Investigating the effect of chronic stress, depressive-like pathology and cognitive impairments on acute myocardial infarction: sex-differentiated effects

Abstract Background/Introduction Depression is an independent risk factor for cardiovascular disease (CVD) with the prevalence rates being higher in women than men in the general population and among patients with CVD. Furthermore, an association between myocardial infarction and cognitive deficits has been proposed, but the pathophysiological mechanisms that are responsible for the brain-heart axis interaction have not been elucidated. Purpose The present study aims to: 1) evaluate sex differences in the effect of chronic unpredictable stress (CUS) on myocardial infarct size (IS) and 2) determine the molecular pathways affected by CUS in the heart. Methods Adult male and female C57BL/6J mice, were randomly divided into 4 groups (n=7/group): CON (Control, sham surgery), iCON (Control, myocardial ischemia/reperfusion (IR)), STR (Stress, sham surgery) and iSTR (Stress, IR). Mice were intermittently exposed to the CUS protocol consisted of 4 different stressors for 6 consecutive weeks. Locomotor activity (open field-OF), anxiety-like alterations (OF, elevated plus-maze-EPM test), depressive-like pathology (tail suspension test- TST) and cognition (Y-maze and Novel Object Recognition-NOR tests) were evaluated. After behavioral evaluation, the animals were subjected to 30 min I followed by 24 h of R or sham surgery and infarct size (IS) was determined via double Evan’s Blue and triphenyltetrazolium chloride staining. In a second series of experiments (n=5/group), the ischemic part of the myocardium was collected at 24h R and subjected to label free proteomic analysis, in order to identify alterations associated with the effect of CUS and IR. Results CUS induced anxiety, depressive-like pathology and cognitive deficits as indicated by the increased time spent in the closed arms of the EPM (p<0.005), the increased immobility time (TST, p<0.05), the reduced preference for the novel object (NOR, p<0.05), and the significant body weight reduction (p<0.001), in both male and female mice. CUS significantly increased IS (p<0.001) in both male and female mice. Proteomic analysis revealed that CUS affected the heart proteome, related to endoplasmic reticulum stress, mitochondrial damage and apoptosis, of both sexes in the absence of IR. Female mice were more susceptible to IR damage in absence of CUS with 248 significant genes (FDR<0.05) being deregulated mainly belonging to Keap-Nrf2-ARE signaling pathway, in contrast to 168 significant genes in male mice. In male mice, CUS exacerbated the IR injury proteome changes mainly related to induction of apoptosis and mitochondrial dysregulation (292 significant genes, FDR<0.05 for males vs 102 for females). Conclusions Chronic exposure to stress increases depressive-like pathology and cognitive deficits, leading to heart proteome alterations and increased IS in both sexes. Sex differences were observed indicating that the coexistence of CUS and IR render the male heart more susceptible to myocardial damage.