Ageing and inflammation strongly drive the risk of cardiovascular disease. Work over the past decade has uncovered a common condition characterized by the positive selection of certain somatic mutations in haematopoietic stem cells in ageing humans. This phenomenon, known as clonal haematopoiesis of indeterminate potential (CHIP), occurs most commonly as a result of mutations in the transcriptional regulators DNMT3A, TET2 and ASXL1. CHIP is associated with a variety of adverse outcomes, including haematological cancer and death. Surprisingly, CHIP is also associated with a doubling of the risk of atherosclerotic cardiovascular disease. Studies in mice support the causality of this relationship. Mutations in TET2, which are among the most commonly found mutations in CHIP, lead to increased expression of inflammatory genes in innate immune cells, potentially explaining the link between mutations and increased cardiovascular risk. Therapies targeting the mutant clones or the increased inflammatory mediators might be useful for ameliorating the risk of cardiovascular disease. We propose that the mutations leading to clonal haematopoiesis contribute to the increased inflammation seen in ageing and thereby explain some of the age-related risk of cardiovascular disease.
Clonal haematopoiesis of indeterminate potential (CHIP) is a common age-related condition characterized by the clonal expansion of haematopoietic stem cells bearing mutations in certain genes, especially DNMT3A, TET2 and ASXL1.
CHIP is associated with increased risk of haematological malignancies and all-cause mortality, but also increased risk of atherosclerotic cardiovascular disease, venous thrombosis and worse outcomes in heart failure.
Mutations associated with CHIP seem to have effects on immune effector cells, such as macrophages and neutrophils, which might account for the increased risk of cardiovascular complications in individuals with CHIP.
No treatments are currently available to lower the risk of cardiovascular disease in those with CHIP, but blockade of inflammatory molecules is a potential strategy to mitigate the effects of CHIP.
Individuals incidentally found to have CHIP should undergo evaluation for lifestyle modifications to reduce the risk of cardiovascular disease.
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The authors were supported by Burroughs Wellcome Fund Career Award for Medical Scientists and Fondation Leducq Transatlantic Network of Excellence (S.J.) and by the National Heart, Lung, and Blood Institute (R01HL080472), AHA (18CSA34080399) and the RRM Charitable Fund (P.L.).
S.J. has filed patents related to the topic of this Review and is a consultant for GRAIL. P.L. is an unpaid consultant to, or is involved in clinical trials for, Amgen, AstraZeneca, Esperion Therapeutics, Ionis Pharmaceuticals, Kowa Pharmaceuticals, Novartis, Pfizer, Sanofi-Regeneron and XBiotech. P.L. is a member of the scientific advisory board for Amgen, Corvidia Therapeutics, DalCor Pharmaceuticals, IFM Therapeutics, Kowa Pharmaceuticals, Medimmune, Novartis, Olatec Therapeutics and XBiotech.
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