Emerging evidence has spurred a considerable evolution of concepts relating to atherosclerosis, and has called into question many previous notions. Here I review this evidence, and discuss its implications for understanding of atherosclerosis. The risk of developing atherosclerosis is no longer concentrated in Western countries, and it is instead involved in the majority of deaths worldwide. Atherosclerosis now affects younger people, and more women and individuals from a diverse range of ethnic backgrounds, than was formerly the case. The risk factor profile has shifted as levels of low-density lipoprotein (LDL) cholesterol, blood pressure and smoking have decreased. Recent research has challenged the protective effects of high-density lipoprotein, and now focuses on triglyceride-rich lipoproteins in addition to low-density lipoprotein as causal in atherosclerosis. Non-traditional drivers of atherosclerosis—such as disturbed sleep, physical inactivity, the microbiome, air pollution and environmental stress—have also gained attention. Inflammatory pathways and leukocytes link traditional and emerging risk factors alike to the altered behaviour of arterial wall cells. Probing the pathogenesis of atherosclerosis has highlighted the role of the bone marrow: somatic mutations in stem cells can cause clonal haematopoiesis, which represents a previously unrecognized but common and potent age-related contributor to the risk of developing cardiovascular disease. Characterizations of the mechanisms that underpin thrombotic complications of atherosclerosis have evolved beyond the ‘vulnerable plaque’ concept. These advances in our understanding of the biology of atherosclerosis have opened avenues to therapeutic interventions that promise to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases.
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P.L. receives funding support from the National Heart, Lung, and Blood Institute (1R01HL134892), the American Heart Association (18CSA34080399), the RRM Charitable Fund and the Simard Fund.
P.L. is an unpaid consultant to, or involved in clinical trials for, Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion, Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Merck, Novartis, Pfizer and Sanofi-Regeneron. P.L. is a member of the scientific advisory boards for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis and XBiotech, Inc. The laboratory of P.L. has received research funding in the past two years from Novartis. P.L. is on the Board of Directors of XBiotech, Inc. P.L. has a financial interest in Xbiotech, a company developing therapeutic human antibodies. The interests of P.L. were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare, in accordance with their conflict of interest policies.
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Libby, P. The changing landscape of atherosclerosis. Nature 592, 524–533 (2021). https://doi.org/10.1038/s41586-021-03392-8