Transcriptomic-based clustering of advanced atherosclerotic plaques identifies subgroups of plaques with differential underlying biology that associate with clinical presentation
Abstract
Abstract Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. However, the diversity and complexity of lesion types highlight the need for improved sub- phenotyping. We hypothesized that unbiased clustering of plaques based on gene expression results in an alternative categorization of late-stage atherosclerotic lesions. We analyzed the gene expression profiles of 654 advanced human carotid plaques. The unsupervised, transcriptome-driven clustering revealed five dominant plaque types. These novel plaque phenotypes associated with clinical presentation (p<0.001) and showed differences in cellular compositions. Validation in coronary segments showed that the molecular signature of these plaques was linked to coronary ischemia. One of the plaque types with most severe clinical symptoms pointed to both inflammatory and fibrotic cell lineages. This highlighted plaque phenotype showed high expression of genes involved in active inflammatory processes, neutrophil degranulation, matrix turnover, and metabolism. For clinical translation, we did a first promising attempt to identify circulating biomarkers that mark these newly identified plaque phenotypes. In conclusion, the definition of the plaque at risk for a thrombotic event can be fine-tuned by in- depth transcriptomic based phenotyping. These differential plaque phenotypes prove clinically relevant for both carotid and coronary artery plaques and point to differential underlying biology of symptomatic lesions.
Authors 37
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
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Marie A.C. Depuydt Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University
Affiliation as printed
Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Leiden, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
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Affiliation as printed
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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Affiliation as printed
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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Affiliation as printed
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Amsterdam University Medical Centers – location AMC, University of Amsterdam, Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
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Biomedical Research Foundation of the Academy of Athens
Affiliation as printed
Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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Biomedical Research Foundation of the Academy of Athens
Affiliation as printed
Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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German Centre for Cardiovascular Research · Deutsches Herzzentrum München · Technical University of Munich
Affiliation as printed
Department of Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany
German Centre for Cardiovascular Research (DZHK e.V.), Partner Site Munich Heart Alliance, Munich, Germany
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Affiliation as printed
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
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University of Oxford · Kennedy Institute of Rheumatology
Affiliation as printed
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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Affiliation as printed
CVPath Institute, Inc, Gaithersburg, MD, USA
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Affiliation as printed
CVPath Institute, Inc, Gaithersburg, MD, USA
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Stanford Medicine · Stanford University
Affiliation as printed
Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA
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Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Amsterdam University Medical Centers – location AMC, University of Amsterdam, Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
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Johan Kuiper Aachen Leiden Academic Centre for Drug Research Division of Biotherapeutics, Leiden University
Affiliation as printed
Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Leiden, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
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Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers
Affiliation as printed
Department of Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Amsterdam, the Netherlands
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Affiliation as printed
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
Department of Biomedical Engineering, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
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University Medical Center Utrecht
Affiliation as printed
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Department of Cardiology, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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Affiliation as printed
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
Department of Biomedical Engineering, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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Gerard Pasterkamp corresponding
Utrecht University · University Medical Center Utrecht
Affiliation as printed
Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
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