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      Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering

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          Abstract

          Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00395-020-00838-4.

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          Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.

          Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.
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            2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).

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              A simple practice guide for dose conversion between animals and human

              Understanding the concept of extrapolation of dose between species is important for pharmaceutical researchers when initiating new animal or human experiments. Interspecies allometric scaling for dose conversion from animal to human studies is one of the most controversial areas in clinical pharmacology. Allometric approach considers the differences in body surface area, which is associated with animal weight while extrapolating the doses of therapeutic agents among the species. This review provides basic information about translation of doses between species and estimation of starting dose for clinical trials using allometric scaling. The method of calculation of injection volume for parenteral formulation based on human equivalent dose is also briefed.
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                Author and article information

                Contributors
                ingo.hilgendorf@universitaets-herzzentrum.de
                Journal
                Basic Res Cardiol
                Basic Res Cardiol
                Basic Research in Cardiology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0300-8428
                1435-1803
                9 December 2020
                9 December 2020
                2020
                : 115
                : 6
                : 78
                Affiliations
                [1 ]GRID grid.5963.9, Department of Cardiology and Angiology I, , University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, ; 55 Hugstetter St, 79106 Freiburg, Germany
                [2 ]GRID grid.5963.9, Institute for Experimental Cardiovascular Medicine, , University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, ; Freiburg, Germany
                [3 ]GRID grid.5963.9, Department of Medicine II, Faculty of Medicine, , Medical Center–University Freiburg, University of Freiburg, ; Freiburg, Germany
                [4 ]The Netherlands Organization for Applied Scientific Research (TNO)-Metabolic Health Research, Leiden, Netherlands
                [5 ]GRID grid.508487.6, ISNI 0000 0004 7885 7602, INSERM Unit 1148, , University Paris Diderot, and Laboratory for Vascular Translational Science, Sorbonne Paris Cité, ; Paris, France
                [6 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Center of Systems Biology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [7 ]GRID grid.231844.8, ISNI 0000 0004 0474 0428, Peter Munk Cardiac Centre, , University Health Network, ; Toronto, Canada
                [8 ]GRID grid.5110.5, ISNI 0000000121539003, Department of Cardiology, , University of Graz, ; Graz, Austria
                Author information
                http://orcid.org/0000-0002-0024-1643
                Article
                838
                10.1007/s00395-020-00838-4
                7725697
                33296022
                5b7b5112-9b94-4aa5-97f0-55832144f299
                © The Author(s) 2020

                Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 September 2020
                : 1 December 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Funded by: Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH (6005)
                Categories
                Original Contribution
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                Cardiovascular Medicine
                atherosclerosis,macrophage,proliferation,plaque regression
                Cardiovascular Medicine
                atherosclerosis, macrophage, proliferation, plaque regression

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