Clonal hematopoiesis in cardiovascular disease and therapeutic implications

Abstract

Clonal hematopoiesis arises from somatic mutations that provide a fitness advantage to hematopoietic stem cells and the outgrowth of clones of blood cells. Clonal hematopoiesis commonly involves mutations in genes that are involved in epigenetic modifications, signaling and DNA damage repair. Clonal hematopoiesis has emerged as a major independent risk factor in atherosclerotic cardiovascular disease, thrombosis and heart failure. Studies in mouse models of clonal hematopoiesis have shown an increase in atherosclerosis, thrombosis and heart failure, involving increased myeloid cell inflammatory responses and inflammasome activation. Although increased inflammatory responses have emerged as a common underlying principle, some recent studies indicate mutation-specific effects. The discovery of the association of clonal hematopoiesis with cardiovascular disease and the recent demonstration of benefit of anti-inflammatory treatments in human cardiovascular disease converge to suggest that anti-inflammatory treatments should be directed to individuals with clonal hematopoiesis. Such treatments could target specific inflammasomes, common downstream mediators such as IL-1β and IL-6, or mutations linked to clonal hematopoiesis.

Fig. 1 |. Somatic mutations and clonal hematopoiesis: at the crossroads of hematological malignancies and cardiovascular disease.

Hematopoietic stem cells accumulate somatic mutations continuously with aging. Some of these mutations confer a competitive advantage to the mutant cell, leading to its clonal expansion in bone marrow and blood. This clonal hematopoiesis is most frequently driven by one single mutation. While clonal hematopoiesis is associated with a large increase in the relative risk of developing a hematologic neoplasia, transition to malignancy typically requires the acquisition of multiple mutations, which is infrequent, even in individuals with clonal hematopoiesis. The main cause of death in individuals exhibiting clonal hematopoiesis is cardiovascular disease. Epidemiological and experimental evidence suggest that some clonal-hematopoiesis-related mutations can contribute to the development and clinical progression of atherosclerosis, heart failure and thrombosis. Heightened inflammatory responses mediated by tissue-infiltrating mutant immune cells are emerging as a central link between clonal hematopoiesis and cardiovascular disease.

Fig. 2 |. Mutation-specific mechanisms linking clonal hematopoiesis to atherosclerotic cardiovascular disease.

Emerging evidence supports that different mutant genes promote inflammation and atherosclerosis through diverse mechanisms. a, TET2-deficient macrophages (purple cells) exhibit increased IL-1β transcript levels and higher NLRP3 inflammasome-mediated IL-1β secretion. Heightened IL-1β levels in the plaque promote P-selectin expression and endothelial cell activation, leading to increased recruitment of circulating leukocytes. IL-1β may further stimulate its own expression in both TET2-mutant cells and WT macrophages (light blue cells) through an autoregulatory autocrine–paracrine feedback loop. b, JAK2^VF expression in macrophages leads to an overactivation of the AIM2 inflammasome, which increases JAK2^VF mutant macrophage proliferation (red cells) in a manner dependent on intrinsic JAK2^VF function and IL-1β signaling. Increased AIM2 inflammasome activity also leads to greater pyroptotic cell death of mutant macrophages (darker red cells), which contributes to the expansion of necrotic cores within the atherosclerotic plaque.