Abstract P3067: Sleep Deprivation In Obesogenic Setting Alters Lipidome And Microbiome Toward Suboptimal Inflammation In Acute Heart Failure

Abstract

Introduction: Sleep is fundamental medicine for cardiac homeostasis and the immune fitness of human health. Sleep-deprived individuals are prone to higher incidences of a heart attack. The lipid-dense diet (obesogenic diet-OBD) is a cumulative risk factor for chronic inflammation in cardiovascular disease, thus understanding how sleep fragmentation (SF) in obesity setting impacts immune and cardiac health is an unmet medical need to develop novel therapeutics. Hypothesis: We hypothesized whether the co-existence of SF with OBD dysregulates gut homeostasis and leukocyte-derived reparative mediators thereby impairing cardiac repair. Methods: Two months old male C57BL/6J mice were randomized into two main groups; control (fed standard lab chow) and OBD (fed 10% w/w safflower oil-enriched diet) for 2 months. For SF, mice were subjected to SF chamber (2-minute interval bar sweep in light period (0700–1900 h) for 3 days. Mice of control, control+SF, OBD control, OBD+SF groups were further subjected to permanent coronary artery ligation to induce acute heart failure. Results: OBD fed mice had higher levels of plasma linolenic acid with a decrease in eicosapentaenoic acid and docosahexaenoic acid. The OBD mice had lower levels of Lactobacillus johnsonii indicating loss of probiotic microbiota. SF in OBD mice increased Firmicutes/Bacteroidetes (F/B) ratio indicative of a detrimental change in SF-directed microbiome signatures. OBD+SF group increased in the neutrophil: lymphocyte ratio suggestive of suboptimal inflammation. As a result of SF, resolution mediators (RvD2, RvD3, RvD5, LXA 4 , PD1, and MaR1) decreased and inflammatory mediators (PGD 2 , PGE 2 , PGF 2a , 6k-PGF 1a ) were increased post- MI in OBD fed mice. At the site of infarction, the proinflammatory cytokines; Ccl2, IL1β , and IL-6 were amplified in OBD+SF indicating a robust proinflammatory milieu. OBD+SF group showed signs of neutropenia in the spleen with pre-activation of CD169 macrophages. Also, brain circadian genes ( Bmal1, Clock) were downregulated in SF subjected control mice but remained elevated in OBD mice post-MI. Conclusion: SF superimposed on obesity dysregulated physiological inflammation and disrupted resolving response thereby impaired cardiac repair and signs of pathological inflammation.