Arteriovenous fistula creation results in cardiac dysfunction and remodeling in a uremic pig model

The arteriovenous fistula (AVF) is required for hemodialysis in end-stage kidney disease (ESKD). AVF creation results in compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling. Relatedly, cardiovascular mortality and morbidity are elevated in patients with ESKD, which worsens in patients with dialysis. Currently, no suitable uremic large animal models exist to investigate the mechanisms of AVF-induced cardiac remodeling. This study aims to characterize cardiovascular changes secondary to AVF creation, supported by percutaneous transluminal angioplasty (PTA), in a uremic pig model. Chronic kidney disease (CKD) was induced via renal embolization, followed by AVF creation 28 days later. AVF stenosis was alleviated 28 days thereafter via PTA, and cardiac magnetic resonance imaging (MRI) was performed at 14, 28, and 42 days post-PTA. Increased end-diastolic volumes were observed in both ventricles, whereas systolic function was preserved. Left ventricular (LV) stroke volume and blood flow through the aorta, pulmonary artery, and vena cava were also increased. In perivascular areas of the LV, senescence markers showed increased p16 expression and decreased p21 expression. The LV showed perivascular fibrosis, with increased cardiomyocyte cross-sectional area, reduced collagen-type IV expression, and matrix metalloproteinase 2 (MMP2) activity, possibly not driven by transforming growth factor-β (TGF-β)/connective tissue growth factor (CTGF)/phosphorylated SMAD signaling. However, CD4⁺ or CD68⁺ cell LV infiltration and inflammatory polarization of resident macrophages were unchanged. In conclusion, AVF creation modified left and right ventricular function and increased peripheral flow, potentially mediated by cellular senescence and fibrosis, resulting in progressive cardiac remodeling. This model may be used to evaluate mechanisms of AVF-induced cardiac disease and potentially investigate the efficacy of senolytics and antifibrotic agents.NEW & NOTEWORTHY The creation of an arteriovenous fistula in a uremic pig induces cardiac remodeling, which resembles contemporary clinical findings in patients with end-stage kidney disease (ESKD) and includes increased end-diastolic volumes and cardiomyocyte hypertrophy, potentially driven by fibrosis and senescence. This novel large animal model may now enable mechanistic and therapeutic studies aiming to ease the unacceptably high burden of cardiovascular disease on patients with ESKD.