Abstract Body: Introduction
Hemodialysis arteriovenous fistulas(AVFs) incite left ventricular(LV) hypertrophy, a major predictor of cardiovascular morbidity and mortality in chronic kidney disease(CKD) patients. However, AVF flow dynamics do not predict cardiac remodeling, suggesting additional biologic determinants. Sex influences AVF maturation, but its role in the myocardial response remains unknown. We hypothesized that female sex confers adaptive cardiomyocyte mitochondrial function, limiting pathological LV remodeling after AVF creation.

Methods
Male and female 8-week-old mice with adenine-induced CKD underwent iliac AVF or sham surgery and were treated with saline or N-acetyl cysteine(NAC; an antioxidant used to investigate myocardial redox biology)(Fig.1A). Cardiac echocardiography was assessed pre- and two weeks post-operatively followed by cardiomyocyte respiratory function testing.

Results
AVF creation produced similar aortic flow increases for both sexes, with associated diameter growth(male +64%, female +109%, p<0.001; baseline size differences)(Fig.1B,C). AVF Heart weight was ~30-40mg greater than sham in both sexes(both p<0.001; Fig.1D–F). Female AVF mice demonstrated an adaptive cardiac phenotype compared to males(Fig.2A–H). Baseline ejection fraction(EF) of 79.8±11.2%(v. male 70.3±15.4%, p=0.03) increased to 94.8±5.1%(v. male 83.1±7.5%, p<0.001) following AVF. Also, LV diastolic volume increase was minimized: 25.6±10.3 μl(v. 29.4±13.4 μl, p=0.3) to 32.8±11.8 μl(v. 46.5±15.1 μl, p<0.001). AVF inflow did not correlate with LV mass, chamber diameter, or EF. Sex-based differences were also observed in cardiomyocyte mitochondrial function(Fig.3A–I). Female AVF mice demonstrated higher oxidative phosphorylation(OXPHOS) capacity, which trended toward correlation with EF(p=0.06). NAC treatment was associated with a trend toward improved respiration in female AVF mice(JO₂ p=0.10; OXPHOS p=0.09), an effect not observed in males(JO₂ p=0.87; OXPHOS p=0.64). OXPHOS values were 2266.1±1217.8 and 2978.5±792.1 for female AVF saline and NAC mice, respectively, exceeding sham cohorts(p=0.06, p=0.02) and male AVF cohorts(p=0.5, p=0.007).

Conclusions
Despite similar AVF flow dynamics, sex influences maladaptive cardiomyopathy. Female mice increased cardiomyocyte mitochondrial function, thereby reducing pathological remodeling, with a potential NAC treatment effect. These findings implicate sex-specific myocardial redox biology as a key modifier of AVF-related cardiac outcomes.