The Immunological Consequences of Clonal Hematopoiesis in Heart Failure

Figures

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  FIGURE 1. Evidence linking TET2‐mediated clonal hematopoiesis to elevated IL‐1β/NLRP3 inflammasome activity in heart failure and cardiovascular disease. Upper left: Blocking the NLRP3 inflammasome has been shown to improve cardiac function in mouse models of heart failure with reduced ejection fraction (HFrEF) with Tet2‐mediated clonal hematopoiesis (CH). Upper right: Mice with a genetic deficiency of the NLRP3 inflammasome exhibit attenuated diastolic dysfunction in mouse models of Tet2‐mediated CH. Middle: Tet2‐deficient macrophages exhibit increased IL‐1β transcription, upregulation of the NLRP3 inflammasome, and consequently greater production of active IL‐1β. Lower left: In a subanalysis of the CANTOS trial, individuals with a previous history of MI harboring hematopoietic TET2 mutations showed a markedly greater reduction in major adverse cardiovascular events (MACE) compared with those without CHIP when treated with the IL‐1β–neutralizing antibody canakinumab. Lower right: In an analysis of the Mass General Brigham Biobank (MGBB) and UK Biobank (UKB), individuals with TET2‐CH who were prescribed colchicine, a broad‐spectrum anti‐inflammatory agent that also inhibits the NLRP3…

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  FIGURE 2. Mechanism by which hematopoietic loss of the Y chromosome promotes heart failure and fibrosis. Hematopoietic stem cells may lose the Y chromosome as a consequence of aging, giving rise to a population of mature leukocytes with LOY. Following cardiac injury or during aging, leukocytes of both genotypes migrate to the heart and participate in various pathophysiological processes. However, LOY macrophages display a pro‐fibrotic phenotype and produce elevated levels of the pro‐fibrotic mediator TGFβ1. Consequently, this promotes an expansion of cardiac fibroblasts and increased extracellular matrix deposition, leading to cardiac fibrosis and a decline in cardiac function. Created with Biorender and adapted from [22] with permission.

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  FIGURE 3. Immune mechanisms by which clonal hematopoiesis (CH) drives experimental heart failure (HF). Age‐related driver mutations (TET2, DNMT3A, ASXL1, JAK2 V617F) induce a pro‐inflammatory macrophage phenotype with heightened inflammasome (NLRP3/AIM2) activity and/or elevated IL‐1β/IL‐6 expression. Following myocardial injury (e.g., ischemia, pressure overload, or angiotensin II), mutant leukocytes infiltrate the heart and promote cardiac damage, contributing to systolic HF. Similarly, TET2 mutations can drive pro‐inflammatory signaling (NLRP3, SPP1) in myeloid cells, leading to myocardial damage and diastolic dysfunction under obesogenic/hypertensive conditions. By contrast, LOY in macrophages promotes a pro‐fibrotic phenotype with enrichment of TGF‐β1–associated genes, contributing to cardiac dysfunction in the setting of pressure overload or aging. Mutations in TP53 and PPM1D, commonly associated with therapy‐related CH, may contribute to anthracycline‐induced cardiotoxicity (AIC) and non‐ischemic cardiac injury, respectively, leading to systolic HF. For TP53, inflammatory and ROS‐mediated mechanisms in neutrophils have been implicated, whereas for PPM1D, elevated NLRP3 inflammasome…