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Cardiovascular diseases are a major cause of mortality and morbidity in the developed countries. Anti-platelet therapy is a cornerstone treatment for patients with cardiovascular diseases. Patients are routinely managed with a combination therapy consisting of aspirin and clopidogrel. Aspirin inhibits cyclooxygenase 1 (COX 1) a crucial intermediate enzyme involved in thromboxane biosynthesis. Clopidogrel on the other hand antagonizes ADP receptor P2Y12. ADP is a weak platelet agonist stored in platelet dense granules and is released upon platelet activation. ADP activates platelets through two purinergic receptors namely P2Y1 and P2Y12 these receptors couple to Gq and Gi class of G-proteins, respectively. P2Y1 causes calcium mobilization through activation of PLC-β. P2Y12 inhibits adenylyl cyclase, causes activation of Rap1B and Akt. Signaling from both the receptors is required for complete integrin activation, thromboxane generation and Erk activation. Previous studies have shown that P2Y12 potentiates fibrinogen receptor activation, secretion, thrombi stabilization, thrombin generation, platelet leukocyte aggregation formation. ThromboxaneA2 (TXA2) is a potent platelet agonist generated through arachidonic acid metabolism in platelets. TXA2 thus, generated after platelet activation acts as a positive feedback mediator along with ADP. Under physiological conditions, platelet activation leads to thrombin generation through coagulation cascades. Generated thrombin activates PAR receptors and ADP is released from dense granules, which further potentiates thromboxane generation downstream of PARs. Current anti-platelet therapy regimens often include P2Y12 antagonists and aspirin in management of patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI) with stent implantation. However, there still exists a need for improved treatment strategies as not all patients benefit from this dual combination therapy. Reasons include, poor responders either to P2Y12 antagonists or to aspirin, or if aspirin is contraindicated in these patient populations. In the current study we evaluated the role of P2Y12 in thromboxane generation under physiological conditions. We studied serum thromboxane generation in a model system wherein P2Y12 was antagonized or deficient. Using pharmacological approaches we show that dosing mice with 30mg/Kg/body weight clopidogrel or 3mg/Kg/body weight prasugrel decreased serum thromboxane levels when compared to the control mice. Pre-treatment of human blood ex vivo with active metabolites of clopidogrel (R361015) or prasugrel (R138727) also led to reduction in thromboxane levels. We also evaluated serum thromboxane levels in P2Y receptor null mice, serum thromboxane levels in P2Y1 null mice were similar to those in wild type littermates, and were inhibited in P2Y12 null mice. Furthermore, serum thromboxane levels in P2Y12 deficient patients, previously described in France and Japan, were also evaluated and these patients had lower serum thromboxane levels compared to normal controls. In a pilot study, serum thromboxane levels were radically reduced in healthy human volunteers upon dosing with clopidogrel, compared to the levels before dosing. In conclusion, P2Y12 antagonism alone can decrease physiological thromboxane levels. Thus P2Y12 regulates physiological thromboxane levels. Further it is known that ADP-induced thromboxane generation is integrin-dependent. However it is not clear if other potent platelet agonists like thrombin require outside-in signaling for thromboxane generation. Our results show that thrombin-induced thromboxane generation was independent of integrins i.e. when platelets were stimulated with PAR agonists in presence of fibrinogen receptor antagonist thromboxane generation was not affected. Since PAR agonists, unlike ADP, activate G12/13 signaling pathways. Hence, we hypothesized that these pathways might play a role in TXA2 generation. Our results show, that inhibition of ADP-induced thromboxane generation by fibrinogen receptor antagonist SC57101 was rescued by costimulation of G12/13 pathways with YFLLRNP. This observation suggested an existence of a common signaling effector downstream of integrins and G12/13 pathways. Next, we evaluated role of three potential tyrosine kinases; c-Src, Syk and FAK (Focal Adhesion Kinase) that are known to be activated by integrins. Our results showed that c-Src and Syk kinase did not play a role in ADP-induced functional responses in platelets. We observed differential activation of FAK downstream of integrins and G12/13 pathways. ADP-induced activation of FAK was integrindependent and SFK-independent. On the other hand selective activation of G12/13 pathway lead to FAK activation, in SFK and Rho dependent manner. We also evaluated specificity of new FAK inhibitor TAE-226 to understand the role of FAK in TXA2 generation. Our results showed that TAE-226 exhibited non-specific effects at higher concentrations. Furthermore, in comparison to WT mice, FAK null mice did not show any difference in TXA2 generation. Therefore, we concluded that differential activation of FAK occurs downstream of Integrins and G12/13 pathways. However, the common effector molecule downstream of integrins and G12/ 13 pathways contributing to TXA2 generation in platelets remains elusive. / Molecular and Cellular Physiology

Background: In the last decade, flow diversion (FD) has been established as hemodynamic treatment for cerebral aneurysms arising from proximal and distal cerebral arteries. However, two significant limitations remain—the need for 0.027” microcatheters required for delivery of most flow diverting stents (FDS), and long-term dual anti-platelet therapy (DAPT) in order to prevent FDS-associated thromboembolism, at the cost of increasing the risk for hemorrhage. This study reports the experience of three neurovascular centers with the p64MW-HPC, a FDS with anti-thrombotic coating that is implantable via a 0.021” microcatheter. Materials and methods: Three neurovascular centers contributed to this retrospective analysis of patients that had been treated with the p64MW-HPC between March 2020 and March 2021. Clinical data, aneurysm characteristics, and follow-up results, including procedural and post-procedural complications, were recorded. The hemodynamic effect was assessed using the O’Kelly–Marotta Scale (OKM). Results: Thirty-two patients (22 female, mean age 57.1 years) with 33 aneurysms (27 anterior circulation and six posterior circulation) were successfully treated with the p64MW-HPC. In 30/32 patients (93.75%), aneurysmal perfusion was significantly reduced immediately post implantation. Follow-up imaging was available for 23 aneurysms. Delayed aneurysm perfusion (OKM A3: 8.7%), reduction in aneurysm size (OKM B1-3: 26.1%), or sufficient separation from the parent vessel (OKM C1-3 and D1: 65.2%) was demonstrated at the last available follow-up after a mean of 5.9 months. In two cases, device thrombosis after early discontinuation of DAPT occurred. One delayed rupture caused a caroticocavernous fistula. The complications were treated sufficiently and all patients recovered without permanent significant morbidity. Conclusion: Treatment with the p64MW-HPC is safe and feasible and achieves good early aneurysm occlusion rates in the proximal intracranial circulation, which are comparable to those of well-established FDS. Sudden interruption of DAPT in the early post-interventional phase can cause in-stent thrombosis despite the HPC surface modification. Deliverability via the 0.021” microcatheter facilitates treatment in challenging vascular anatomies.

Purpose of Review: To review the clinical evidence on the use of percutaneous coronary intervention (PCI) revascularization options in left main (LM) disease in comparison with coronary artery bypass graft (CABG). Coronary artery disease (CAD) involving the LM is associated with high morbidity and mortality. Though CABG remains the gold standard for complex CAD involving the LM artery, recent trials have shown a trend towards non-inferiority of the LM PCI when compared with CABG in certain subset of patients. Recent Findings: Two recent major randomized trials compared the outcomes of PCI versus CABG in the LM and multi-vessel disease with LM involvement. The NOBLE trial included patients with all range of Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) scores and utilized biolimus drug-eluting stent (DES). The trial concluded that MACCE (major adverse cardiac and cerebrovascular event) was significantly higher with PCI (28%) when compared with CABG (18%) but overall stroke and motility were not different. EXCEL trial evaluated the same treatment option in low to intermediate SYNTAX score population with third-generation everolimus DES platform as PCI option. Results showed no significant differences in the composite primary endpoints of death, stroke, and myocardial infarction (MI) at the end of 30 days (22% versus 19.2%, p = 0.13), although repeat revascularization was higher in PCI group (16.9% versus 10%). Summary: Recent evidence suggests that PCI is an acceptable alternative to treat symptomatic LM stenosis in select group of patients. In low to medium SYNTAX score, particularly in patients without diabetes mellitus, PCI remains a viable option. Future trials focusing on evaluating subset of patients who would benefit from one particular revascularization option in comparison with other is warranted.