Timing of invasive strategy in non-ST-elevation acute coronary syndrome: a meta-analysis of randomized controlled trials

AIMS: The optimal timing of an invasive strategy (IS) in non-ST-elevation acute coronary syndrome (NSTE-ACS) is controversial. Recent randomized controlled trials (RCTs) and long-term follow-up data have yet to be included in a contemporary meta-analysis. METHODS AND RESULTS: A systematic review of RCTs that compared an early IS vs. delayed IS for NSTE-ACS was conducted by searching MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. A meta-analysis was performed by pooling relative risks (RRs) using a random-effects model. The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), recurrent ischaemia, admission for heart failure (HF), repeat re-vascularization, major bleeding, stroke, and length of hospital stay. This study was registered with PROSPERO (CRD42021246131). Seventeen RCTs with outcome data from 10 209 patients were included. No significant differences in risk for all-cause mortality [RR: 0.90, 95% confidence interval (CI): 0.78-1.04], MI (RR: 0.86, 95% CI: 0.63-1.16), admission for HF (RR: 0.66, 95% CI: 0.43-1.03), repeat re-vascularization (RR: 1.04, 95% CI: 0.88-1.23), major bleeding (RR: 0.86, 95% CI: 0.68-1.09), or stroke (RR: 0.95, 95% CI: 0.59-1.54) were observed. Recurrent ischaemia (RR: 0.57, 95% CI: 0.40-0.81) and length of stay (median difference: -22 h, 95% CI: -36.7 to -7.5 h) were reduced with an early IS. CONCLUSION: In all-comers with NSTE-ACS, an early IS does not reduce all-cause mortality, MI, admission for HF, repeat re-vascularization, or increase major bleeding or stroke when compared with a delayed IS. Risk of recurrent ischaemia and length of stay are significantly reduced with an early IS

The Role of Activated Platelets in the Regulation of a Pro-Atherogenic Monocyte Phenotype

Platelets are circulating megakaryocytic fragments that have a well-established role in athero-thrombosis. Monocytes are circulating leucocytes which migrate to sites of endothelial damage, infiltrate a nascent plaque and avidly accumulate lipids to become foam cells. Evidence is provided to show that activated platelets accelerate this process by promoting a pro-atherogenic phenotype in monocytes and monocyte-derived monocytes (MDMs). A cross-linked collagen peptide mimetic (CRP-XL) was used to specifically activate platelets and monocytes were subsequently isolated and cultured using a methodology developed to minimise platelet contamination and iatrogenic activation. Activated platelets were shown to induce the formation of CD16pos monocytes from the previously CD16neg classical subset. This was accompanied by surface integrin (ICAM1, CD11b) and chemokine receptor expression (CXCR1, CXCR6) consistent with a pro-inflammatory phenotype. Platelets also induced the formation of intracellular lipid droplets in circulating monocytes and subsequently increased foam cells in MDMs which was dependent on the formation of monocyte-platelet aggregates (MPAs). This was shown to be as a result of both dysregulated cholesterol metabolism in MDMs and increased ingestion of platelets by monocytes. The in-vivo relevance of these findings were assessed in the FOAMI study, an observation, laboratory-based study of patients with non ST-elevation Myocardial Infarction (NSTEMI). Many of the in-vitro findings were recapitulated in patients within the first 24hrs of an MI, with increased intracellular lipid droplets, increased pro-inflammatory CD16pos monocyte subset and increased formation of foam cells above that seen in age-matched controls (AMC). Novel evidence is therefore provided to show that platelets induce a pro-atherogenic phenotype in monocytes and promote foam cell formation in MDMs. This has potentially important implications in the management of coronary artery disease (CAD) and might provide new therapeutic insights

Comparison of the Release of microRNA and extracellular vescicles from platelets in response to different agonists

On activation platelets release microRNA and extracellular vesicles (EV) into the circulation. The release of EV from platelets has been shown to be dependent on the agonist; here we investigated whether the microRNA profile or EV released from platelets was also agonist specific. Washed platelets from healthy subjects were maximally stimulated with agonists specific for the receptors for collagen (GPVI), thrombin (PAR1/PAR4), or ADP (P2Y1/P2Y12) with/without inhibiting secondary mediators, using aspirin to block COX-1 and apyrase to remove ADP. The released microRNA was profiled using TaqMan microRNA microarray cards. Platelet-derived EV (pdEV) were characterised by size (Nanoparticle Tracking Analysis; NTA), for procoagulant activity (Annexin-V binding and support of thrombin generation), and for the EV markers CD63 and HSP70. Platelet activation triggered the release of 57-79 different microRNA, dependent upon agonist, with a core of 46 microRNA observed with all agonists. There was a high level of correlation between agonists (r >0.98; p<0.0001 for all), and with the microRNA content of the parent platelets (r2 >0.98; p<0.0001). The 46 microRNA seen in all samples are predicted to have significant effects on the translation of proteins involved in endocytosis, cell cycle control and differentiation. MiR-223-3p was most abundant in all samples and has previously been implicated in myeloid lineage development and demonstrated to have antiinflammatory effects. Stimulation through GPVI produced a pdEV population with significantly more procoagulant activity than the other agonists. Apyrase significantly reduced microRNA and pdEV release, while aspirin had little effect. These data suggest that all tested agonists trigger the release of a similar microRNA profile whilst the procoagulant activity of the pdEV was agonist dependent. ADP was shown to play an important role in the release of both microRNA and pdEV

Comparison of the release of microRNAs and extracellular vesicles from platelets in response to different agonists

<p>On activation platelets release microRNAs and extracellular vesicles (EV) into circulation. The release of EV from platelets has been shown to be dependent on the agonist; in this study, we investigated whether the microRNA profile or EV released from platelets was also agonist specific.</p> <p>Washed platelets from healthy subjects were maximally stimulated with agonists specific for the receptors for collagen (Glycoprotein VI (GPVI)), thrombin (PAR1/PAR4), or ADP (P2Y1/P2Y12) with/without inhibiting secondary mediators, using aspirin to block cyclooxygenase-1 and apyrase to remove ADP. The released microRNAs were profiled using TaqMan microRNA microarray cards. Platelet-derived EV (pdEV) were characterized by size (Nanoparticle Tracking Analysis, NTA), for procoagulant activity (Annexin-V binding and support of thrombin generation), and for the EV markers CD63 and HSP70.</p> <p>Platelet activation triggered the release of 57–79 different microRNAs, dependent upon agonist, with a core of 46 microRNAs observed with all agonists. There was a high level of correlation between agonists (<i>r</i>² > 0.98; <i>p</i> < 0.0001 for all), and with the microRNA content of the parent platelets (<i>r</i>² > 0.98; <i>p</i> < 0.0001). The 46 microRNAs seen in all samples are predicted to have significant effects on the translation of proteins involved in endocytosis, cell cycle control, and differentiation. MiR-223-3p was the most abundant in all samples and has previously been implicated in myeloid lineage development and demonstrated to have anti-inflammatory effects. Stimulation through GPVI produced a pdEV population with significantly more procoagulant activity than the other agonists. Apyrase significantly reduced microRNA and pdEV release, while aspirin had little effect.</p> <p>These data suggest that all tested agonists trigger the release of a similar microRNA profile while the procoagulant activity of the pdEV was agonist dependent. ADP was shown to play an important role in the release of both microRNAs and pdEV.</p