Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans.

Multiomics of Tissue Extracellular Vesicles Identifies Unique Modulators of Atherosclerosis and Calcific Aortic Valve Stenosis.

Background: Fewer than 50% of patients who develop aortic valve calcification have concomitant atherosclerosis, implying differential pathogenesis. Although circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs are associated with early mineralization, but their cargoes, functions, and contributions to disease remain unknown.

Methods: Disease stage-specific proteomics was performed on human carotid endarterectomy specimens (n=16) and stenotic aortic valves (n=18).

The Role of «Novel» Biomarkers of Systemic Inflammation in the Development of Early Hospital Events after Aortic Valve Replacement in Patients with Aortic Stenosis.

Introduction: The pathogenesis of aortic stenosis includes the processes of chronic inflammation, calcification, lipid metabolism disorders, and congenital structural changes. The goal of our study was to determine the predictive value of novel biomarkers of systemic inflammation and some hematological indices based on the numbers of leukocytes and their subtypes in the development of early hospital medical conditions after mechanical aortic valve replacement in patients with aortic stenosis.

Materials And Methods: This was a cohort study involving 363 patients who underwent surgical intervention for aortic valve pathology between 2014 and 2020.

Colchicine in Cardiac Surgery: The COCS Randomized Clinical Trial.

In patients who underwent cardiac surgery, first-time postoperative atrial fibrillation (POAF) is associated with increased incidence of hospital-acquired complications and mortality. Systemic inflammation is one of confirmed triggers of its development. The anti-inflammatory properties of colchicine can be effective for the POAF prevention.

Long-Term Preoperative Atorvastatin or Rosuvastatin Use in Adult Patients before CABG Does Not Increase Incidence of Postoperative Acute Kidney Injury: A Propensity Score-Matched Analysis.

Background: Acute kidney injury (AKI) is among the expected complications of cardiac surgery. Statins with pleiotropic anti-inflammatory and antioxidant effects may be effective in the prevention of AKI. However, the results of studies on the efficacy and safety of statins are varied and require further study.

Colchicine for Prevention of Atrial Fibrillation after Cardiac Surgery in the Early Postoperative Period.

Background: Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery. It has been proven to be associated with an increase in the incidence of early complications and mortality, an increase in the rate of hospital stay duration, and economic costs of their treatment. One of the pharmaceutical drugs recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) for preventing POAF is colchicine (class IIB).

A Smooth Muscle Cell-Enriched Long Noncoding RNA Regulates Cell Plasticity and Atherosclerosis by Interacting With Serum Response Factor.

Objective: Vascular smooth muscle cell (VSMC) plasticity plays a critical role in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) are emerging as important regulators in the vessel wall and impact cellular function through diverse interactors. However, the role of lncRNAs in regulating VSMCs plasticity and atherosclerosis remains unclear.

Targeted delivery of protein arginine deiminase-4 inhibitors to limit arterial intimal NETosis and preserve endothelial integrity.

Aims: Recent evidence suggests that 'vulnerable plaques', which have received intense attention as underlying mechanism of acute coronary syndromes over the decades, actually rarely rupture and cause clinical events. Superficial plaque erosion has emerged as a growing cause of residual thrombotic complications of atherosclerosis in an era of increased preventive measures including lipid lowering, antihypertensive therapy, and smoking cessation. The mechanisms of plaque erosion remain poorly understood, and we currently lack validated effective diagnostics or therapeutics for superficial erosion.

Long noncoding RNA integrates a DNA-PK-mediated DNA damage response and vascular senescence.

Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 () is highly expressed in the vascular endothelium and decreases during lesion progression.

Stage-dependent differential effects of interleukin-1 isoforms on experimental atherosclerosis.

Aims: Targeting interleukin-1 (IL-1) represents a novel therapeutic approach to atherosclerosis. CANTOS demonstrated the benefits of IL-1β neutralization in patients post-myocardial infarction with residual inflammatory risk. Yet, some mouse data have shown a prominent role of IL-1α rather than IL-1β in atherosclerosis, or even a deleterious effect of IL-1 on outward arterial remodelling in atherosclerosis-susceptible mice.

Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion.

Rationale: Neutrophils likely contribute to the thrombotic complications of human atheromata. In particular, neutrophil extracellular traps (NETs) could exacerbate local inflammation and amplify and propagate arterial intimal injury and thrombosis. PAD4 (peptidyl arginine deiminase 4) participates in NET formation, but an understanding of this enzyme's role in atherothrombosis remains scant.

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.

Methods: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls.

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

Rationale: Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation.

Objective: This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion.

TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion.

Aims: Superficial erosion of atheromata causes many acute coronary syndromes, but arises from unknown mechanisms. This study tested the hypothesis that Toll-like receptor-2 (TLR2) activation contributes to endothelial apoptosis and denudation and thus contributes to the pathogenesis of superficial erosion.

Methods And Results: Toll-like receptor-2 and neutrophils localized at sites of superficially eroded human plaques.

Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.

Rationale: Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation.

Objective: To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis.

Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis.

Objective: Evidence has linked collagen loss with the onset of acute coronary events. This study tested the hypothesis that selective matrix metalloproteinase-13 (MMP-13) collagenase inhibition increases collagen content in already established and nascent mouse atheromas.

Methods And Results: In vitro and in situ experiments documented the selectivity and efficacy of an orally available MMP-13 inhibitor (MMP13i-A).

Hypoxia but not inflammation augments glucose uptake in human macrophages: Implications for imaging atherosclerosis with 18fluorine-labeled 2-deoxy-D-glucose positron emission tomography.

Objectives: This study investigated the regulation of glucose uptake in cells that participate in atherogenesis by stimuli relevant to this process, to gain mechanistic insight into the origin of the (18)fluorine-labeled 2-deoxy-D-glucose (FdG) uptake signals observed clinically.

Background: Patient studies suggest that positron emission tomography (PET) using FdG can detect "active" atherosclerotic plaques, yet the mechanism giving rise to FdG signals remains unknown.

Methods: We exposed cells to conditions thought to operate in atheroma and determined rates of glucose uptake.

Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation.

Objective: To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow-derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo.

Methods And Results: Prostaglandin E(2) (PGE(2)) through activation of EP4, can mute inflammation. Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR(-/-)) mice transplanted with either EP4(+/+) (EP4(+/+)/LDLR(-/-)) or EP4(-/-) (EP4(-/-)/LDLR(-/-)) bone marrow received infusions of angiotensin II to induce AAA.

Lack of EP4 receptors on bone marrow-derived cells enhances inflammation in atherosclerotic lesions.

Aim: prostaglandin E(2), by ligation of its receptor EP4, suppresses the production of inflammatory cytokines and chemokines in macrophages in vitro. Thus, activation of EP4 may constitute an endogenous anti-inflammatory pathway. This study investigated the role of EP4 in atherosclerosis in vivo, and particularly its impact on inflammation.

[Dynamics of accumulation of CYP2B mRNA in the liver of rats from various strains during induction with xenobiotics].

The transcription level of CYP2B1/2 gene in the liver of Sprague-Dawley (SD), Brattleboro (BL) and Wistar (W) rats treated with isosafrol (IS), Arochlor 1254 (AC), phenobarbital (PB) and triphenildioxane (TPD) was studied. The quantity of CYP2B1/2 mRNA was assessed by dot-blot analysis at 18, 48 and 72 hours after inducers administration. The mRNA level in SD and BL rats treated with PB reached its maximum by 18 hours followed by fast decline.

Endurance fitness and orthostatic tolerance.

Background: Several lower body negative pressure studies conducted in recent years have suggested that aerobically fit individuals have poo-orthostatic tolerance (OT).

Hypothesis: There will be significant differences between OT of highly fit endurance runners and unfit individuals.

Methods: Subjects were 17 men and 17 women aged 29-42 yr who were administered two orthostatic tests (20 min standing) before, and 5 min following a VO2max test.

Advantages of a low-oxygen environment in space cabins.

The advantages of having a low-oxygen environment in space cabins are discussed. The major advantage is a sharply reduced fire hazard, which is a major threat in manned space flights. At 1 atm, for example, 15% O2 (9,000 ft altitude equivalent) would not support most fires and could accommodate the crew with respect to hypoxia, decompression sickness (DCS), and other requirements.

Aerobic fitness norms for males and females aged 6 to 75 years: a review.

An extensive literature review was performed of studies where VO2max was measured directly in healthy, untrained subjects in the USA, Canada and 7 European countries to establish absolute (L/min) and relative (ml.kg-1.min-1) VO2max norms in males and females aged 6-75 years.

Hemodynamic responses during prolonged sitting.

Eight young men (group A) underwent 5 h of quiet sitting, preceded by 30 min of recumbency, 20 min of standing, and 20 s of walking, and five other young men (group B) underwent 70 min of sitting, preceded by recumbency only, to determine the effects of prolonged sitting and previous posture on hemodynamic responses (measured by impedance plethysmography). Group A showed more calf blood pooling and a decrease in thigh blood flow during sitting in comparison with the control group, but after 1 h of sitting hemodynamic responses of the two groups were similar. Sitting for 5 h (1st vs.

Physiologic responses to exercise in normal and obese women.

The present study examines the possibility that the reduced activity commonly found in obese individuals could stem from a reduced physiological responsiveness to exercise. Responses to bicycle ergometer exercise (300 kpm/min) of four obese and four normal weight women were observed in a metabolic ward. This resulted in decreases in exercise heart rate and oxygen consumption, indicating an improvement in mechanical efficiency and suggesting an increase in physical working capacity.