Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease

Abstract

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.

Fig. 1 ∣. Cardiovascular conditions related to CHIP-associated mutations.

Clonal haematopoiesis of indeterminate potential (CHIP) is associated with atherosclerosis, heart failure and thrombosis. Putative mechanisms for each of these pathologies are shown. Accelerated atherosclerosis in the setting of mutations in TET2 likely occurs due to increased expression of inflammatory molecules in lesional macrophages, such as IL1B, IL6, and IL8, which act to recruit immune cells to vessel walls, thus leading to growth of the plaque. Similarly, risk of heart failure may be due to enhanced inflammation in cardiac macrophages, which leads to progressive dysfunction of the myocardium. Increased thrombotic risk is especially common in those with activating JAK2 mutations, and may be due to enhanced NETosis in mutated neutrophils. NET, neutrophil extracellular trap; VCAM1, vascular cell adhesion protein 1.

Fig. 2 ∣. Mutational spectrum and prevalence of clonal haematopoiesis.

a ∣ The most commonly mutated genes in clonal haematopoiesis. The relative number of mutations in each gene is proportional to its representation on the circle’s circumference. b ∣ The prevalence of clonal haematopoiesis according to age^,.