Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice

Aims: Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPase regulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation, actin cytoskeleton organization and monocyte adhesion. We investigated the vascular effects of pharmacological inhibition of Rac1 GTPase in mice. Methods and Results: We treated wild-type and apolipoprotein E-deficient (ApoE−/−) mice with Clostridium sordellii lethal toxin (LT), a Rac1 inhibitor, and assessed vascular oxidative stress, expression and activity of involved proteins, endothelial function, macrophage infiltration, and atherosclerosis development. LT-treated wild-type mice displayed decreased vascular NADPH oxidase activity and ROS production. Therapeutic LT doses had no impact on behavior, food intake, body weight, heart rate, blood pressure, vascular and myocardial function, differential blood count, and vascular permeability. ApoE−/− mice were fed a cholesterol-rich diet and were treated with LT or vehicle. LT treatment led to decreased aortic Rac1 GTPase activity, NADPH oxidase activity and ROS production, but had no impact on expression and membrane translocation of NADPH oxidase subunits and RhoA GTPase activity. LT-treated mice showed improved aortic endothelium-dependent vasodilation, attenuated atherosclerotic lesion formation and reduced macrophage infiltration of atherosclerotic plaques. Concomitant treatment of cholesterol-fed ApoE−/− mice with LT, the specific synthetic Rac1 inhibitor NSC 23766 or simvastatin comparably reduced aortic Rac1 activity, NADPH oxidase activity, oxidative stress, endothelial dysfunction, atherosclerosis development, and macrophage infiltration. Conclusions: These findings identify an important role of the small GTPase Rac1 in atherogenesis and provide a potential target for anti-atherosclerotic therapy

Effects of cardiovascular single pill combinations compared with identical multi-pill therapies on healthcare cost and utilization in Germany

Aim: This study assessed whether a single pill combination (SPC) is associated with lower direct healthcare costs. Materials & methods: Anonymized claims data of patients ≥18 years treated with drugs for cardiovascular (CV)-related diseases either as a single pill combination or multi-pill combination (followup to 1 year) were evaluated. After propensity score matching, 59,336 out of 1,369,840 patients were analyzed. Results: In all cohorts, patients receiving a single pill combination had a lower frequency of general practitioner and specialist visits. The patients also had a significantly lower ratio of all-cause hospitalization days and number of CV-related prescriptions as well as all-cause prescriptions (with one exception) compared with those receiving a multi-pill combination. Conclusion: Direct CV-related costs were significantly lower in four out of seven comparisons, with a trend toward lower costs in the other three comparisons

2023 ESC Guidelines for the management of acute coronary syndromes.

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Angiotensin II Type 1 Receptor Antagonism Improves

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Prospective clinical evaluation of chairside-fabricated zirconia-reinforced lithium silicate ceramic partial crowns—5-year results

Objectives!#!A university-based randomized clinical study evaluated the 5-year performance of chairside-fabricated zirconia-reinforced lithium silicate (ZLS)-ceramic partial crowns.!##!Material and methods!#!Forty-five patients were restored with 61 chairside-fabricated ZLS-restorations (Cerec SW 4.2, Dentsply Sirona, Germany; Vita Suprinity, Vita Zahnfabrik, Germany). Deviating from the manufacturers' recommendations, restorations with reduced minimum material thicknesses (MMT) were fabricated: group 1, MMT = 0.5-0.74 mm (n = 31); group 2, MMT = 0.75-1.0 mm (n = 30). For luting, a self-adhesive cement (SAC) or a total-etch technique with a composite cement (TEC) was applied. Statistical evaluation was performed by time-to-event analysis (Kaplan-Meier). Possible covariates of the survival (SVR) and success rates (SCR), evaluated in a Cox regression model, were MMT, restoration position (premolar/molar), and cementation technique (SAC vs. TEC).!##!Results!#!Forty patients (54 restorations, premolars, n = 23; molars, n = 31) participated in the 5-year follow-up. Five losses due to ceramic fractures occurred in group 1 (n = 28) (SVR: 83.0% [95% confidence interval (CI): 0.71-0.96]). Group 2 (n = 26) showed no losses (SVR: 100%). The success rate for partial crowns placed on premolars was 100% and 69% (95% CI: 0.54-0.84) for molar restorations. Recementation was required in 4 restorations with SAC (SCR: 86% [95% CI: 0.73-0.99]; SCR-DC: 100%). Restorations in group 2 showed a significantly reduced risk of material fracture hazard ratio (HR) = 0.09, p = 0.0292) compared with the restorations in group 1. Molar partial crowns showed an increased risk for a clinical intervention (HR = 5.26, p = 0.0222) compared to premolar restorations.!##!Conclusions!#!Material thickness and position of the restoration are risk factors influencing the survival and success rate of ZLS-ceramic partial crowns.!##!Clinical relevance!#!Observation of an MMT of at least 0.75-1.0 mm for ZLS-ceramics is essential to avoid material-related fractures.!##!Clinical trial registration!#!German Clinical Trails Register (trial number: DRKS00005611)