The systemic autoimmune disease rheumatoid arthritis (RA) is characterized by increased cardiovascular mortality and morbidity and is an independent cardiovascular risk factor. Cardiovascular diseases (CVDs) result from accelerated atherogenesis, which is a consequence of endothelial dysfunction in the early stages of the disease. Endothelial dysfunction is a functional and reversible alteration of endothelial cells and leads to a shift in the properties of the endothelium towards reduced vasodilation, a pro-inflammatory state, and proliferative and prothrombotic properties. In RA, endothelial dysfunction can occur in the large vessels (such as the conduit arteries) and in the small vessels of the microvasculature, which supply oxygen and nutrients to the tissue and control inflammation, repair and fluid exchange with the surrounding tissues. Growing evidence suggests that microvascular endothelial dysfunction contributes to CVD development, as it precedes and predicts the development of conduit artery atherosclerosis and associated risk factors. As such, numerous studies have investigated microvascular endothelial dysfunction in RA, including its link with disease activity, disease duration and inflammation, the effect of treatments on endothelial function, and possible circulating biomarkers of microvascular endothelial dysfunction. Such findings could have important implications in the cardiovascular risk management of patients with RA.
Introduction and objective: Nowadays, investigations of heart physiology and pathophysiology rely more and more upon image analysis, whether for the detection and characterization of events in single cells or for the mapping of events and their characteristics across an entire tissue. These investigations require extensive skills in image analysis and/or expensive software, and their reproducibility may be a concern. Our objective was to build a robust, reliable and open-source software tool to quantify excitation–contraction related experimental data at multiple scales, from single isolated cells to the whole heart. Methods and results: A free and open-source ImageJ plugin, Spiky, was developed to detect and analyze peaks in experimental data streams. It allows rapid and easy analysis of action potentials, intracellular calcium transient and contraction data from cardiac research experiments. As shown in the provided examples, both classical bi-dimensional data (XT signals) and video data obtained from confocal microscopy and optical mapping experiments (XYT signals) can be analyzed. Spiky was written in ImageJ Macro Language and JAVA, and works under Windows, Mac and Linux operating systems. Conclusion: Spiky provides a complete working interface to process and analyze cardiac physiology research data.
Ectopic activity in the pulmonary vein cardiac muscle sleeves can both induce and maintain human atrial fibrillation. A central issue in any study of the pulmonary veins is their difference from the left atrial cardiac muscle. Here, we attempt to summarize the physiological phenomena underlying the occurrence of ectopic electrical activity in animal pulmonary veins. We emphasize that the activation of multiple signaling pathways influencing not only myocyte electrophysiology but also the means of excitation–contraction coupling may be required for the initiation of triggered or automatic activity. We also gather information regarding not only the large-scale structure of cardiac muscle sleeves but also recent studies suggesting that cellular heterogeneity may contribute to the generation of arrythmogenic phenomena and to the distinction between pulmonary vein and left atrial heart muscle.
BackgroundRheumatoid arthritis (RA) is associated with increased cardiovascular (CV) risk [1] secondary to endothelial dysfunction (ED) [2]. There is accumulating evidence that methotrexate (MTX), first intention DMARD, reduces CV risk in RA [3], but the mechanisms involved are still unknown.ObjectivesThe aim of this study was to determine the effect of MTX on endothelial function in arthritis and to investigate its effect on endothelial pathways.MethodsExperiments were conducted in the adjuvant-induced arthritis (AIA) model in Lewis rat. At onset of arthritis, rats were treated by a sub-cutaneous injection of MTX (1 mg/kg/week) or phosphate buffer saline (vehicle) for 3 weeks. Arthritis score was daily monitored. At the end of treatment, thoracic aorta was harvested to measure the relaxation to acetylcholine on pre-constricted aortic rings in the presence or not of inhibitor of nitric oxide (NO) synthase (L-NAME), arginase (nor-NOHA), EDHF (Apamin/Charybdotoxin), or a superoxide dismutase analog (Tempol). The effect of norepinephrine (NE) and sodium nitroprusside (SNP) was studied on endothelium-denuded aortic rings. The effect of MTX on hind paw radiographic score, serum lipids and plasma pro-inflammatory cytokines (TNFα and IL-1β) levels was measured.ResultsAs compared to Vehicle rats, MTX significantly reduced arthritis score (p<0.01) but did not change radiographic score. It reduced plasma cytokines levels (p=0.02) but not total cholesterol and triglycerides levels. MTX did not change Ach-induced relaxation as compared to Vehicle. As regards endothelial pathways, MTX increased vascular NOS activity (p<0.0001) and decreased superoxide anions production but did change neither COX-2 and arginase activities nor EDHF production. Vascular smooth muscle reactivity to NE and SNP was unchanged by the treatment.ConclusionsDespite a reduction of clinical and biological inflammation, MTX did not improve endothelial function in AIA rats. The study of endothelial mechanisms highlights the role of COX and arginase as seminal targets for reducing ED in RA. This study suggests that other mechanisms than improvement of endothelial function are involved in the CV benefits of MTX in RA that remain to be elucidated. Our data also suggest that the adjunction of drugs targeting endothelial function to MTX in RA patients might improve their CV prognostic.References
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