Martinus I. F. J. Oerlemans

Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs

Previous studies investigating the role of circulating microRNAs in acute coronary syndrome (ACS) were based on small patient numbers, performed no comparison with established markers of cardiac injury and did not have appropriate controls. We determined the potential diagnostic value of circulating microRNAs as novel early biomarkers in 332 suspected ACS patients on presentation to the emergency department (ED) in a prospective single‐centre study including cardiac miRNAs (miR‐1, ‐208a and ‐499), miR‐21 and miR‐146a. Levels of all miRs studied were significantly increased in 106 patients diagnosed with ACS, even in patients with initially negative high‐sensitive (hs) troponin or symptom onset <3 h. MiR‐1, miR‐499 and miR‐21 significantly increased the diagnostic value in all suspected ACS patients when added to hs‐troponin T (AUC 0.90). These three miRs were strong predictors of ACS independent of clinical co‐variates including patient history and cardiovascular risk factors. Interestingly, the combination of these three miRs resulted in a significantly higher AUC of 0.94 than hs‐troponin T (0.89). Circulating microRNAs hold great potential as novel early biomarkers for the management of suspected ACS patients.

MicroRNA-214 inhibits angiogenesis by targeting Quaking and reducing angiogenic growth factor release

AIMS Angiogenesis is a critical component of many pathological conditions in adult tissues and is essential for embryonic development. MicroRNAs are indispensable for normal vascular development, but their exact role in regulating angiogenesis remains unresolved. Previously, we have observed that miR-214 is differentially expressed in compensatory arteriogenesis. Here, we investigated the potential role of miR-214 in the process of angiogenesis. METHODS AND RESULTS miR-214 is expressed in all major vascular cell types, and modulation of miR-214 levels in endothelial cells significantly affected tubular sprouting. In vivo silencing of miR-214 enhanced the formation of a perfused vascular network in implanted Matrigel plugs and retinal developmental angiogenesis in mice. miR-214 directly targets Quaking, a protein critical for vascular development. Quaking knockdown reduced pro-angiogenic growth factor expression and inhibited endothelial cell sprouting similar to miR-214 overexpression. In accordance, silencing of miR-214 increased the secretion of pro-angiogenic growth factors, including vascular endothelial growth factor, and enhanced the pro-angiogenic action of the endothelial cell-derived conditioned medium, whereas miR-214 overexpression had the opposite effect. CONCLUSION Here, we report a novel role for miR-214 in regulating angiogenesis and identify Quaking as a direct target of miR-214. The anti-angiogenic effect of miR-214 is mediated through the down-regulation of Quaking and pro-angiogenic growth factor expression. This study presents miR-214 as a potential important target for pro- or anti-angiogenic therapies.

Human versus porcine mesenchymal stromal cells: phenotype, differentiation potential, immunomodulation and cardiac improvement after transplantation

Although mesenchymal stromal cells (MSCs) have been applied clinically to treat cardiac diseases, it is unclear how and to which extent transplanted MSCs exert their beneficial effects. To address these questions, pre‐clinical MSC administrations are needed for which pigs appear to be the species of choice. This requires the use of porcine cells to prevent immune rejection. However, it is currently unknown to what extent porcine MSCs (pMSCs) resemble human MSCs (hMSCs). Aim of this study was to compare MSC from porcine bone marrow (BM) with human cells for phenotype, multi‐lineage differentiation potential, immune‐modulatory capacity and the effect on cardiac function after transplantation in a mouse model of myocardial infarction. Flow cytometric analysis revealed that pMSC expressed surface antigens also found on hMSC, including CD90, MSCA‐1 (TNAP/W8B2 antigen), CD44, CD29 and SLA class I. Clonogenic outgrowth was significantly enriched following selection of CD271+ cells from BM of human and pig (129 ± 29 and 1961 ± 485 fold, respectively). hMSC and pMSC differentiated comparably into the adipogenic, osteogenic or chondrogenic lineages, although pMSC formed fat much faster than hMSC. Immuno‐modulation, an important feature of hMSC, was clearly demonstrated for pMSC when co‐cultured with porcine peripheral blood cells stimulated with PMA and pIL‐2. Finally, pMSC transplantation after myocardial infarction attenuated adverse remodelling to a similar extent as hMSC when compared to control saline injection. These findings demonstrate that pMSCs have comparable characteristics and functionality with hMSCs, making reliable extrapolation of pre‐clinical pMSC studies into a clinical setting very well possible.

Circulating MicroRNAs as Novel Biomarkers for the Early Diagnosis of Acute Coronary Syndrome

Small non-coding microRNAs (miRNAs) are important physiological regulators of post-transcriptional gene expression. miRNAs not only reside in the cytoplasm but are also stably present in several extracellular compartments, including the circulation. For that reason, miRNAs are proposed as diagnostic biomarkers for various diseases. Early diagnosis of acute coronary syndrome (ACS), especially non-ST elevated myocardial infarction and unstable angina pectoris, is essential for optimal treatment outcome, and due to the ongoing need for additional identifiers, miRNAs are of special interest as biomarkers for ACS. This review highlights the nature and cellular release mechanisms of circulating miRNAs and therefore their potential role in the diagnosis of myocardial infarction. We will give an update of clinical studies addressing the role of circulating miRNA expression after myocardial infarction and explore the diagnostic value of this potential biomarker.

Necrostatin‐1 alleviates reperfusion injury following acute myocardial infarction in pigs

In rodents, it has previously been shown that necrostatin‐1 (Nec‐1) inhibits RIP1, a central regulator of programmed necrosis, thereby decreasing cell death and reducing infarct size (IS) after ischaemia/reperfusion (I/R) injury. To address unanswered questions on feasibility and efficacy of Nec‐1 in a large animal model, we assessed the effects of Nec‐1 in a porcine I/R model, relevant to human disease.

Circulating Extracellular Vesicles Contain miRNAs and are Released as Early Biomarkers for Cardiac Injury

Plasma-circulating microRNAs have been implicated as novel early biomarkers for myocardial infarction (MI) due to their high specificity for cardiac injury. For swift clinical translation of this potential biomarker, it is important to understand their temporal and spatial characteristics upon MI. Therefore, we studied the temporal release, potential source, and transportation of circulating miRNAs in different models of ischemia reperfusion (I/R) injury. We demonstrated that extracellular vesicles are released from the ischemic myocardium upon I/R injury. Moreover, we provided evidence that cardiac and muscle-specific miRNAs are transported by extracellular vesicles and are rapidly detectable in plasma. Since these vesicles are enriched for the released miRNAs and their detection precedes traditional damage markers, they hold great potential as specific early biomarkers for MI.

Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs: Potential value of circulating miRNAs

Previous studies investigating the role of circulating microRNAs in acute coronary syndrome (ACS) were based on small patient numbers, performed no comparison with established markers of cardiac injury and did not have appropriate controls. We determined the potential diagnostic value of circulating microRNAs as novel early biomarkers in 332 suspected ACS patients on presentation to the emergency department (ED) in a prospective single‐centre study including cardiac miRNAs (miR‐1, ‐208a and ‐499), miR‐21 and miR‐146a. Levels of all miRs studied were significantly increased in 106 patients diagnosed with ACS, even in patients with initially negative high‐sensitive (hs) troponin or symptom onset <3 h. MiR‐1, miR‐499 and miR‐21 significantly increased the diagnostic value in all suspected ACS patients when added to hs‐troponin T (AUC 0.90). These three miRs were strong predictors of ACS independent of clinical co‐variates including patient history and cardiovascular risk factors. Interestingly, the combination of these three miRs resulted in a significantly higher AUC of 0.94 than hs‐troponin T (0.89). Circulating microRNAs hold great potential as novel early biomarkers for the management of suspected ACS patients.

Early assessment of acute coronary syndromes in the emergency department

Previous studies investigating the role of circulating microRNAs in acute coronary syndrome (ACS) were based on small patient numbers, performed no comparison with established markers of cardiac injury and did not have appropriate controls. We determined the potential diagnostic value of circulating microRNAs as novel early biomarkers in 332 suspected ACS patients on presentation to the emergency department (ED) in a prospective single‐centre study including cardiac miRNAs (miR‐1, ‐208a and ‐499), miR‐21 and miR‐146a. Levels of all miRs studied were significantly increased in 106 patients diagnosed with ACS, even in patients with initially negative high‐sensitive (hs) troponin or symptom onset <3 h. MiR‐1, miR‐499 and miR‐21 significantly increased the diagnostic value in all suspected ACS patients when added to hs‐troponin T (AUC 0.90). These three miRs were strong predictors of ACS independent of clinical co‐variates including patient history and cardiovascular risk factors. Interestingly, the combination of these three miRs resulted in a significantly higher AUC of 0.94 than hs‐troponin T (0.89). Circulating microRNAs hold great potential as novel early biomarkers for the management of suspected ACS patients.