Male mice are predominantly selected in preclinical myocardial fibrosis models because they exhibit higher susceptibility to pro-fibrotic signaling and develop more robust, uniform cardiac remodeling than age-matched females.
This sexual dimorphism is largely driven by hormonal regulation. Androgens such as testosterone promote pro-inflammatory cytokine expression and fibroblast activation, accelerating extracellular matrix deposition. In contrast, circulating estrogens exert cardioprotective effects, attenuating pathological remodeling and blunting fibrosis following cardiovascular insult.
In study design, using male cohorts maximizes the phenotypic effect size and reduces intra-group variance, allowing researchers to detect compound efficacy with smaller animal cohorts. However, relying exclusively on male animals presents an interpretation risk by obscuring potential sex-divergent pharmacodynamics or efficacy differences in female cardiac tissue.
Dual-sex validation should be prioritized when evaluating sex-specific therapeutic targets, investigating drugs with suspected hormonal interactions, or meeting regulatory guidance for IND-enabling safety and efficacy packages.