REITERATED MALE VIOLENCE JEOPARDIZES CARDIAC HOMEOSTASIS IN FEMALE MICE

Psychosocial stress is increasingly recognized as a contributor to cardiovascular disease, particularly in women, who have been shown to be more vulnerable to mental stress–induced myocardial ischemia (MSIMI). Nevertheless, the neurobiological mechanisms linking social stress, such as intimate partner violence-related stress, to cardiac pathology remain poorly defined, in part due to a historical focus on male subjects. Here, we used the Reiterated Male-to-Female Violent Interaction (RMFVI) paradigm to examine how psychosocial stress alters cardiac structure, function, and neurocardiac signaling in female mice. Adult C57BL6/J female mice underwent echocardiography before and after RMFVI. Cardiac remodeling was assessed by LV histology, and transcriptomic profiling was followed by Ingenuity Pathway Analysis (IPA). RMFVI induced eccentric LV remodeling characterized by increased LV internal diameter during diastole (p=0.00005) and systole (p=0.0058). Heart rate was significantly elevated (p=0.0006), indicating sustained autonomic activation. Histological analysis revealed increased interstitial fibrosis (p=0.013) and right ventricular wall hypertrophy. Transcriptomic profiling demonstrated extracellular matrix remodeling, with upregulation of Timp1/3, downregulation of Mmp9/14 and Adam19, and increased fibroblast activation. IPA analyses identified activation of inflammation, ferroptosis, and neutrophil extracellular trap signaling. Importantly, RMFVI disrupted neurocardiac signaling. NGF and BDNF expression was reduced, while GDNF receptor components (Gfra1, Gfra4, and Ret) were upregulated, suggesting compensatory sympathetic remodeling, coupled with impaired parasympathetic response. In conclusion, our data show that psychosocial stress leads to maladaptive cardiac remodeling in females, sustained by impaired neurocardiac control, paving the way for a deeper understanding of how psychosocial stress endangers the female heart.