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      The Potential of Fibroblast Activation Protein-Targeted Imaging as a Biomarker of Cardiac Remodeling and Injury

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          Abstract

          Purpose of Review

          Cardiovascular disease features adverse fibrotic processes within the myocardium, leading to contractile dysfunction. Activated cardiac fibroblasts play a pivotal role in the remodeling and progression of heart failure, but conventional diagnostics struggle to identify early changes in cardiac fibroblast dynamics. Emerging imaging methods visualize fibroblast activation protein (FAP) as a marker of activated fibroblasts, enabling non-invasive quantitative measurement of early cardiac remodeling.

          Recent Findings

          Retrospective analysis of oncology patient cohorts has identified cardiac uptake of FAP radioligands in response to various cardiovascular conditions. Small scale studies in dedicated cardiac populations have revealed FAP upregulation in injured myocardium, wherein the area of upregulation predicts subsequent ventricle dysfunction. Recent studies have demonstrated that silencing of FAP-expressing fibroblasts can reverse cardiac fibrosis in disease models.

          Summary

          The parallel growth of FAP-targeted imaging and therapy provides the opportunity for imaging-based monitoring and refinement of treatments targeting cardiac fibroblast activation.

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          Most cited references38

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          Cardiac Fibrosis: The Fibroblast Awakens.

          Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.
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            Cells of the adult human heart

            Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.
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              CAR T cells produced in vivo to treat cardiac injury

              Fibrosis affects millions of people with cardiac disease. We developed a therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified messenger RNA (mRNA) in T cell–targeted lipid nanoparticles (LNPs). The efficacy of these in vivo–reprogrammed CAR T cells was evaluated by injecting CD5-targeted LNPs into a mouse model of heart failure. Efficient delivery of modified mRNA encoding the CAR to T lymphocytes was observed, which produced transient, effective CAR T cells in vivo. Antifibrotic CAR T cells exhibited trogocytosis and retained the target antigen as they accumulated in the spleen. Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury. In vivo generation of CAR T cells may hold promise as a therapeutic platform to treat various diseases.
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                Author and article information

                Contributors
                Thackeray.James@mh-hannover.de
                Journal
                Curr Cardiol Rep
                Curr Cardiol Rep
                Current Cardiology Reports
                Springer US (New York )
                1523-3782
                1534-3170
                1 May 2023
                1 May 2023
                2023
                : 25
                : 6
                : 515-523
                Affiliations
                GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Nuclear Medicine, Hannover Medical School, , Translational Cardiovascular Molecular Imaging, ; Carl Neuberg Str 1, 30625 Hannover, Germany
                Author information
                http://orcid.org/0000-0002-9031-100X
                Article
                1869
                10.1007/s11886-023-01869-8
                10188581
                37126137
                cc691045-daf2-491f-a7b7-d732530acfdf
                © The Author(s) 2023

                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
                : 20 March 2023
                Funding
                Funded by: Medizinische Hochschule Hannover (MHH) (3118)
                Categories
                Nuclear Cardiology (V Dilsizian, Section Editor)
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2023

                Cardiovascular Medicine
                cardiac fibroblast,heart failure,molecular imaging,myocardial infarction,fibroblast activation protein,fibrosis

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