Deep Immune Phenotyping of Heart Failure to identify molecular signatures of Metabolically- Induced dysregulations in Peripheral Blood Mononuclear Cells reveals perturbations in cytotoxic activity

Background: Heart failure (HF) is a major global health issue with an increasingly recognized role of metabolic dysregulation and systemic inflammation in its pathogenesis. The present study aims to elucidate the perturbations in molecular pathways induced by metabolic dysregulation in HF.

Methods: We analysed Peripheral Blood Mononuclear Cells (PBMCs) of 64 patients diagnosed with different degrees of heart failure complicated by metabolic dysfunction from the MyoVasc and MyoMobile studies, two well-characterised heart failure cohorts. The patients are rigorously characterized based on their clinical, biochemical, and echocardiographic profiles. PBMCs were isolated and subjected to single-cell RNA sequencing (scRNA-seq). The scRNA-seq allows for high-resolution dissection of cell populations, enabling precise identification of cell-type-specific gene expression profiles. Our computational analysis pipeline implemented data pre-processing, dimensionality reduction, and unsupervised clustering algorithms, followed by cell type annotation using well-established marker genes. This robust methodology allowed us to uncover the heterogeneity of PBMCs at an unprecedented single-cell level and to identify cell populations most affected by HF and metabolic dysfunction.

Results: To investigate dysregulation of immune cell types in Heart Failure with preserved Ejection Fraction (HFpEF) and reduced Ejection Fraction (HFrEF), we tested for differential abundance and differential gene expression with metabolic dysregulation as comorbidity. Our results indicate significant changes in several cytotoxic cell type abundance. Network analysis of the respective differential gene expression elucidates between immune cells, as well as their role in inflammatory signaling and hypoxia. Further, we found separate cell clusters being greatly enriched in cells from individuals with the combination of metabolic dysfunction and HF. The characterization of dysregulated expression in these cells allows us to uncover the role of these subtypes in the onset of HF through metabolic dysregulation.

Conclusion: In summary, our investigation presents extensive evidence supporting the systemic disruption of inflammatory pathways and hypoxia response in individuals with Heart Failure (HF) accompanied by metabolic dysfunction. The results underscore the significance of inflammation and cytotoxic activity in the pathophysiology of this patient cohort, emphasizing the potential of single-cell transcriptomics in elucidating the intricate interplay between HF and metabolic dysregulation. Furthermore, the acquired knowledge may inform future studies exploring the use of inflammation and hypoxia markers for early detection and therapeutic monitoring in HF patients with metabolic dysfunction. Subsequent research endeavors should delve into therapeutic interventions targeting these dysregulated pathways and further characterizing distinct cell clusters to enhance outcomes in individuals with HF and metabolic dysfunction, ultimately advancing our understanding of the role of immune cells in HF complicated by metabolic dysregulation.