Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction.

Antiplatelet medication is standard of care in acute myocardial infarction (AMI). However, it may have obscured beneficial properties of the activated platelet secretome. We identify platelets as major source of a sphingosine-1-phosphate (S1P) burst during AMI, and find its magnitude to favorably associate with cardiovascular mortality and infarct size in STEMI patients over 12 months. Experimentally, administration of supernatant from activated platelets reduces infarct size in murine AMI, which is blunted in platelets deficient for S1P export (Mfsd2b) or production (Sphk1) and in mice deficient for cardiomyocyte S1P receptor 1 (S1P1). Our study reveals an exploitable therapeutic window in antiplatelet therapy in AMI as the GPIIb/IIIa antagonist tirofiban preserves S1P release and cardioprotection, whereas the P2Y12 antagonist cangrelor does not. Here, we report that platelet-mediated intrinsic cardioprotection is an exciting therapeutic paradigm reaching beyond AMI, the benefits of which may need to be considered in all antiplatelet therapies.

Optogenetic activation of mGluR1 signaling in the cerebellum induces synaptic plasticity.

Neuronal plasticity underlying cerebellar learning behavior is strongly associated with type 1 metabotropic glutamate receptor (mGluR1) signaling. Activation of mGluR1 leads to activation of the Gq/11 pathway, which is involved in inducing synaptic plasticity at the parallel fiber-Purkinje cell synapse (PF-PC) in form of long-term depression (LTD). To optogenetically modulate mGluR1 signaling we fused mouse melanopsin (OPN4) that activates the Gq/11 pathway to the C-termini of mGluR1 splice variants (OPN4-mGluR1a and OPN4-mGluR1b). Activation of both OPN4-mGluR1 variants showed robust Ca2+ increase in HEK cells and PCs of cerebellar slices. We provide the prove-of-concept approach to modulate synaptic plasticity via optogenetic activation of OPN4-mGluR1a inducing LTD at the PF-PC synapse in vitro. Moreover, we demonstrate that light activation of mGluR1a signaling pathway by OPN4-mGluR1a in PCs leads to an increase in intrinsic activity of PCs in vivo and improved cerebellum driven learning behavior.

Sphingosine-1-phosphate improves outcome of no-reflow acute myocardial infarction via sphingosine-1-phosphate receptor 1.

AIMS: Therapeutic options targeting post-ischaemic cardiac remodelling are sparse. The bioactive sphingolipid sphingosine-1-phosphate (S1P) reduces ischaemia/reperfusion injury. However, its impact on post-ischaemic remodelling independently of its infarct size (IS)-reducing effect is yet unknown and was addressed in this study. METHODS AND RESULTS: Acute myocardial infarction (AMI) in mice was induced by permanent ligation of the left anterior descending artery (LAD). C57Bl6 were treated with the S1P lyase inhibitor 4-deoxypyridoxine (DOP) starting 7 days prior to AMI to increase endogenous S1P concentrations. Cardiac function and myocardial healing were assessed by cardiovascular magnetic resonance imaging (cMRI), murine echocardiography, histomorphology, and gene expression analysis. DOP effects were investigated in cardiomyocyte-specific S1P receptor 1 deficient (S1PR1 Cardio Cre+) and Cre- control mice and S1P concentrations measured by LC-MS/MS. IS and cardiac function did not differ between control and DOP-treated groups on day one after LAD-ligation despite fourfold increase in plasma S1P. In contrast, cardiac function was clearly improved and myocardial scar size reduced, respectively, on Day 21 in DOP-treated mice. The latter also exhibited smaller cardiomyocyte size and reduced embryonic gene expression. The benefit of DOP treatment was abolished in S1PR1 Cardio Cre+. CONCLUSIONS: S1P improves cardiac function and myocardial healing post AMI independently of initial infarct size and accomplishes this via the cardiomyocyte S1PR1. Hence, in addition to its beneficial effects on I/R injury, S1PR1 may be a promising target in post-infarction myocardial remodelling as adjunctive therapy to revascularization as well as in patients not eligible for standard interventional procedures.

Risk prediction of bleeding and MACCE by PRECISE-DAPT score post-PCI.

BACKGROUND: Guidelines recommend the PRECISE-DAPT (PD) score to adapt duration of dual antiplatelet therapy due to bleeding risk. However, there is first evidence that PD predicts mortality and ischemic events as well. METHODS: We investigated PD Score in 994 patients after percutaneous coronary intervention (PCI). PD was correlated with clinically frequently used scores. Major adverse cardiac and cerebrovascular events (MACCE) and Thrombolysis in Myocardial Infarction (TIMI) bleeding were assessed during one-year follow-up. RESULTS: 524 patients had PD < 25 and 470 patients PD ≥ 25 (47%). Rate of major and minor bleeding was higher in the PD ≥ 25 group (major bleeding: Hazard ratio [HR] 2.9, 95% confidence interval [Cl] 1.01-8.16, p = 0.049; minor bleeding: HR 3.94, 95% Cl 1.36-9.19, p = 0.0096). Rate of MACCE, death and myocardial infarction were higher as well (MACCE: HR 2.0, 95% Cl 1.52-2.71, p < 0.0001; death: HR 3.9, 95% Cl 2.12-5.68, p < 0.0001; MI: HR 2.1, 95% Cl 1.26-3.43, p = 0.0041). Rate of stroke/transient ischemic attack did not differ between groups. Discriminative potency to predict major and minor bleeding, MACCE, death and MI were high with nearly equal cut-off values calculated by Youden's index (YI) (major bleeding: Area under the curve [AUC] 0.66; p = 0.026; YI 32; minor bleeding: AUC 0.72; p = 0.001; YI 28; MACCE: AUC 0.62; p < 0.0001; YI 24). CONCLUSION: In our cohort, PD score predicted bleeding moderately in post-PCI patients. In this study, ischemic events were predicted as well. Adaption of antiplatelet therapy duration by PD score is accurate. Nevertheless, it should be well-balanced with patient-related risk for ischemic events.