Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease

Abstract

The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).

Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

“…One murine model of TET2-deficient clonal hematopoiesis implicates macrophage TET2 deficiency in accelerated atherogenesis and CVD, 16,44 whereas another recent case control analysis revealed higher rates of atherosclerotic heart disease associated with mutations in DNMT3A, TET2, ASXL1, and JAK2 among CHIP patients. 15 Although clonal hematopoiesis does not always result in a clinical presentation of MDS, 8,11,12 our data showing a steadily increasing incidence of cardiovascular and cerebrovascular events from the time of MDS diagnosis may suggest a common underlying pathophysiology. Although the SEER database does not contain comprehensive molecular data, we noted that among patients with RARS, which is enriched for SF3B1 mutations and characterized by slower rates of progression, the proportion of deaths attributed to MDS was relatively steady with time, whereas the proportion of deaths attributed to CVD increased as patients lived longer from their time of diagnosis.…”

“…13,15 This may relate to an interaction between the clonal cells and the endothelium or to a shared predisposition to both problems; for instance, a germ line DNA repair defect that both accelerates atherogenesis and increases the risk of clonal hematopoiesis. One murine model of TET2-deficient clonal hematopoiesis implicates macrophage TET2 deficiency in accelerated atherogenesis and CVD, 16,44 whereas another recent case control analysis revealed higher rates of atherosclerotic heart disease associated with mutations in DNMT3A, TET2, ASXL1, and JAK2 among CHIP patients.…”

“…13 CHIP patients appear to specifically have an increased risk of atherosclerotic heart disease. 15,16 It is not known whether this cardiovascular risk is specific to CHIP, or whether patients with similar mutations and with an MDS diagnosis also carry this increased risk.…”

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

“…For example, in obstructive sleep apnea, the accumulation of CD36 + macrophages within the aortic wall has been ascribed to histone modifications, ultimately accelerating CVD development (45). Clonal hematopoiesis and CVD have been brought to attention in a recent publication, where the authors report that the risk for CVD increases in patients carrying Tet2 mutations in their PBMCs (46). In terms of a possible involvement of changes in the micro RNA (miRNA) profile, the comparison of 2 recent reports makes miR223 a likely candidate to be involved in psoriasis-induced macrophage differentiation changes (47,48).…”

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

“…Although low allele fractions suggest that the JAK2 p.V617F mutation is from subclonal tumor cells in the tested samples, there is an alternative interpretation pertaining to an aging-related phenomenon referred to as clonal hematopoiesis of indeterminate potential (CHIP) [51]. Defined as the presence of a genetically distinct, hematopoietic stem cell-derived subpopulation of blood cells harboring somatic mutations but without apparent hematological abnormalities, CHIP is common among older individuals and is associated with an increased risk of hematological cancers and cardiovascular diseases [52][53][54]. It is conceivable the JAK2 p.V617F mutation we detected is due to infiltrating hematological cells in persons with CHIP.…”