Arteriovenous fistula-induced cardiac remodeling shows cardioprotective features in mice

Abstract

Objective Arteriovenous fistulae (AVF) placed for hemodialysis have high flow rates that can stimulate left ventricular (LV) hypertrophy. LV hypertrophy generally portends poor cardiac outcomes, yet clinical studies point to superior cardiac-specific outcomes for patients with AVF when compared with other dialysis modalities. We hypothesize that AVF induce physiologic cardiac hypertrophy with cardioprotective features. Methods We treated 9- to 11-week-old C57Bl/6 male and female mice with sham laparotomy or an aortocaval fistula via a 25G needle. Cardiac chamber size and function were assessed with serial echocardiography, and cardiac computed tomography angiography. Hearts were harvested at 5 weeks postoperatively, and the collagen content was assessed with Masson's trichrome. Bulk messenger RNA sequencing was performed from LV of sham and AVF mice at 10 days. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis (Qiagen) to identify affected pathways and predict downstream biological effects. Results Mice with AVF had similar body weight and wet lung mass, but increased cardiac mass compared with sham-operated mice. AVF increased cardiac output while preserving LV systolic and diastolic function, as well as indices of right heart function; all four cardiac chambers were enlarged, with a slight decrement in the relative LV wall thickness. Histology showed preserved collagen density within each of the four chambers without areas of fibrosis. RNA sequencing captured 19 384 genes, of which 857 were significantly differentially expressed, including transcripts from extracellular matrix-related genes, ion channels, metabolism, and cardiac fetal genes. The top upstream regulatory molecules predicted include activation of angiogenic (Vegf, Akt1), procardiomyocyte survival (Hgf, Foxm1, Erbb2, Lin9, Areg), and inflammation-related (CSF2, Tgfb1, TNF, Ifng, Ccr2, IL6) genes, as well as the inactivation of cardiomyocyte antiproliferative factors (Cdkn1a, FoxO3, α-catenin). The predicted downstream effects include a decrease in heart damage, and increased arrhythmia, angiogenesis, and cardiogenesis. There were no significant sex-dependent differences in the AVF-stimulated cardiac adaptation. Conclusions AVF stimulate adaptive cardiac hypertrophy in wild-type mice without heart failure or pathologic fibrosis. Transcriptional correlates suggest AVF-induced cardiac remodeling has some cardioprotective, although also arrhythmogenic features. (JVS–Vascular Science 2021;2:110-28.) Clinical Relevance Arteriovenous fistulae (AVF) are commonly used as access for hemodialysis in patients with end-stage renal disease. AVF induce a high-output state that is associated with long-term structural cardiac remodeling, including left ventricle hypertrophy, but this element has uncertain clinical significance. Although left ventricle hypertrophy has traditionally been associated with an in...

Inflammation and Cardiovascular Disease Associated With Hemodialysis for End-Stage Renal Disease

“…Nevertheless, AVF induces inflammation in HD patients, firstly by stimulating the production of oxidative stress markers during endovascular fistula formation, inducing intimal hyperplasia, and exacerbating local inflammation. Second, AVF for hemodialysis can lead to a hyperdynamic state of circulating blood, stimulating left ventricular hypertrophy and leading to a poor cardiac prognosis ( Lee et al, 2021 ).…”

A central arteriovenous fistula reduces systemic hypertension in a mouse model

“…Furthermore, this data is consistent with our previous data showing potential cardiac-protective effects of an AVF. 21 Together these data suggest the beneficial effect of a central AVF to lower the blood pressure in resistant hypertension, as well as induce protective cardiac remodeling.…”