Background— The Nordic Aortic Valve Intervention (NOTION) trial was the first to randomize all-comers with severe native aortic valve stenosis to either transcatheter aortic valve replacement (TAVR) with the CoreValve self-expanding bioprosthesis or surgical aortic valve replacement (SAVR), including a lower-risk patient population than previous trials. This article reports 2-year clinical and echocardiographic outcomes from the NOTION trial. Methods and Results— Two-hundred eighty patients from 3 centers in Denmark and Sweden were randomized to either TAVR (n=145) or SAVR (n=135) with follow-up planned for 5 years. There was no difference in all-cause mortality at 2 years between TAVR and SAVR (8.0% versus 9.8%, respectively; P =0.54) or cardiovascular mortality (6.5% versus 9.1%; P =0.40). The composite outcome of all-cause mortality, stroke, or myocardial infarction was also similar (15.8% versus 18.8%, P =0.43). Forward-flow hemodynamics were improved following both procedures, with effective orifice area significantly more improved after TAVR than SAVR (effective orifice area, 1.7 versus 1.4 cm 2 at 3 months). Mean valve gradients were similar after TAVR and SAVR. When patients were categorized according to Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) (<4% versus ≥4%), there was no statistically significant difference for TAVR and SAVR groups in the composite outcome for low-risk (14.7%, 95% confidence interval, 8.3–21.2 versus 16.8%; 95% confidence interval, 9.7–23.8; P =0.58) or intermediate-risk patients (21.1% versus 27.1%; P =0.59). Conclusions— Two-year results from the NOTION trial demonstrate the continuing safety and effectiveness of TAVR in lower-risk patients. Longer-term data are needed to verify the durability of this procedure in this patient population. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01057173.

Aspirin, an anti-inflammatory and antithrombotic drug, has become the focus of intense research as a potential anticancer agent owing to its ability to reduce tumor proliferation in vitro and to prevent tumorigenesis in patients. Studies have found an anticancer effect of aspirin when used in low, antiplatelet doses. However, the mechanisms through which low-dose aspirin works are poorly understood. In this study, we aimed to determine the effect of aspirin on the cross talk between platelets and cancer cells. For our study, we used two colon cancer cell lines isolated from the same donor but characterized by different metastatic potential, SW480 (nonmetastatic) and SW620 (metastatic) cancer cells, and a pancreatic cancer cell line, PANC-1 (nonmetastatic). We found that SW480 and PANC-1 cancer cell proliferation was potentiated by human platelets in a manner dependent on the upregulation and activation of the oncoprotein c-MYC. The ability of platelets to upregulate c-MYC and cancer cell proliferation was reversed by an antiplatelet concentration of aspirin. In conclusion, we show for the first time that inhibition of platelets by aspirin can affect their ability to induce cancer cell proliferation through the modulation of the c-MYC oncoprotein.

This study examines mechanisms by which changes in tissue oxygen tension elicit vasomotor responses and whether localized changes in oxygen tension initiates conducted vasomotor responses in mouse cremaster arterioles. Intravital microscopy was used to visualize the mouse cremaster microcirculation. The cremaster was superfused with Krebs' solution with different oxygen tensions, and a gas exchange chamber was used to induce localized changes in oxygen tension. In arterioles where red blood cells were removed by buffer perfusion, arterioles responded with same magnitudes of vasodilatation (DeltaD = 16.0 +/- 4.9 microm) when changing from high (PO(2) = 242.5 +/- 13.3 mm Hg) to low (PO(2) = 22.5 +/- 4.8 mm Hg) oxygen tension as seen in the intact cremaster circulation (DeltaD = 18.7 +/- 1.0 microm). Blockade of NO synthases by L: -NAME and adenosine receptors by DPCPX had no effects on vasomotor responses to low or high oxygen. Induction of localized low (PO(2) = 23.3 +/- 5.7 mmHg) or high (PO(2) = 300.0 +/- 25.7 mm Hg) oxygen tension caused vasodilatation or -constriction locally and at a site 1,000 microm upstream (distantly). Glibenclamide blocker of ATP-sensitive K(+) channels inhibited vasodilatation and -constriction to low (PO(2) = 16.0 +/- 6.4 mm Hg) and high (PO(2) = 337.4 +/- 12.8 mm Hg) oxygen tension. 1) ATP-sensitive K(+) channels seem to mediate, at least in part, vasodilatation and vasoconstriction to low and high oxygen tension; 2) Red blood cells are not necessary for inducing vasodilatation and vasoconstriction to low or high oxygen tension; 3) localized changes in the oxygen tension cause vasomotor responses, which are conducted upstream along arterioles in mouse cremaster microcirculation.

BackgroundATP-sensitive K+ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca2+ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO2.ResultsChange from “high” oxygen tension (PO2 = 153.4 ± 3.4 mmHg) to “low” oxygen tension (PO2 = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 μm to 32.9 ± 0.9 μm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca2+ channels using 3 μM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO2. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO2, but had no effect on dilation to low PO2.ConclusionsWe conclude that: 1) L-type Ca2+ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO2.

Background: Human coagulation factor (F) XI deficiency, a defect of the contact activation system, protects against venous thrombosis, stroke, and heart attack, whereas FXII, plasma prekallikrein, or kininogen deficiencies are asymptomatic. FXI deficiency, inhibition of FXI production, activated FXI (FXIa) inhibitors, and antibodies to FXI that interfere with FXI/FXII interactions reduce experimental thrombosis and inflammation. FXI inhibitors are antithrombotic in patients, and FXI and FXII deficiencies are atheroprotective in apolipoprotein E-deficient mice. Objectives: Investigate the effects of pharmacological targeting of FXI in experimental models of atherogenesis and established atherosclerosis. Methods and Results: Low-density lipoprotein receptor-knockout (Ldlr −/−) mice were administered high-fat diet (HFD) for 8 weeks; concomitantly, FXI was targeted with anti-FXI antibody (14E11) or FXI antisense oligonucleotide (ASO). 14E11 and FXI-ASO reduced atherosclerotic lesion area in proximal aortas when compared with controls, and 14E11 also reduced aortic sinus lesions. In an established disease model, in which therapy was given after atherosclerosis had developed, Ldlr −/− mice were fed HFD for 8 weeks and then administered 14E11 or FXI-ASO weekly until 16 weeks on HFD. In this established disease model, 14E11 and FXI-ASO reduced atherosclerotic lesion area in proximal aortas, but not in aortic sinus. In cultures of human endothelium, FXIa exposure disrupted VE-Cadherin expression and increased endothelial lipoprotein permeability. Strikingly, we found that 14E11 prevented the disruption of VE-Cadherin expression in aortic sinus lesions observed in the atherogenesis mouse model. Conclusion: Pharmacological targeting of FXI reduced atherogenesis in Ldlr −/− mice.

Patients undergoing SAVR had a larger LV mass regression at 1 year compared with patients undergoing TAVR, which may be due to increasing amounts of PVL and pacemakers in the TAVR group.

Spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating ITAM-mediated signaling downstream of platelet glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK have been developed as anti-neoplastic and anti-inflammatory therapeutics and have also gained interest as anti-platelet agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. These inhibitors include, four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659, four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib), and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to collagen, dense granule secretion, and alpha granule secretion in response to the GPVI agonist CRP-XL. Similarly, these TKIs reduced the percentage of activated integrin αIIbβ3 on the platelet surface in response to CRP-XL, as determined by PAC-1 binding. While all TKIs tested inhibited PLCγ2 phosphorylation following GPVI-mediated activation, other downstream signaling events proximal to PI3K and PKC were differentially affected. In addition, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered the organization of PI3K around microtubules during platelets spreading on fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.

Despite the transient hyporeactivity of neonatal platelets, full-term neonates do not display a bleeding tendency, suggesting potential compensatory mechanisms which allow for balanced and efficient neonatal hemostasis. This study aimed to utilize small-volume, whole blood platelet functional assays to assess the neonatal platelet response downstream of the hemostatic platelet agonists thrombin and ADP. Thrombin activates platelets via the protease-activated receptors (PARs) 1 and 4, whereas ADP signals via the receptors P2Y 1 and P2Y 12 as a positive feedback mediator of platelet activation. We observed that neonatal and cord blood-derived platelets exhibited diminished PAR1-mediated granule secretion and integrin activation relative to adult platelets, correlating to reduced PAR1 expression by neonatal platelets. PAR4-mediated granule secretion was blunted in neonatal platelets, correlating to lower PAR4 expression as compared to adult platelets, while PAR-4 mediated GPIIb/IIIa activation was similar between neonatal and