Sleep deprivation in obesogenic setting alters lipidome and microbiome toward suboptimal inflammation in acute heart failure

Abstract

AbstractSleep is a fundamental medicine for cardiac homeostasis, and sleep‐deprived individuals are prone to higher incidences of 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 an obesity setting impacts immune and cardiac health is an unmet medical need. We hypothesized whether the co‐existence of SF with OBD dysregulates gut homeostasis and leukocyte‐derived reparative/resolution mediators, thereby impairing cardiac repair. Two‐month‐old male C57BL/6J mice were randomized first into two groups, then four groups; Control, control + SF, OBD, and OBD + SF mice subjected to myocardial infarction (MI). OBD mice had higher levels of plasma linolenic acid with a decrease in eicosapentaenoic and docosahexaenoic acid. The OBD mice had lower Lactobacillus johnsonii indicating a loss of probiotic microbiota. SF in OBD mice increased Firmicutes/Bacteroidetes ratio indicative of a detrimental change in SF‐directed microbiome. OBD + SF group increased in the neutrophil: lymphocyte ratio suggestive of suboptimal inflammation. As a result of SF, resolution mediators (RvD2, RvD3, RvD5, LXA4, PD1, and MaR1) decreased and inflammatory mediators (PGD2, PGE2, PGF2a, 6k‐PGF1a) were increased in OBD mice post‐MI. At the site of infarction, the proinflammatory cytokines Ccl2, IL1β, and IL‐6 were amplified in OBD + SF indicating a robust proinflammatory milieu post‐MI. Also, brain circadian genes (Bmal1, Clock) were downregulated in SF‐subjected control mice, but remained elevated in OBD mice post‐MI. SF superimposed on obesity dysregulated physiological inflammation and disrupted resolving response thereby impaired cardiac repair and signs of pathological inflammation.