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

Abstract

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.

The Diabetic Cardiorenal Nexus

“…Elasticity and contractility were studied in juvenile rats after banding of the pulmonary artery. Female rats survived longer, demonstrating lower levels of right ventricular fibrosis, and lower degrees of expression of the calcium/calcineurin cascade [144].…”

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

“…Using these surgical approaches, delineated RV failure can be achieved 7 weeks from PA banding, as demonstrated by a reduced ejection fraction and cardiac output and severely dilated right chambers [ 70 ], with temporal sex-related differences in developing the HF phenotype (observed less contractile and diastolic dysfunction and fibrosis in females) [ 71 ]. The grade of PA banding contributes directly to the timing of the transition to a decompensated RV response, which can start manifesting after 1–3 weeks from the procedure in case of severe PA constriction [ 70 , 72 ].…”

Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice

“…Current understanding of sexual dimorphism in RV pressure overload remodeling is largely based upon pre-clinical studies demonstrating the cardioprotection of the potent estrogen 17bestradiol (E2) against various cardiac stressors. [3][4][5][6][7][8][9] The mechanistic details of E2 cardioprotection in the RV, however, are not well defined. Recently a cardioprotective E2/ERa signaling axis was identified in the pressure overloaded RV---E2/ERa upregulation of apelin, a pro-contractile and pro-survival peptide.…”