Abstract 225: Pulmonary Hypertension Induced Right Ventricle Fibrosis is Associated With Male Gender

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Pulmonary hypertension (PH) is a rare but incurable disease. The primary reason of PH mediated mortality is right ventricle (RV) failure. There is a well-established sexual dimorphism in regard to PH, with females generally associated with higher susceptibility to develop PH, while males possess lower survival rate. We hypothesized that sex difference in PH mediated mortality is associated with sex difference in mechanisms of RV failure development, with males being more prone to develop RV dysfunction. The angioproliferative PH was induced in 8 week old male and female rats by bolus injection of VEGF receptor 2 antagonist, SU5416 (20 mg/kg, s.c.) followed by 4 weeks of exposure to hypoxia (10%±0.5 O2) and 10 weeks of normoxia (21% O2). We found that PH induced a significantly higher mortality in males comparing to females, although the increase in RV peak systolic pressure (RVPSP) was similar in both genders (95.8±13.5 vs. 84.6±18.2; p=0.636; N=5). At the early stage of PH (4 weeks) both males and females had possessed the similar levels of PH induced increase in RV free wall (RVFW) thickness, assessed by Doppler echocardiography. However, starting from 8 week RV hypertrophy continues to progress in males only, while RVFW thickness in females was found to be preserved (RVFW at 12 week, mm: 2.1±0.2 vs. 1.2±0.1; p=0.003; N=5-6). After 14 weeks of study there was a significant impairment of RV relaxation and RV diastolic function in male group only (RV peak diastolic pressure (RVPDP), mmHg: -0.6±0.9 vs. -5.4±0.9; p=0.008; N=4-5). Finally, Masson’s trichrome staining revealed severe fibrosis in the RV of male, but not female rats with PH (fibrotic score: 2.5±0.3 vs. 0.7±0.2; p=0.0007; N=5-6), which was associated with endothelial nitric oxide synthase (eNOS) uncoupling, assessed by measuring caveolin expression (fold male Cont: 0.3±0.003 vs. 1.9±0.3; p=0.002; N=4) and eNOS dependent increase in superoxide generation. We conclude that males with PH have a high risk of mortality due to increased cardiac fibrosis development, which, in turn, leads to RV failure. The severe oxidative stress with subsequent injury of myocardial tissue may be responsible for RV fibrotic changes in males, which are lack of female sex hormones known to exert strong anti-oxidant protection.