Flierl et al. show that phosphorothioate (PS) oligonucleotides activate platelets via interacting with the collagen receptor GPVI. As PS backbone modification is currently used for nucleotide-based drug candidates, the findings suggest that this widely used method may present a risk to patients in the form of arterial thrombosis.

Background: Limited progress has been made in the management of cardiogenic shock (CS). Morbidity and mortality of refractory CS remain high. The effects of mechanical circulatory support (MCS) are promising, although many aspects are elusive. We evaluated efficacy and safety of early combined MCS (Impella microaxial pump + venoarterial extracorporeal membrane oxygenation [VA-ECMO]) in refractory CS and aimed to determine factors for decision-making in combined MCS. Methods and Results: We analyzed 69 consecutive patients with refractory CS from our registry requiring combined MCS. In 12 cases, therapy was actively withdrawn according to patient’s will. Patients were severely sick (Survival After Venoarterial ECMO score mean±SD, –8.9±4.4) predicting 30% in-hospital survival; ventilation 94%, dialysis 56%. Impella pumps and VA-ECMO were combined early (duration of combined MCS: median 94 hours; interquartile range, 49–150 hours). Early MCS escalation stabilized patients rapidly, reducing number and doses of catecholamines ( P <0.05 versus baseline) while hemodynamics improved. Reflecting an improved microcirculation, lactate levels normalized within 24 hours ( P <0.05 versus baseline). Despite refractory CS and disease severity, survival was favorable (on MCS 61%, 30 days 49%, 6 months 40%). In multivariate Cox-regression, duration of shock-to-first device (hours, hazard ratio, 1.05 [95% CI, 1.01–1.08]; P =0.007) and lactate levels after 12 hours of MCS (hazard ratio, 1.28 [95% CI, 1.09–1.51]; P =0.002) independently predicted survival. Additional right ventricular failure predisposed to futility (hazard ratio, 8.48 [95% CI, 1.85–38.91]; P =0.006). Conclusions: The early and consequent combination of MCS by Impella microaxial pumps and VA-ECMO enables stabilization and may rescue high-risk patients with refractory CS at low overall risk. Independent predictors of survival may guide prognostication, decision-making, and allocation of medical resources.

Background and purpose: Diabetes-associated vascular dysfunction contributes to increased cardiovascular risk. We investigated whether the phosphodiesterase-5 inhibitor sildenafil would improve vascular function in diabetic rats. Experimental approach: Male Wistar rats were injected with streptozotocin (50 mg kg -1 , i.v.) to induce insulin-deficient diabetes. Direct effects of sildenafil as well as modification of endothelium-dependent and -independent vasorelaxation were investigated in vitro. The effects of acute and chronic (2 week) treatment in vivo of sildenafil on vascular function were also characterized in isolated aortic segments in organ bath chambers 4 weeks after diabetes induction. Key results: Sildenafil induced a concentration-dependent vasorelaxation, which was attenuated by the nitric oxide (NO) synthase inhibitor, N G -nitro-L-arginine. Acetylcholine-induced endothelium-dependent as well as endothelium-independent relaxation induced by the NO donor, DEA-NONOate, was significantly reduced in aortae from diabetic rats. Incubation with sildenafil in vitro normalized both endothelium-dependent and -independent relaxation in aortae from diabetic rats. Acute as well as chronic in vivo treatment with sildenafil resulted in enhanced endothelium-dependent and -independent vasorelaxation. Superoxide formation was increased in diabetes, associated with enhanced membrane expression of the NAD(P)H oxidase subunit gp91 phox and Rac, which were both reduced by chronic treatment with sildenafil. Conclusions and implications:We demonstrate that sildenafil treatment rapidly and chronically improves vascular relaxation in diabetic rats. Treatment with sildenafil might provide a similarly beneficial effect in diabetic patients.

Background The chemokine fractalkine, CX3CL1, bears unique features within the chemokine family: it exists in a membrane bound form acting as an adhesion molecule and surface receptor; however, when cleaved by ADAM 10, it functions as a soluble chemokine. Fractalkine and its chemokine receptor CX3CR1 are known to have multiple roles in diverse human diseases, for example inflammatory diseases, rheumatoid arthritis, renal diseases and atherosclerosis.