Editors' ChoiceMyocardial Infarction

Hidden agendas: Clonal hematopoiesis accelerates heart failure

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Science Translational Medicine  28 Mar 2018:
Vol. 10, Issue 434, eaat3885
DOI: 10.1126/scitranslmed.aat3885


Clonal hematopoiesis driven by TET2 deficiency accelerates post-infarct remodeling and heart failure through the NLRP3 inflammasome and IL-1β production.

Aging is a major risk factor for cardiovascular diseases including heart failure. A mechanistic basis explaining why aging is linked to these pathologies has remained elusive. Recently, it has been discovered that aging is associated with clonal hematopoiesis, a phenomenon by which somatic mutations accumulate within bone marrow progenitors. Dominant clones then emerge as a consequence of robust proliferation rates and/or survival advantage over the remainder of the progenitor pool. Deep sequencing focused on genes associated with hematopoietic malignancies previously revealed that loss-of-function mutations in the epigenetic modifier TET2 increased with age and were associated with increased risk of cardiovascular events. The mechanism by which TET2 mutations exert these effects, however, was unknown. To simulate TET2-mediated clonal hematopoiesis, Sano et al. utilized a mixed bone marrow chimera strategy to generate mice where approximately 60% of bone marrow-derived leukocytes were derived from Tet2–/– clones. Compared with controls, mice harboring Tet2–/– bone marrow progenitors displayed accelerated heart failure progression as evidenced by reduced left ventricular ejection fraction and increased chamber remodeling in both ischemic and pressure overload heart failure models. Mechanistically, the authors revealed that TET2 deficiency in myeloid cells mediates these phenotypes through enhanced NLRP3 inflammasome activation and interleukin-1β (IL-1β) production.

This study provides a presumptive explanation for why aging is associated with inflammation and heart failure. Specifically, emergence of hematopoietic clones that harbor mutations not only conferring a fitness advantage but also influencing immune cell function could influence disease pathogenesis and clinical outcomes. While mutations in TET2 appear to fit this model, it is likely that not all mutations that drive clonal hematopoiesis (i.e., DNMT3, ASXL1, JAK2) will have secondary effects on immune cell behavior. Much remains to be learned regarding how TET2 mutations enhance inflammasome activation, which immune cell types are affected by TET2 mutations, and whether TET2 mutations impact other pathologies, such as infection, malignancy, and organ transplantation. Regardless, these studies establish a new mechanism that links aging with cardiovascular disease and identify IL-1β signaling as a potential therapeutic target for patients with TET2-associated clonal hematopoiesis.

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