Maladaptive Myeloid Lipid Metabolism Promotes Cardiac Diastolic Dysfunction Through Splenic Hematopoiesis

Rationale: Diastolic dysfunction, including during heart failure with preserved ejection fraction (HFpEF), is a widespread morbidity with limited therapeutic options. Though heterogeneous in etiology, major risk factors include hyperlipidemia, hypertension, and elevated inflammation. Inflammatory macrophages have been implicated in the promotion of diastolic dysfunction; however underlying mechanistic insight remains in its infancy. Objective: We set out to define the heterogeneity of the cardiac immune response during diastolic dysfunction to identify cell and molecular protagonists relevant to HFpEF. We hypothesized that systemic metabolic perturbations during HFpEF were promoting cardiac inflammation and fibrosis. Methods and Results: Diastolic dysfunction was induced by a combination of high fat diet (HFD) and iNOS inhibition (L-NAME). scRNAseq of the myocardium revealed significant alterations in the composition of cardiac macrophage subsets. Gene ontology analyses depicted a specific induction of pro-fibrotic and lipid handling pathways, including the fatty acid receptor Cd36. In live animals, myeloid deficiency of Cd36 prevented diastolic dysfunction and was associated with dampened cardiac inflammation. When investigating immune cell sourcing during HFpEF, it was found that a splenic hematopoietic niche formed in wild-type mice. Within splenic macrophages, HFpEF-associated risk factors activated mitochondrial metabolism, as well as expression of vascular cell adhesion molecule-1 (VCAM-1), the latter which has been shown to retain hematopoietic stem cells in the spleen. In vitro treatment of splenic macrophages with high fat was sufficient to induce expression of Vcam1, an effect found to be mediated by mitochondrial reactive oxygen species activation of the transcription factor Spic. Conclusions: Our data suggest a critical role for myeloid metabolism in the sourcing of detrimental-monocyte-derived macrophages from the spleen, to the heart.