Clonal Hematopoiesis: A New Step Linking Inflammation to Heart Failure

Abstract

Heart failure is a common disease with poor prognosis that is associated with cardiac immune cell infiltration and dysregulated cytokine expression. Recently, the clonal expansion of hematopoietic cells with acquired (i.e., nonheritable) DNA mutations, a process referred to as clonal hematopoiesis, has been reported to be associated with cardiovascular diseases including heart failure. Mechanistic studies have shown that leukocytes that harbor these somatic mutations display altered inflammatory characteristics that worsen the phenotypes associated with heart failure in experimental models. In this review, we summarize recent epidemiological and experimental evidence that support the hypothesis that clonal hematopoiesis-mediated immune cell dysfunction contributes to heart failure and cardiovascular disease in general.

Keywords: ASXL1, additional sex combs like 1; DNMT3A; DNMT3A, DNA methyltransferase-3A; HSPCs, hematopoietic stem and progenitor cells; IL, interleukin; Il-1β inflammasome; JAK2; JAK2, janus kinase 2; MPN, myeloproliferative neoplasm; PPM1D, protein phosphatase, Mg2+/Mn2+ dependent 1D; TET2; TET2, ten-eleven translocation-2; TNF, tumor necrosis factor; TNF-α; TP53, tumor protein 53; VAF, variant allele fraction; hsCRP, high-sensitivity C-reactive protein.

Graphical abstract

Figure 1

Summary of Clonal Hematopoiesis Reported in 3 Studies (A) The frequency of clonal hematopoiesis increases with age. Shown are the time courses of clonal hematopoiesis detection in 3 studies of patient cohorts that were unselected for hematologic disorders , , . (B) A comparison of frequencies of known and unknown driver genes in the 3 studies. In Jaiswal et al. , the exome sequence of 160 candidate driver genes (i.e., genes known to be recurrently mutated in hematologic malignancies) were analyzed. In Genovese et al. , whole exome sequencing revealed that a substantial proportion of clonal hematopoiesis events could not be attributed to known driver genes. The study of Zink et al. used a nonbiased whole genome sequencing approach. The frequency of mutations in candidate driver genes accounted for approximately 20% of the total number of clonal events. This work indicates that the occurrence of clonal hematopoiesis approaches inevitability with advancing age and that we have a limited understanding of the diverse mechanisms that can contribute to this process.

Figure 2

Tet2-Deficiency Activates Many Steps in the Production of IL-1β Tet2-deficiency activates many steps in the production of interleukin (IL)-1β by macrophages. This condition increases IL-1β transcript expression by increasing histone acetylation at the IlL1β promoter. Tet2-deficient cells also exhibit increased NLRP3 expression and caspase-1 activity. Accordingly, Tet2 deficiency leads to elevated levels of pro–IL-1β processing and IL-1β secretion. HDAC = histone deacetylase.

Central Illustration

Clonal Hematopoiesis Can Alter Immune Cell Function and Contribute to Heart Failure Hematopoietic stem and progenitor cells (HSPCs) acquire random somatic mutations over time. Occasionally, these mutations occur in driver genes (yellow circles) that provide the HSPC with a competitive advantage, and this leads to clonal expansion in a limiting bone marrow niche. This process is referred to as clonal hematopoiesis, and it can be prevalent in individuals who lack overt signs of hematologic disorders. These mutant HSPCs give rise to progeny immune cells that harbor the mutant gene. This condition may alter the phenotype of the leukocyte and contribute to heart failure.