Abstract Or108: The role of SARM1 in regulation of immune response in heart failure with preserved ejection fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is an unmet medical need. Recent studies have shown that HFpEF is associated with immune dysregulation and decline in nicotinamide adenine dinucleotide (NAD + ) levels. However, the molecular mechanisms linking these factors in HFpEF are not completely understood. Sterile alpha and TIR motif-containing 1 (SARM1) is a NAD + consuming enzyme that may regulate immune response and NAD + metabolism. Here, we investigated the role of SARM1 in HFpEF pathophysiology. We utilized a two-hit diet model to induce HFpEF in mice (HFpEF diet: high-fat diet and L-NAME). Wild-type (WT) mice on HFpEF diet showed progressive decline in diastolic function (e.g. decreased E’/A’, increased relaxation time, IVRT) at 5- and 15-week, associated with unchanged systolic function and increased cardiac hypertrophy. Despite decline in NAD + levels as previously reported in HFpEF hearts, qPCR analysis showed no significant differences in the expression of enzymes involved in NAD + biosynthesis including the salvage, Preiss-Handler and de novo pathways. We employed RNA-sequencing to identify cardiac gene signatures that are associated with HFpEF. Gene ontology analysis showed activation of various immune pathways in HFpEF hearts. Using flow cytometry analysis, we observed around 66% increase in total leukocytes (CD45+) number, along with infiltration of both T cells (CD3+ CD4+/CD8+) and myeloid cell populations (CD11b+) in HFpEF hearts. To understand the role of SARM1 in HFpEF pathogenesis, we subjected global SARM1 knock out (KO) mice to HFpEF diet. SARM1 KO hearts had improved diastolic function and reduced hypertrophy after 15-week HFpEF diet. RNA-sequencing of SARM1 KO-HFpEF hearts showed downregulations of transcripts in immune activation pathways, compared to WT-HFpEF hearts. In summary, our findings suggest that SARM1 may regulate immune activation pathways and promote HFpEF pathogenesis. We plan to determine the intricate relationships between immune dysregulation, metabolic stress, and cardiac dysfunction in HFpEF pathogenesis. The future direction may identify potential avenues for targeted therapeutic interventions aimed at modulating immune responses for HFpEF.