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      Investigation of the pathophysiology of cardiopulmonary bypass using rodent extracorporeal life support model

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          Abstract

          Background

          Extracorporeal life support (ECLS) systems are life-saving devices used for treating patients with severe cardiopulmonary failure. In this study, we implemented a rat model of ECLS without the administration of inotropes or vasopressors.

          Methods

          The rats underwent 5 min of untreated asphyxial cardiac arrest and were resuscitated by ECLS for 30 min. The right external jugular vein and right femoral artery were separately cannulated to the ECLS outflow and inflow, respectively. Thereafter, ECLS was terminated, wounds were closed, and mechanical ventilation was provided for another 90 min. Subsequently, blood gas and hemodynamic analyses were performed. The plasma levels of C-reactive protein (CRP), interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α) were measured 120 min after reperfusion.

          Results

          The metabolic rate of lactate in the group of asphyxial cardiac arrest rescued by ECLS was slow; therefore, the pH at 120 min after reperfusion was significantly lower in this group than that in the group of normal rats treated with ECLS. The hemodynamic data showed no between-group differences. The plasma levels of CRP, IL-6, IL-10, and TNF-α increased after ECLS treatment.

          Conclusions

          We successfully established a rodent ECLS model, which might be a useful approach for studying the pathophysiology induced by ECLS under clinical conditions.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12872-017-0558-6) contains supplementary material, which is available to authorized users.

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          Most cited references23

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          Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis.

          Extracorporeal life-support as an adjunct to cardiac resuscitation has shown encouraging outcomes in patients with cardiac arrest. However, there is little evidence about the benefit of the procedure compared with conventional cardiopulmonary resuscitation (CPR), especially when continued for more than 10 min. We aimed to assess whether extracorporeal CPR was better than conventional CPR for patients with in-hospital cardiac arrest of cardiac origin. We did a 3-year prospective observational study on the use of extracorporeal life-support for patients aged 18-75 years with witnessed in-hospital cardiac arrest of cardiac origin undergoing CPR of more than 10 min compared with patients receiving conventional CPR. A matching process based on propensity-score was done to equalise potential prognostic factors in both groups, and to formulate a balanced 1:1 matched cohort study. The primary endpoint was survival to hospital discharge, and analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00173615. Of the 975 patients with in-hospital cardiac arrest events who underwent CPR for longer than 10 min, 113 were enrolled in the conventional CPR group and 59 were enrolled in the extracorporeal CPR group. Unmatched patients who underwent extracorporeal CPR had a higher survival rate to discharge (log-rank p<0.0001) and a better 1-year survival than those who received conventional CPR (log rank p=0.007). Between the propensity-score matched groups, there was still a significant difference in survival to discharge (hazard ratio [HR] 0.51, 95% CI 0.35-0.74, p<0.0001), 30-day survival (HR 0.47, 95% CI 0.28-0.77, p=0.003), and 1-year survival (HR 0.53, 95% CI 0.33-0.83, p=0.006) favouring extracorporeal CPR over conventional CPR. Extracorporeal CPR had a short-term and long-term survival benefit over conventional CPR in patients with in-hospital cardiac arrest of cardiac origin.
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            The role of shear stress in the pathogenesis of atherosclerosis.

            Although the pathobiology of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an essential feature of atherogenesis. This fluid drag force acting on the vessel wall is mechanotransduced into a biochemical signal that results in changes in vascular behavior. Maintenance of a physiologic, laminar shear stress is known to be crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, thrombosis and inflammation of the vessel wall. Thus, shear stress is atheroprotective. It is also recognized that disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. Additionally, vascular endothelium has been shown to have different behavioral responses to altered flow patterns both at the molecular and cellular levels and these reactions are proposed to promote atherosclerosis in synergy with other well-defined systemic risk factors. Nonlaminar flow promotes changes to endothelial gene expression, cytoskeletal arrangement, wound repair, leukocyte adhesion as well as to the vasoreactive, oxidative and inflammatory states of the artery wall. Disturbed shear stress also influences the site selectivity of atherosclerotic plaque formation as well as its associated vessel wall remodeling, which can affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts. Thus, shear stress is critically important in regulating the atheroprotective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis.
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              In vivo roles of factor XII.

              Coagulation factor XII (FXII, Hageman factor, EC = 3.4.21.38) is the zymogen of the serine protease, factor XIIa (FXIIa). FXII is converted to FXIIa through autoactivation induced by "contact" to charged surfaces. FXIIa is of crucial importance for fibrin formation in vitro, but deficiency in the protease is not associated with excessive bleeding. For decades, FXII was considered to have no function for coagulation in vivo. Our laboratory developed the first murine knockout model of FXII. Consistent with their human counterparts, FXII(-/-) mice have a normal hemostatic capacity. However, thrombus formation in FXII(-/-) mice is largely defective, and the animals are protected from experimental cerebral ischemia and pulmonary embolism. This murine model has created new interest in FXII because it raises the possibility for safe anticoagulation, which targets thrombosis without influence on hemostasis. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema during hypersensitivity reactions. Independent of its protease activity, FXII exerts mitogenic activity with implications for angiogenesis. The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology.
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                Author and article information

                Contributors
                hippo0703@gmail.com
                u901060@msn.com
                hsiyuyu@gmail.com
                yschen1234@gmail.com
                +886-2-2312-3456 , wchemail@gmail.com
                Journal
                BMC Cardiovasc Disord
                BMC Cardiovasc Disord
                BMC Cardiovascular Disorders
                BioMed Central (London )
                1471-2261
                15 May 2017
                15 May 2017
                2017
                : 17
                : 123
                Affiliations
                [1 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Department of Physiology, , College of Medicine, National Taiwan University, ; No. 1, Sec. 1, Ren’ai Rd., Zhongzheng Dist., Taipei, 10051 Taiwan
                [2 ]ISNI 0000 0004 0572 7815, GRID grid.412094.a, Department of Surgery, , National Taiwan University Hospital, Hsin-Chu Branch, ; NO. 25, Lane 442, Sec. 1, Jingguo Rd., Hsin-Chu, 30059 Taiwan
                [3 ]ISNI 0000 0004 0572 7815, GRID grid.412094.a, Cardiovascular Surgery, Department of Surgery, , National Taiwan University Hospital, ; No. 7, Zhongshan S. Rd., Zhongzheng Dist., Taipei, 10002 Taiwan
                Article
                558
                10.1186/s12872-017-0558-6
                5433070
                28506218
                c2f999aa-0128-4392-a5bf-108f826d6bfb
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 25 December 2016
                : 8 May 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100005762, National Taiwan University Hospital;
                Award ID: 106-16
                Funded by: National Science Council of Taiwan
                Award ID: MOST 102-2314-B-002-169-MY2
                Funded by: National Taiwan University Hospital, Hsin-Chu Branch
                Award ID: 105-HCH018; 105-HCH060
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Cardiovascular Medicine
                asphyxial cardiac arrest,extracorporeal life support,inflammatory response,rat model

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