Immune-related transcriptomic and epigenetic variation with cytokine changes across heart failure phenotypes

Abstract

Heart failure (HF) is characterized by complex systemic alterations that extend beyond the local environment in the myocardium, yet the molecular signatures present in peripheral, circulating immune cells remain incompletely defined. In mice, a shift toward pro-inflammatory macrophages has been linked to fibrosis and heart failure. Epigenetic modulators have also been associated with cardiac dysregulation and inflammation, including promotion of hypertrophy, fibroblast proliferation and arterial stiffness in rodents.

For the current molecular study, we used biological material and an existing data set from a HF-cohort. To investigate HF-associated systemic changes in immune cells, we profiled the transcriptome and investigated the chromatin accessibility in peripheral white blood cells from patients with new onset HF (n=12) and compared with that of age- and gender-matched healthy controls (n=6). HF cases were stratified into heart failure with reduced ejection fraction (HFrEF; n=6) and heart failure with preserved ejection fraction (HFpEF; n=6) to explore phenotype-specific molecular patterns. In parallel, we evaluated data on 158 circulating plasma proteins to assess systemic inflammatory and metabolic signaling.

Frozen EDTA whole blood samples were used for both bulk ATAC and bulk RNA sequencing. The plasma immune profile was retrieved from an existing data set from the HF-cohort where the plasma proteome has been investigated in detail by a multi-parameter approach.

The transcriptomics data reveal that HFpEF cases have a more inflammatory-related systemic immune phenotype, while HFrEF cases have alterations in pathways correlated to metal- and potassium ion transport and regulation as well as neuron development and differentiation. The ATAC sequencing did not reveal major changes in the global chromatin landscape between the HF- phenotypes and/or controls. However, the integrative analysis combining the transcriptomic and ATAC sequencing data suggest 10 chromatin sites that are likely to impact transcription factor binding, and thereby also gene expression. Additionally, the integration of the data sets further emphasized differences, separating HFpEF, HFrEF and healthy controls into distinct groups. Finally, a primary analysis of the proteomics data showed a potential difference between the HF-phenotypes, highlighting proteins linked to inflammation, such as IL18BP, IL1RT2, SPON2 and SOD2.

In conclusion, our findings suggest that there are fundamental mechanistic differences between HFpEF and HFrEF. This supports the hypothesis that HFpEF represents a hyper-inflammatory condition, which may have substantial clinical implications.Integrative analysis of RNA and ATAC seqFor image description, please refer to the figure legend and surrounding text.