Development and validation of an integrated preclinical model mimicking cardiometabolic risk in postmenopausal female rats

Abstract

Abstract Cardiovascular disease (CVD) remains the leading cause of death in postmenopausal women, often exacerbated by coexisting metabolic disorders such as obesity and type 2 diabetes mellitus. Existing preclinical models fail to capture the multifactorial nature of these overlapping risk factors in a sex-specific context. Here, we present a novel, translationally relevant cardiometabolic model in female Wistar rats that integrates estrogen deficiency, dietary excess, and diabetic stress to mimic postmenopausal disease progression. The model exhibits pronounced cardiometabolic dysfunction, including obesity, insulin resistance, dyslipidemia, QTc prolongation, reduced QRS amplitude, and elevated markers of myocardial injury (Troponin T, CK-MB) and systemic inflammation (IL-6, IL-1β, TNF-α) ( p  < 0.05). These hallmarks closely mirror human postmenopausal cardiometabolic syndrome, providing a clinically relevant platform for mechanistic studies. Notably, this model allows investigation of mitochondrial dysfunction, oxidative stress, and endothelial impairment, while enabling preclinical evaluation of targeted pharmacological interventions, including hormone replacement therapy, metabolic modulators, anti-inflammatory agents, and cardioprotective strategies. By bridging preclinical findings with clinical applications, this approach offers a powerful tool to advance personalized therapeutic strategies for high-risk postmenopausal women, addressing a critical gap in translational cardiovascular research.