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Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown.Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and the cardiac tissue. We demonstrate that CHIP augments macrophage-to-cardiac fibroblasts interactions. Mechanistically, the secretome ofDNMT3A-silenced monocytes leads to myofibroblast activation, partially through epidermal growth factor (EGFR) signaling. Harboring DNMT3A CHIP-driver mutations is associated with increased cardiac interstitial fibrosis in mice and patients, and, thereby, may contribute to the poor outcome.These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies.Graphical abstract

Aims Clonal hematopoiesis (CH), defined as the presence of an expanded somatic blood cell clone due to acquired mutations in leukemia driver genes, was shown to be associated with increased mortality in patients with chronic ischemic heart failure with reduced ejection fraction (HFrEF). Mechanistically, circulating monocytes of mutation carriers display increased expression of proinflammatory genes involved in inflammasome and IL-6 signaling. Inherited single nucleotide variants (SNPs) in the IL-6 pathway are well known to affect inflammatory activation. Therefore, we investigated whether known SNPs in genes encoding for components of the inflammasome/IL-6 signaling pathway modulate fatal outcomes in HFrEF patients with CH. Methods and results In a total of 446 patients with chronic HFrEF, peripheral blood or bone marrow mononuclear cells were analyzed for the CH driver mutations DNMT3A and TET2 as well as 40 preselected SNPs affecting genes in the NLRP3 inflammasome/IL-6 signaling pathway. The 103 patients carrying a CH driver mutation demonstrated significantly increased mortality compared to the 343 patients without CH mutations (25,24% vs 13.99% at five years; p=0.0064). We identified three commonly occurring variants known to disrupt IL-6 signaling (rs2228145, rs4129267 and rs4537545) which are in strong linkage disequilibrium and present in more than 50% of CH carriers. As illustrated in Figure 1A, harboring one of those SNPs abrogated the increased mortality risk in patients with HFrEF and CH (p≤0.05 for each SNP). On the contrary, three different SNPs namely rs2250417, which is associated with increased IL-18 levels as well as rs4722172 and rs4845625, which are known to activate IL-6 signaling, were identified to mediate fatal outcomes in patients with HFrEF and CH (p Conclusion Among CHIP carriers with HFrEF, inherited variants in loci encoding for genes involved in inflammatory signaling associate with mortality. These data not only provide mechanistic insights into inflammatory mechanisms contributing to fatal outcome of HFrEF in CH carriers but may also inform trials evaluating precision-targeted anti-inflammatory therapy in patients with DNMT3A and TET2 mutations and chronic HFrEF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Center of Cardiovascular Research;Cardiopulmonary Institute, Frankfurt, Germany