Atherosclerotic Plaque Epigenetic Age Acceleration Predicts a Poor Prognosis and Is Associated With Endothelial-to-Mesenchymal Transition in Humans

作者：Ernest Diez Benavente, Robin J. G. Hartman, Tim R. Sakkers, Marian Wesseling, Yannicke Sloots, Lotte Slenders, Arjan Boltjes, Barend M. Mol, Gert Jan de Borst, Dominique P.V. de Kleijn, Koen H.M. Prange, Menno P.J. de Winther, Johan Kuiper, Mete Civelek, Sander W. van der Laan, Steve Horvath, N. Charlotte Onland‐Moret, Michal Mokrý, Gerard Pasterkamp, Hester M. den Ruijter · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2024 · DOI：10.1161/atvbaha.123.320692 · 被引用次数：23 · 研究领域：Epigenetics and DNA Methylation、Congenital heart defects research、Birth, Development, and Health

BACKGROUND: Epigenetic age estimators (clocks) are predictive of human mortality risk. However, it is not yet known whether the epigenetic age of atherosclerotic plaques is predictive for the risk of cardiovascular events. METHODS: Whole-genome DNA methylation of human carotid atherosclerotic plaques (n=485) and of blood (n=93) from the Athero-Express endarterectomy cohort was used to calculate epigenetic age acceleration (EAA). EAA was linked to clinical characteristics, plaque histology, and future cardiovascular events (n=136). We studied whole-genome DNA methylation and bulk and single-cell transcriptomics to uncover molecular mechanisms of plaque EAA. We experimentally confirmed our in silico findings using in vitro experiments in primary human coronary endothelial cells. RESULTS: Male and female patients with severe atherosclerosis had a median chronological age of 69 years. The median epigenetic age was 65 years in females (median EAA, −2.2 [interquartile range, −4.3 to 2.2] years) and 68 years in males (median EAA, −0.3 [interquartile range, −2.9 to 3.8] years). Patients with diabetes and a high body mass index had higher plaque EAA. Increased EAA of plaque predicted future events in a 3-year follow-up in a Cox regression model (univariate hazard ratio, 1.7; P =0.0034) and adjusted multivariate model (hazard ratio, 1.56; P =0.02). Plaque EAA predicted outcome independent of blood EAA (hazard ratio, 1.3; P =0.018) and of plaque hemorrhage (hazard ratio, 1.7; P =0.02). ...