Abstract
Hemodialysis arteriovenous fistulas(AVFs) promote left ventricular(LV) hypertrophy, a known predictor of cardiovascular mortality in patients with chronic kidney disease(CKD). AVF flow dynamics do not reliably predict cardiac remodeling suggesting additional causal biological determinants. Sex influences AVF maturation but its role in myocardial adaptation is unknown. We previously demonstrated sex-dependent protective effects of N-acetylcysteine(NAC) on skeletal muscle in a murine iliac AVF model. This study sought to evaluate whether iliac AVF creation produces compensated cardiac hypertrophy, investigate sex as a modifier of cardiac myocyte mitochondrial adaptation, and test NAC supplementation as a therapeutic strategy. Male and female C57BL/6J mice with adenine-induced CKD underwent iliac AVF or sham surgery with saline or NAC treatment. Ultrasound, echocardiography, and cardiac myocyte mitochondrial respiratory testing were performed. AVF creation produced significant aortic flow increases and corresponding diameter growth(male +64%, female +109%, p<0.001). Heart weight increased ~30-40mg over sham for both sexes(p<0.001). Female AVF mice demonstrated higher ejection fraction(94.8±5.1% vs. male-83.1±7.5%, p<0.001) and attenuated diastolic volume increase(32.8±11.8μl vs. 46.5±15.1μl, p=0.003). AVF inflow did not correlate with LV mass or ejection fraction. Cardiac mitochondrial oxidative phosphorylation(OXPHOS) was higher in female AVF mice(sex-effect p=0.01). NAC did not alter cardiac structure or function. Murine iliac AVF creation results in compensated cardiac hypertrophy without heart failure replicating observations documented in patients. Female AVF mice demonstrated greater cardiomyocyte size and respiratory function, plus exaggerated systolic function and minimized dilated cardiomyopathy, supporting sex as a modifier of the compensated cardiac response after AVF creation. NAC was not protective against maladaptive cardiac remodeling or function.