Chronic psychological stress is a recognized, yet understudied risk factor for heart disease, with potential sex-specific effects. We investigated whether chronic stress triggers sex-dependent cardiac dysfunction in isolated Wistar rat hearts subjected to ischemia-reperfusion injury. The experimental cohort underwent 1 h of daily restraint stress for 4 wk versus matched controls, followed by euthanasia (sodium pentobarbital) and heart excision for ex vivo perfusion. Blood analysis revealed sex-specific alterations in stress hormones and inflammatory markers. When compared with controls, chronic restraint stress (CRS) males displayed decreased plasma brain-derived neurotrophic factor (BDNF) levels (P < 0.05), whereas CRS females exhibited elevated plasma adrenocorticotropic hormone (ACTH) (P < 0.01) and reduced corticosterone (P < 0.001) alongside lower serum estradiol (P < 0.001) and estradiol/progesterone ratio (P < 0.01). Of note, CRS females showed increased serum cardiac troponin T (P < 0.05) and tumor necrosis factor-α (TNF-α) (P < 0.01) with suppressed interleukin (IL)-1α, IL-1β, IL-6, and IL-10 levels (P < 0.05) when compared with controls. Ex vivo Langendorff perfusions revealed that CRS female hearts displayed impaired postischemic functional recovery for baseline stroke volume (SV, P < 0.01), work performance (P < 0.05), aortic output (AO, P < 0.05), coronary flow (CF, P < 0.01), and overall cardiac output (CO, P < 0.01) when compared with matched controls and CRS males (P < 0.05). Our findings reveal intriguing sex-specific responses at both the systemic and functional levels in stressed hearts. Here, the dysregulation of stress hormones, proinflammatory state, and potential underlying cardiomyopathy in females following the stress protocol renders them more prone to damage following myocardial ischemia. This study emphasizes the importance of incorporating sex as a biological variable in cardiac research focusing on stress-related cardiomyopathy.NEW & NOTEWORTHY Although chronic psychological stress is a risk factor for cardiovascular diseases, the underlying mechanisms remain poorly understood. This study revealed that chronic restraint stress resulted in systemic changes (dysregulated stress hormones, proinflammatory state) and potential cardiomyopathy in females versus controls and their male counterparts. The stressed female hearts also displayed reduced functional recovery following ex vivo ischemia-reperfusion. This highlights the importance of incorporating sex as a biological variable in cardiac research.
Keywords: cardiac dysfunction; cellular-senescence; chronic stress; female; ischemia-reperfusion.