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Female rats are less prone to clinical heart failure than male rats in a juvenile rat model of right ventricular pressure load.

Sex is increasingly emerging as determinant of right ventricular (RV) adaptation to abnormal loading conditions. It is unknown, however, whether sex-related differences already occur in childhood. Therefore, this study aimed to assess sex differences in a juvenile model of early RV pressure load by pulmonary artery banding (PAB) during transition from pre- to post-puberty. 3-weeks old rat pups (n=57, 30-45g) were subjected to PAB or sham surgery. Animals were sacrificed either before or after puberty (4 and 8 weeks post-surgery, respectively). Male PAB rats demonstrated failure to thrive already after 4 weeks, whereas females did not. After 8 weeks, female PAB rats showed less clinical symptoms of RV failure than male PAB rats. RV pressure-volume analysis demonstrated increased end-systolic elastance after 4 weeks in females only, and a trend toward preserved end-diastolic elastance in female PAB rats compared to males (p=0.055). Histology showed significantly less RV myocardial fibrosis in female compared to male PAB rats 8 weeks after surgery. Myosin heavy chain 7/6 ratio switch and calcineurin signaling were less pronounced in female PAB rats, compared to males. In this juvenile rat model of RV pressure load, female rats appeared to be less prone to clinical heart failure, compared to males. This was driven by increased RV contractility before puberty, and better preservation of diastolic function with less RV myocardial fibrosis after puberty. These findings show that RV adaptation to increased loading differs between sexes already before the introduction of pubertal hormones.