Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation

Background: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role. Methods: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1-/-) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro. Results: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1-/- mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease IIbβ3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (IIbβ3) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.Fil: Senchenkova, Elena Y.. State University of Louisiana; Estados UnidosFil: Ansari, Junaid. State University of Louisiana; Estados UnidosFil: Becker, Felix. University Hospital Muenster; AlemaniaFil: Vital, Shantel A.. State University of Louisiana; Estados UnidosFil: Al-Yafeai, Zaki. State University of Louisiana; Estados UnidosFil: Sparkenbaugh, Erica M.. University North Carolina Chapel Hill; Estados UnidosFil: Pawlinski, Rafal. University North Carolina Chapel Hill; Estados UnidosFil: Stokes, Karen Y.. State University of Louisiana; Estados UnidosFil: Carroll, Jennifer L.. State University of Louisiana; Estados UnidosFil: Dragoi, Ana-Maria. State University of Louisiana; Estados UnidosFil: Qin, Cheng Xue. Baker Heart And Diabetes Institute; AustraliaFil: Ritchie, Rebecca H.. Baker Heart And Diabetes Institute; AustraliaFil: Sun, Hai. University Hospital Muenster; AlemaniaFil: Cuellar-Saenz, Hugo H.. State University of Louisiana; Estados UnidosFil: Rubinstein Guichon, Mara Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Columbia University; Estados UnidosFil: Han, Yiping W.. Columbia University; Estados UnidosFil: Orr, A. Wayne. University Hospital Muenster; AlemaniaFil: Perretti, Mauro. Queen Mary University Of London; Reino UnidoFil: Granger, D. Neil. State University of Louisiana; Estados UnidosFil: Gavins, Felicity N.E.. State University of Louisiana; Estados Unido

Adverse events related to AtriCure EPi-Sense Coagulation Device-Analysis of the FDA MAUDE database

INTRODUCTION: The AtriCure EPi-Sense Device is used for the hybrid convergent procedure, an emerging treatment for persistent atrial fibrillation (AF) and long-standing persistent AF. However, data on the AE related to the EPi-Sense device are scarce. METHODS: Keyword EPI-SENSE was searched on the MAUDE database. There were 80 device reports from 2016 to 2020. After excluding reports when the device was not returned for evaluation, 79 device reports were included for final analysis. RESULTS: The adverse events (AE) were broadly classified into 11 categories. The most common complications were pericardial effusion (25.3%), stroke (17.7%), and atrioesophageal fistula (AEF) (8.9%). Death was reported in 15 (19%) cases, 3 of which were due to pulmonary embolism, 6 due to AEF, 3 due to unknown cause, 1 due to sepsis, 2 due to events related to acute renal failure. DISCUSSION: Pericardial effusion is a common AE reported in patients with convergence procedures and is well documented in the CONVERGE trial. The convergent procedure is unique in that the epicardial ablations are performed on the posterior wall with the radiofrequency probe directed towards the heart and away from the esophagus which in theory should reduce esophageal injuries. Despite that, a high number of AEF were noticed. Finally, there were also some reports of saline perfusion malfunction which can lead to injuries due to overheating. CONCLUSION: This analysis of the AE related to the EPi-Sense device highlights several major AE that are previously unreported

Decreased bioavailability of hydrogen sulfide links vascular endothelium and atrial remodeling in atrial fibrillation

Oxidative stress drives the pathogenesis of atrial fibrillation (AF), the most common arrhythmia. In the cardiovascular system, cystathionine γ-lyase (CSE) serves as the primary enzyme producing hydrogen sulfide (HS), a mammalian gasotransmitter that reduces oxidative stress. Using a case control study design in patients with and without AF and a mouse model of CSE knockout (CSE-KO), we evaluated the role of HS in the etiology of AF. Patients with AF (n = 51) had significantly reduced plasma acid labile sulfide levels compared to patients without AF (n = 65). In addition, patients with persistent AF (n = 25) showed lower plasma free sulfide levels compared to patients with paroxysmal AF (n = 26). Consistent with an important role for HS in AF, CSE-KO mice had decreased atrial sulfide levels, increased atrial superoxide levels, and enhanced propensity for induced persistent AF compared to wild type (WT) mice. Rescuing HS signaling in CSE-KO mice by Diallyl trisulfide (DATS) supplementation or reconstitution with endothelial cell specific CSE over-expression significantly reduced atrial superoxide, increased sulfide levels, and lowered AF inducibility. Lastly, low HS levels in CSE KO mice was associated with atrial electrical remodeling including longer effective refractory periods, slower conduction velocity, increased myocyte calcium sparks, and increased myocyte action potential duration that were reversed by DATS supplementation or endothelial CSE overexpression. Our findings demonstrate an important role of CSE and HS bioavailability in regulating electrical remodeling and susceptibility to AF