of myocardial infarction.

Hyperglycemia during myocardial infarction (MI) has a strong and direct association with mortality. In stable patients and experimental models, statins favor the elevation of glycaemia. The present study investigated whether short-course treatment with statins during MI can influence glucose homeostasis and thus the clinical outcome. In this prospective study, euglycemic hyperinsulinemic clamp (EHC) was performed at second (D2) and sixth (D6) day after MI in patients randomized to simvastatin (S)10 or 80 mg/day during hospitalization (n = 27). In addition, patients (n = 550) were treated without (WS) or with simvastatin (S) at 20, 40 or 80 mg/day had HOMA2S on admission (D1) and fifth (D5) day after MI. According to EHC, insulin sensitivity increased by 20 ± 60% in S10 and decreased by -6 ± 28% in S80 (p = 0.025). Consistently, the changes in HOMA2S between D1 and D5 were 40 ± 145% (WS), 22 ± 117% (S20), 16 ± 61% (S40) and -2% ± 88% (S80) (p = 0.001). In conclusion, statin during the acute phase of MI reduces insulin sensitivity in a dose-dependent manner.

Neutrophils release their chromatin into the extracellular space upon activation. These web-like structures are called neutrophil extracellular traps (NETs) and have potent prothrombotic and proinflammatory properties. In ST-elevation myocardial infarction (STEMI), NETs correlate with increased infarct size. The interplay of neutrophils and monocytes impacts cardiac remodeling. Monocyte subsets are classified as classical, intermediate and non-classical monocytes. In the present study, in vitro stimulation with NETs led to an increase of intermediate monocytes and reduced expression of CX3CR1 in all subsets. Intermediate monocytes have been associated with poor outcome, while non-classical CX3CR1-positive monocytes could have reparative function after STEMI. We characterized monocyte subsets and NET markers at the culprit lesion site of STEMI patients (n = 91). NET surrogate markers were increased and correlated with larger infarct size and with fewer non-classical monocytes. Intermediate and especially non-classical monocytes were increased at the culprit site compared to the femoral site. Low CX3CR1 expression of monocytes correlated with high NET markers and increased infarct size. In this translational system, causality cannot be proven. However, our data suggest that NETs interfere with monocytic differentiation and receptor expression, presumably promoting a subset shift at the culprit lesion site. Reduced monocyte CX3CR1 expression may compromise myocardial salvage.

Background: This study aimed to investigate the angiotensin converting enzyme (ACE) co-expression genes and their pathways involved in ST-segment elevation myocardial infarction (STEMI) at different time points., Methods: The array data set of GSE59867 was examined for the ACE co-expression genes in peripheral blood samples from 111 patients with STEMI at four time points (admission, discharge, and 1 and 6 months after MI). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Gene Ontology (GO) annotation and protein-protein interaction (PPI) of the co-expression genes were determined using online analytical tools. The Cytoscape software was used to create modules and hub genes., Results: The number of biological processes (BP), cellular components (CC) and molecular functions (MF) was 43, 22 and 24 at admission; 18, 19 and 11 at discharge; 30, 37 and 21 at 1 month after MI; and 12, 19 and 14 at 6 months after MI; respectively. There were 6 BP, 8 CC and 4 MF enriched at every time point. The co-expression genes were substantially enriched in 12, 5, 6 and 14 KEGG pathways at the four time points, respectively, but no KEGG pathway was found to be common in all time points. We identified 132 intersectional co-expression genes (90 positive and 42 negative) from the four time points and 17 BP, 13 CC, 11 MF and 7 KEGG pathways were enriched. In addition, the PPI network contained 129 nodes and 570 edges, and only 1 module was identified to be significantly enriched in just 1 BP (chromatin-mediated maintenance of transcription)., Conclusions: The results of the present study showed that the ACE co-expression genes and their pathways involved in STEMI were significantly different at four different time points. These findings may be helpful for further understanding the functions and roles of ACE in different stages of STEMI, and providing reference for the treatment of STEMI.

Background: The relevance of neutrophil extracellular traps (NETs) in acute ST-elevation myocardial infarction (STEMI) is unclear. We explored the temporal profile of circulating NET markers and their associations to myocardial injury and function and to adverse clinical events in STEMI patients., Methods and Results: In 259 patients, blood samples were drawn before and after PCI, on day 1, and after 4 months. Double-stranded deoxyribonucleic acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) were measured in serum by a nucleic acid stain and ELISA. Cardiac magnetic resonance imaging assessed microvascular obstruction (MVO), area at risk, infarct size, myocardial salvage index, left ventricular ejection fraction (LVEF), and change in indexed left ventricular end-diastolic volume (LVEDVi). Clinical events were registered after 12 months. dsDNA and MPO-DNA levels were highest before PCI, with reduced levels thereafter (all p ≤ 0.02). Patients with high vs. low day 1 dsDNA levels (>median; 366 ng/ml) more frequently had MVO, larger area at risk, larger infarct size acutely and after 4 months, and lower myocardial salvage index (all p < 0.03). Moreover, they had lower LVEF acutely and after 4 months, and larger change in LVEDVi (all p ≤ 0.014). High day 1 dsDNA levels also associated with risk of having a large infarct size (>75th percentile) and low LVEF (≤49%) after 4 months when adjusted for gender, time from symptoms to PCI, and infarct localization (OR 2.3 and 3.0, both p < 0.021), and patients with high day 1 dsDNA levels were more likely to experience an adverse clinical event, also when adjusting for peak troponin T (hazard ratio 5.1, p = 0.012). No such observations were encountered for MPO-DNA., Conclusions: High day 1 dsDNA levels after STEMI were associated with myocardial infarct size, adverse left ventricular remodeling, and clinical outcome. Although the origin of dsDNA could be discussed, these observations indicate a potential role for dsDNA in acute myocardial ischemia. This trial is registered with S-08421d, 2008/10614 (Regional Committee for Medical Research Ethics in South-East Norway (2008))., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2019 Ragnhild Helseth et al.)