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      The Liver and Kidneys mediate clearance of cardiac troponin in the rat

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          Abstract

          Cardiac-specific troponins (cTn), troponin T (cTnT) and troponin I (cTnI) are diagnostic biomarkers when myocardial infarction is suspected. Despite its clinical importance it is still not known how cTn is cleared once it is released from damaged cardiac cells. The aim of this study was to examine the clearance of cTn in the rat. A cTn preparation from pig heart was labeled with fluorescent dye or fluorine 18 ( 18 F). The accumulation of the fluorescence signal using organ extracts, or the 18 F signal using positron emission tomography (PET) was examined after a tail vein injection. The endocytosis of fluorescently labeled cTn was studied using a mouse hepatoma cell line. Close to 99% of the cTnT and cTnI measured with clinical immunoassays were cleared from the circulation two hours after a tail vein injection. The fluorescence signal from the fluorescently labeled cTn preparation and the radioactivity from the 18F-labeled cTn preparation mainly accumulated in the liver and kidneys. The fluorescently labeled cTn preparation was efficiently endocytosed by mouse hepatoma cells. In conclusion, we find that the liver and the kidneys are responsible for the clearance of cTn from plasma in the rat.

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          Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway.

          Z Qian (2002)
          The membrane transferrin receptor-mediated endocytosis or internalization of the complex of transferrin bound iron and the transferrin receptor is the major route of cellular iron uptake. This efficient cellular uptake pathway has been exploited for the site-specific delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant cells that overexpress the transferrin receptors. This is achieved either chemically by conjugation of transferrin with therapeutic drugs, proteins, or genetically by infusion of therapeutic peptides or proteins into the structure of transferrin. The resulting conjugates significantly improve the cytotoxicity and selectivity of the drugs. The coupling of DNA to transferrin via a polycation or liposome serves as a potential alternative to viral vector for gene therapy. Moreover, the OX26 monoclonal antibody against the rat transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain.
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            Association of High-Sensitivity Cardiac Troponin I Concentration With Cardiac Outcomes in Patients With Suspected Acute Coronary Syndrome

            Question What is the optimal high-sensitivity cardiac troponin I concentration at presentation to risk-stratify patients with suspected acute coronary syndrome? Findings In an individual patient-level meta-analysis of 22 457 patients from 9 countries, troponin I concentrations were less than 5 ng/L in 49%, among whom 5 per 1000 patients had a myocardial infarction or cardiac death at 30 days. Meaning Among patients with suspected acute coronary syndrome, a high-sensitivity cardiac troponin I threshold of less than 5 ng/L identified patients at low risk of cardiac events; further research is needed to assess the clinical utility of this test. Importance High-sensitivity cardiac troponin I testing is widely used to evaluate patients with suspected acute coronary syndrome. A cardiac troponin concentration of less than 5 ng/L identifies patients at presentation as low risk, but the optimal threshold is uncertain. Objective To evaluate the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome. Data Sources Systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases from January 1, 2006, to March 18, 2017. Study Selection Prospective studies measuring high-sensitivity cardiac troponin I concentrations in patients with suspected acute coronary syndrome in which the diagnosis was adjudicated according to the universal definition of myocardial infarction. Data Extraction and Synthesis The systematic review identified 19 cohorts. Individual patient-level data were obtained from the corresponding authors of 17 cohorts, with aggregate data from 2 cohorts. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random-effects model. Main Outcomes and Measures The primary outcome was myocardial infarction or cardiac death at 30 days. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data. Results Of 11 845 articles identified, 104 underwent full-text review, and 19 cohorts from 9 countries were included. Among 22 457 patients included in the meta-analysis (mean age, 62 [SD, 15.5] years; n = 9329 women [41.5%]), the primary outcome occurred in 2786 (12.4%). Cardiac troponin I concentrations were less than 5 ng/L at presentation in 11 012 patients (49%), in whom there were 60 missed index or 30-day events (59 index myocardial infarctions, 1 myocardial infarction at 30 days, and no cardiac deaths at 30 days). This resulted in a negative predictive value of 99.5% (95% CI, 99.3%-99.6%) for the primary outcome. There were no cardiac deaths at 30 days and 7 (0.1%) at 1 year, with a negative predictive value of 99.9% (95% CI, 99.7%-99.9%) for cardiac death. Conclusions and Relevance Among patients with suspected acute coronary syndrome, a high-sensitivity cardiac troponin I concentration of less than 5 ng/L identified those at low risk of myocardial infarction or cardiac death within 30 days. Further research is needed to understand the clinical utility and cost-effectiveness of this approach to risk stratification. This systematic review evaluates the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome.
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              Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction.

              In a previous study on the diagnostic efficiency of troponin T measurements in patients with suspected acute myocardial infarction (AMI), the authors found a high variability of troponin T serum concentration changes on day 1 in patients with AMI who underwent thrombolytic treatment. Therefore, the aims of the present study were to investigate the intracellular compartmentation of troponin T and to analyze the effects of AMI reperfusion on the appearance kinetics of cardiac troponin T in serum. Cardiac troponin T was measured with a newly developed bideterminant sandwich assay using cardiospecific, affinity-purified polyclonal antibodies and peroxidase-labeled monoclonal antibody. An unbound cytosolic troponin T pool was found in ultracentrifuged homogenates of myocardial tissue of different species ranging from 0.013 to 0.036 mg/g wet weight. The soluble troponin T molecule had electrophoretic properties identical to troponin T compartmented in the myofibrils. The clinical study group comprised 57 patients with AMI undergoing thrombolytic treatment. Blood flow to the infarct zone and point of time of reperfusion were tested by immediate and late angiography. The appearance of troponin T in serum on day 1 after the onset of AMI depended strongly on reperfusion and on duration of ischemia before reperfusion. Thus, in patients with early reperfused AMI, a marked peak in troponin T serum concentrations was found at 14 hours after the onset of pain. This early troponin T peak was absent in patients with AMI reperfusion occurring greater than 5.5 hours after the onset of pain and in patients with nonreperfused AMI. By contrast, the kinetics of troponin T release after the first day after AMI were unaffected by reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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                Author and article information

                Contributors
                ola.hammarsten@clinchem.gu.se
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                22 April 2020
                22 April 2020
                2020
                : 10
                : 6791
                Affiliations
                [1 ]Institute of Biomedicine, Department of Laboratory Medicine, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden
                [2 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Department of Biomedicine, University of Bergen, ; Bergen, Norway
                [3 ]ISNI 0000 0001 0775 6028, GRID grid.5371.0, Department of Biology and Biotechnology, Biology and Biological Engineering, Chemical Biology, Chalmers University of Technology, ; Gothenburg, Sweden
                [4 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, ; Uppsala, Sweden
                Author information
                http://orcid.org/0000-0002-1253-6342
                Article
                63744
                10.1038/s41598-020-63744-8
                7176693
                32322013
                4a781297-da08-4005-a574-72f92dbc0a09
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 November 2019
                : 27 March 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100004257, Helse Vest (Western Norway Regional Health Authority);
                Award ID: 911974
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100002794, Cancerfonden (Swedish Cancer Society);
                Funded by: Hjärt-Lungfonden, Smärtafonden, ALF/LUA at SU
                Categories
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                © The Author(s) 2020

                Uncategorized
                diagnostic markers,cardiovascular biology,cardiovascular diseases
                Uncategorized
                diagnostic markers, cardiovascular biology, cardiovascular diseases

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