Bridging discovery and clinical science: A framework for advancing atherosclerosis research using innovative models
Atherosclerosis, vol. 418, pp. 120787
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death, with substantial residual risk persisting despite current lipid-lowering, antithrombotic, antihypertensive, weight-management, and anti-inflammatory therapies. This unmet clinical need reflects the multifactorial and heterogeneous nature of ASCVD, which is not fully captured by traditional discovery approaches. Recent advances in large-scale datasets, multi-omics technologies, polygenic risk scores, and artificial intelligence offer unprecedented opportunities to disentangle disease complexity and identify novel therapeutic targets and biomarkers. However, translation into clinically actionable strategies requires robust validation in models that faithfully recapitulate human disease. Conventional two-dimensional cell cultures and standard murine models have provided important mechanistic insights but often fail to reflect human-specific features such as lipid metabolism, hemodynamics, and plaque destabilization. To address these limitations, advanced in vitro and ex vivo platforms are emerging, including induced pluripotent stem cell-derived vascular systems, microphysiological vessel-on-chip devices, vascularized organoids, and ex vivo human tissue models. These systems offer controlled, human-relevant microenvironments for scalable perturbation testing and support personalized therapeutic development. Nevertheless, in vivo models remain essential for capturing systemic physiology, inter-organ crosstalk, and pharmacokinetic and pharmacodynamic responses, underscoring the need for complementary, rather than replacement, use of model systems. In this review, we propose an integrated framework linking data-driven target and biomarker discovery to validation in human-relevant experimental models, supported by selective use of in vivo systems. By aligning multi-omics and AI-based discovery with advanced preclinical platforms, this approach aims to improve translational success and accelerate the development of precision therapies for ASCVD.
Authors 14
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Kaloyan Takov corresponding
Affiliation as printed
National Heart & Lung Institute, Imperial College London, London, United Kingdom. Electronic address: k.takov@imperial.ac.uk
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Marie A.C. Depuydt Aachen
Leiden University · Lund University · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Leiden, the Netherlands; Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Department of Medical Biochemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences (ACS), Atherosclerosis & Aortic Disease, Amsterdam UMC, Amsterdam, the Netherlands
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Affiliation as printed
School of Public Health, Imperial College London, London, United Kingdom
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Affiliation as printed
Hypertension and Cardiovascular Risk Research Center, Medical and Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Bologna, Italy
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University of Freiburg · Universitäts-Herzzentrum Freiburg-Bad Krozingen
Affiliation as printed
Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen and Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Affiliation as printed
Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università Degli Studi di Milano, Milan, Italy
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Affiliation as printed
Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, BioHealth Graz, Austria
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Affiliation as printed
Department of Intensive Cardiac Therapy, National Institute of Cardiology, Warsaw, Poland
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Affiliation as printed
Department of Laboratory Medicine, Medical University Vienna, Vienna, Austria
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Affiliation as printed
Department of Clinical and Experimental Medicine, Magna Græcia University, Catanzaro, Italy
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
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Amsterdam University Medical Centers · Amsterdam institute for Immunology and Infectious Diseases · Amsterdam Cardiovascular Sciences · University of Amsterdam
Affiliation as printed
Department of Medical Biochemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences (ACS), Atherosclerosis & Aortic Disease, Amsterdam UMC, Amsterdam, the Netherlands; Amsterdam Institute for Immunology and Infectious Diseases (AII), Inflammatory Diseases, Amsterdam UMC, Amsterdam, the Netherlands
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Laura Parma corresponding
German Centre for Cardiovascular Research · Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians University, Pettenkoferstrasse 8a & 9, 80336, Munich, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Pettenkoferstrasse 8a & 9, 80336, Munich, Germany. Electronic address: Laura.Parma@med.uni-muenchen.de
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Sanne L. Maas corresponding Aachen Department of Internal Medicine I (Cardiology) Institute for Molecular Cardiovascular Research
Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany; Institute for Molecular Cardiovascular Research (IMCAR), Uniklinik RWTH Aachen, RWTH Aachen University, Aachen, Germany; Aachen-Maastricht Institute for Cardio-Renal Disease (AMICARE), Uniklinik RWTH Aachen, RWTH Aachen University, Aachen, Germany. Electronic address: smaas@ukaachen.de
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