MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation

Arroyo, Ana B.; Reyes-García, Asunción M. de los; Rivera‐Caravaca, José Miguel; Valledor, Patricia; García-Barberá, Nuria; Roldán, Vanessa; Vicente, Vicente; Martı́nez, Constantino; Gónzález-Conejero, Rocío

doi:10.1161/atvbaha.117.310597

Cited by 55 publications

(58 citation statements)

References 48 publications

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“…Hence, in our study we also explored the ability of several markers of neutrophil activation, in order to identify PDAC and DECC patients at high risk of developing VTE during follow-up. To that end, we measured different plasma markers of neutrophil activation following the strategy addressed in previous studies [51][52][53][54][55][56][57]. We have observed an increase in calprotectin and MPO plasma levels in those patients who developed VTE compared with those who did not.…”

Section: Discussionmentioning

confidence: 95%

“…Different markers of neutrophil activation were measured in every plasma sample obtained during follow-up from the 32 patients studied herein, following the strategy addressed in previous studies [51][52][53][54][55][56][57]. Cell-free DNA (cfDNA; Quant-iT PicoGreen dsDNA kit, Life Technologies, Eugene, OR, USA) and nucleosomes (Cell Death Detection ELISA PLUS kit, Roche, Mannheim, Germany) were measured as markers of the nuclear content of neutrophils released by neutrophils upon NETosis.…”

Section: Quantification Of Neutrophil Activation Markersmentioning

confidence: 99%

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MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma

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Larsen

et al. 2020

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Cancer-associated venous thrombosis (VTE) increases mortality and morbidity. However, limited tools are available to identify high risk patients. Upon activation, neutrophils release their content through different mechanisms, thereby prompting thrombosis. We explored plasma microRNAs (miRNAs) and neutrophil activation markers to predict VTE in pancreatic ductal adenocarcinoma (PDAC) and distal extrahepatic cholangiocarcinoma (DECC). Twenty-six PDAC and 6 DECC patients recruited at cancer diagnosis, were examined for deep vein thrombosis and pulmonary embolisms, and were then followed-up with clinical examinations, blood collections, and biCUS. Ten patients developed VTE and were compared with 22 age- and sex-matched controls. miRNA expression levels were measured at diagnosis and right before VTE, and neutrophil activation markers (cell-free DNA, nucleosomes, calprotectin, and myeloperoxidase) were measured in every sample obtained during follow-up. We obtained a profile of 7 miRNAs able to estimate the risk of future VTE at diagnosis (AUC = 0.95; 95% Confidence Interval (CI) (0.987, 1)) with targets involved in the pancreatic cancer and complement and coagulation cascades pathways. Seven miRNAs were up- or down-regulated before VTE compared with diagnosis. We obtained a predictive model of VTE with calprotectin as predictor (AUC = 0.77; 95% CI (0.57, 0.95)). This is the first study that addresses the ability of plasma miRNAs and neutrophil activation markers to predict VTE in PDAC and DECC.

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Section: Discussionmentioning

confidence: 95%

Section: Quantification Of Neutrophil Activation Markersmentioning

confidence: 99%

MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma

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et al. 2020

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“…patients with atrial fibrillation or artificial heart valves) are usually treated with long‐term anticoagulation. Prior studies indicate that NETs play a role in the development of cardiovascular events in patients with atrial fibrillation despite anticoagulant therapy (Arroyo et al , ). The exclusion of these patients in our study could have further reduced the number of arterial events and could thus have influenced the result regarding the association of NETs and ATE.…”

Section: Discussionmentioning

confidence: 99%

Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

et al. 2019

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Summary Prior studies indicate that neutrophil extracellular traps ( NET s) are associated with arterial thromboembolism ( ATE ) and mortality. We investigated the association between NET formation biomarkers (citrullinated histone H3 [H3Cit], cell‐free DNA [cfDNA], and nucleosomes) and the risk of ATE and all‐cause mortality in patients with cancer. In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for ATE and death. Nine‐hundred and fifty‐seven patients were included. The subdistribution hazard ratios for ATE of H3Cit, cfDNA and nucleosomes were 1·0 per 100 ng/ml increase (95% confidence interval [95% CI]: 0·7–1·4, P = 0·949), 1·0 per 100 ng/ml (0·9–1·2, P = 0·494) increase and 1·1 per 1‐unit increase (1·0–1·2, P = 0·233), respectively. Three‐hundred and seventy‐eight (39·5%) patients died. The hazard ratio ( HR ) for mortality of H3Cit and cfDNA per 100 ng/ml increase was 1·1 (1·0–1·1, P < 0·001) and 1·1 (1·0–1·1, P < 0·001), respectively. The HR for mortality of nucleosome levels per 1‐unit increase was 1·0 (1·0–1·1, P = 0·233). H3Cit, cfDNA and nucleosome levels were not associated with the risk of ATE in patients with cancer. Elevated H3Cit and cfDNA levels were associated with higher mortality in patients with cancer.

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“…cfDNA could be released into plasma by apoptotic or necrotic cells. Following the strategy addressed in previous studies [25][26][27][28][29]33,34,54,55], we evaluated whether the different markers of neutrophil activation measured in plasma had the same cellular origin by means of their correlation. We found a significant correlation between levels of cfDNA and calprotectin (r = 0.28; p < 0.0001), similar to that observed in previous plasma studies [27,33], and also between neutrophil count and calprotectin (Spearman r = 0.18; p = 0.003) indicating that they might have, to some extent, the same origin, probably an increased activation of neutrophils or NETosis.…”

Section: Discussionmentioning

confidence: 99%

Increase of Neutrophil Activation Markers in Venous Thrombosis—Contribution of Circulating Activated Protein C

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et al. 2020

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Upon activation, neutrophils release their content through different mechanisms like degranulation and NETosis, thus prompting thrombosis. The natural anticoagulant activated protein C (APC) inhibits neutrophil NETosis and, consequently, this may lower the levels of neutrophil activation markers in plasma, further diminishing the thrombotic risk exerted by this anticoagulant. We aimed to describe the status of markers of neutrophil activation in plasma of patients with venous thrombosis, their association with the thrombotic risk and the potential contribution of APC. We quantified three markers of neutrophil activation (cell-free DNA, calprotectin, and myeloperoxidase) in 253 patients with venous thromboembolism (VTE) in a stable phase (192 lower extremity VTE and 61 splanchnic vein thrombosis) and in 249 healthy controls. In them, we also quantified plasma APC, soluble endothelial protein C receptor (EPCR), and soluble thrombomodulin (TM), and we genotyped two genetic regulators of APC: the EPCR gene (PROCR) haplotypes (H) and the TM gene (THBD) c.1418C>T polymorphism. We found a significant increase in plasma cell-free DNA (p < 0.0001), calprotectin (p = 0.0001) and myeloperoxidase (p = 0.005) in VTE patients compared to controls. Furthermore, all three neutrophil activation markers were associated with an increase in the thrombotic risk. Cell-free DNA and calprotectin plasma levels were significantly correlated (Spearman r = 0.28; p < 0.0001). As expected, the natural anticoagulant APC was significantly decreased in VTE patients (p < 0.0001) compared to controls, what was mediated by its genetic regulators PROCR-H1, PROCR-H3, and THBD-c.1418T, and inversely correlated with cell-free DNA levels. This is the largest case-control study that demonstrates the increase in markers of neutrophil activation in vivo in VTE patients and their association with an increased thrombotic risk. This increase could be mediated by low APC levels and its genetic regulators, which could also increase NETosis, further enhancing thrombosis and inflammation.

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MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation

Abstract: NE activity can provide new ACE prognostic information in AF patients. These findings provide evidence of a potential role of miR-146a in neutrophil extracellular trap generation and cardiovascular risk in AF.

Cited by 55 publications

References 48 publications

MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma

MicroRNAs and Neutrophil Activation Markers Predict Venous Thrombosis in Pancreatic Ductal Adenocarcinoma and Distal Extrahepatic Cholangiocarcinoma

Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

Increase of Neutrophil Activation Markers in Venous Thrombosis—Contribution of Circulating Activated Protein C

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