Abstract
Abstract only
Introduction:
While heart failure (HF) is a leading cause of death and indication for transplant in single ventricle (SV) patients, the molecular mechanisms underlying HF progression are poorly understood. Chronic inflammation can initiate and accelerate pathological outcomes in patients with virtually every form of cardiovascular disease, yet our understanding of the impacts of immunologic alterations in SV are inadequate. Here, we test the hypothesis that peripheral immune cells (PBMCs) from SV patients display a pro-inflammatory and metabolically dysfunctional phenotype that contributes to progressive cardiac dysfunction.
Methods:
Pediatric SV patients were categorized based on ventricular function, including those with reduced systolic function (SVHF, n=32), Fontan failure (Fontan Failure, n=7), or healthy control (healthy control, n=18). PBMCs were isolated from whole blood by density gradient centrifugation. To assess the impact of the PBMC extracellular milieu, we treated isolated cardiomyocytes with human plasma. Mitochondrial bioenergetics were assessed using the Seahorse Bioanalyzer (Agilent). Statistical analysis was performed using a Kruskal-Wallis and post-hoc Dunn’s multiple comparisons test. Total RNA sequencing was performed to identify dysregulated pathways.
Results:
PBMCs from SVHF patients display decreased metabolic function (OCR, A) and increased glycolysis (ECAR, B). PBMCs from SVHF patients also display significant alterations in immune, inflammatory, and metabolic pathways (C). Moreover, plasma from SVHF patients decreases cardiomyocyte energetics.
Conclusions:
These data suggest that immune cells from SV patients display a pro-inflammatory and metabolically dysfunctional phenotype, with an increased dependence on glycolysis. Therefore, our data highlight a role for SV PBMCs to potentiate progressive cardiac dysfunction in this population and provide a novel avenue for therapeutic intervention.