Colchicine prevents accelerated atherosclerosis in TET2-mutant clonal haematopoiesis.

Autor:	Zuriaga MA; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain., Yu Z; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 75 Ames St., Cambridge, MA 02142, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.184, Boston, MA 02114, USA., Matesanz N; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain., Truong B; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 75 Ames St., Cambridge, MA 02142, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.184, Boston, MA 02114, USA., Ramos-Neble BL; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain., Asensio-López MC; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.; Cardiology Department, Hospital Virgen de la Arrixaca, IMIB-Arrixaca and University of Murcia, Murcia, Spain., Uddin MM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 75 Ames St., Cambridge, MA 02142, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.184, Boston, MA 02114, USA., Nakao T; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 75 Ames St., Cambridge, MA 02142, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.184, Boston, MA 02114, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Niroula A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.; SciLifeLab, University of Gothenburg, Gothenburg, Sweden.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Zorita V; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain., Amorós-Pérez M; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain., Moro R; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain., Ebert BL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Honigberg MC; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 75 Ames St., Cambridge, MA 02142, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.184, Boston, MA 02114, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Pascual-Figal D; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.; Cardiology Department, Hospital Virgen de la Arrixaca, IMIB-Arrixaca and University of Murcia, Murcia, Spain.; CIBER en Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain., Natarajan P; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 75 Ames St., Cambridge, MA 02142, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 3.184, Boston, MA 02114, USA.; Department of Medicine, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA., Fuster JJ; Program on Novel Mechanisms of Atherosclerosis, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro, 3, 28029 Madrid, Spain.; CIBER en Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain.
Jazyk:	angličtina
Zdroj:	European heart journal [Eur Heart J] 2024 Aug 30. Date of Electronic Publication: 2024 Aug 30.
DOI:	10.1093/eurheartj/ehae546
Abstrakt:	Background and Aims: Somatic mutations in the TET2 gene that lead to clonal haematopoiesis (CH) are associated with accelerated atherosclerosis development in mice and a higher risk of atherosclerotic disease in humans. Mechanistically, these observations have been linked to exacerbated vascular inflammation. This study aimed to evaluate whether colchicine, a widely available and inexpensive anti-inflammatory drug, prevents the accelerated atherosclerosis associated with TET2-mutant CH. Methods: In mice, TET2-mutant CH was modelled using bone marrow transplantations in atherosclerosis-prone Ldlr-/- mice. Haematopoietic chimeras carrying initially 10% Tet2-/- haematopoietic cells were fed a high-cholesterol diet and treated with colchicine or placebo. In humans, whole-exome sequencing data and clinical data from 37 181 participants in the Mass General Brigham Biobank and 437 236 participants in the UK Biobank were analysed to examine the potential modifying effect of colchicine prescription on the relationship between CH and myocardial infarction. Results: Colchicine prevented accelerated atherosclerosis development in the mouse model of TET2-mutant CH, in parallel with suppression of interleukin-1β overproduction in conditions of TET2 loss of function. In humans, patients who were prescribed colchicine had attenuated associations between TET2 mutations and myocardial infarction. This interaction was not observed for other mutated genes. Conclusions: These results highlight the potential value of colchicine to mitigate the higher cardiovascular risk of carriers of somatic TET2 mutations in blood cells. These observations set the basis for the development of clinical trials that evaluate the efficacy of precision medicine approaches tailored to the effects of specific mutations linked to CH. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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