Abstract 18959: Glycosphingolipid-Mediated Cardiomyocyte and Immune Cell Dysfunction in Hypoplastic Left Heart Syndrome

• Published in: Circulation (New York, N.Y.) N.Y.), 2023-11, Vol.148 (Suppl_1)
• Main Authors: Turner, Mary E, Pietra, Ashley E, Sanchez, Erin E, Garcia, Anastacia M
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.148.suppl_1.18959

Abstract only Introduction: Hypoplastic Left Heart Syndrome (HLHS) is the leading indication for heart transplant and the most common cause of cardiovascular death in infants. However, the mechanisms associated with heart failure progression in HLHS are poorly understood. Glycosphingolipids (GSLs) have been implicated in a variety of biological and disease processes, however, the role of GSLs in the context of HLHS pathophysiology have not been explored. Here we test the hypothesis that aberrant GSLs drive maladaptive cardiac and immune cell responses and predispose HLHS patients to pathologic remodeling and eventual cardiac dysfunction. Methods: GSL content was measured by mass-spectrometry. To test the direct effect of the specific GSL species, lactosylceramide (LacCer), cardiac and peripheral immune cells (PBMCs) were treated with liposomes containing 3uM LacCer (C18:0 and C24:0). Mitochondrial respiration was assessed using the Seahorse Bioanalyzer (Agilent). Expression of metabolic proteins were assessed by western blot. Statistical analysis between 2 groups was performed using an unpaired T-test. Results: LacCer is significantly increased in heart tissue and in isolated PBMCs from patients with HLHS (A), and isolated mitochondria are highly enriched with LacCer. Moreover, exogenous LacCer is sufficient to impair cardiomyocyte mitochondrial fatty acid beta-oxidation (B), induce ROS generation, and decrease the expression of metabolic proteins Additionally, exogenous LacCer is sufficient to promote inflammation and decrease mitochondrial bioenergetics in PBMCs (C). Conclusions: These data highlight a novel role for LacCer in modulating cardiomyocyte and immune cell phenotypes and suggest aberrant GSLs contribute to the HLHS pathophysiology. Elucidation of the molecular mechanisms involved in impaired immune cell and cardiomyocyte responses in HLHS is crucial and these data suggest a unique avenue for therapeutic intervention in this population.