Aims

Clonal hematopoiesis (CH) 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. Inherited genetic variants (SNP) 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, blood or bone marrow cells were analyzed for the CH driver mutations DNMT3A and TET2 as well as 48 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 (p=0.0064). We identified three commonly occurring variants known to disrupt IL-6 signaling (rs2228145, rs4129267 and rs4537545), which abrogated the increased mortality risk in patients with HFrEF and CH (p≤0.05 for each SNP). On the contrary, three different SNPs (rs2250417, which is associated with increased IL-18 levels; rs4722172 and rs4845625, which are known to activate IL-6 signaling) were identified to mediate fatal outcomes in patients with HFrEF and CH; p<0.05 for each). None of the assessed SNPs influenced outcomes in patients without DNMT3A or TET2 mutations. Single Cell RNA-sequencing of circulating monocytes of patients with HFrEF revealed increased inflammatory signaling in DNMT3A mutation carriers harboring IL6/IL18 activating SNPs . 

Conclusion

Among CH carriers with HFrEF, inherited variants in loci encoding for genes involved in inflammatory signaling interact with mortality risk. 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 CH and chronic HFrEF.