Cardiovascular events are the primary cause of death among dialysis patients. While arteriovenous fistulas (AVFs) are the access of choice for hemodialysis patients, AVF creation can lead to a volume overload (VO) state in the heart. We developed a three-dimensional (3D) cardiac tissue chip (CTC) with tunable pressure and stretch to model the acute hemodynamic changes associated with AVF creation to complement our murine AVF model of VO. In this study, we aimed to replicate the hemodynamics of murine AVF models in vitro and hypothesized that if 3D cardiac tissue constructs were subjected to “volume overload” conditions, they would display fibrosis and key gene expression changes seen in AVF mice. Mice underwent either an AVF or sham procedure and were sacrificed at 28 days. Cardiac tissue constructs composed of h9c2 rat cardiac myoblasts and normal adult human dermal fibroblasts in hydrogel were seeded into devices and exposed to 100 mg/10 mmHg pressure (0.4 s/0.6 s) at 1 Hz for 96 h. Controls were exposed to “normal” stretch and experimental group exposed to “volume overload”. RT-PCR and histology were performed on the tissue constructs and mice left ventricles (LVs), and transcriptomics of mice LVs were also performed. Our tissue constructs and mice LV both demonstrated cardiac fibrosis as compared to control tissue constructs and sham-operated mice, respectively. Gene expression studies in our tissue constructs and mice LV demonstrated increased expression of genes associated with extracellular matrix production, oxidative stress, inflammation, and fibrosis in the VO conditions vs. control conditions. Our transcriptomics studies demonstrated activated upstream regulators related to fibrosis, inflammation, and oxidative stress such as collagen type 1 complex, TGFB1, CCR2, and VEGFA and inactivated regulators related to mitochondrial biogenesis in LV from mice AVF. In summary, our CTC model yields similar fibrosis-related histology and gene expression profiles as our murine AVF model. Thus, the CTC could potentially play a critical role in understanding cardiac pathobiology of VO states similar to what is present after AVF creation and may prove useful in evaluating therapies.
Introduction: Cardiovascular disease is the primary cause of death amongst end-stage renal disease (ESRD) patients. Though arteriovenous fistulas (AVFs) are the access of choice for hemodialysis, joining a high-pressure artery and low-pressure vein leads to cardiac volume overload acutely. Debate exists as to the cardiac ramifications of AVFs, due in part to the difficulty of recruiting ESRD patients and controls for prospective studies. Animal models have been essential in AVF studies, but their usefulness is limited by interspecies differences in physiology and other factors. Thus, we have developed a three-dimensional (3D) cardiac tissue chip with tunable pressure and stretch to model the acute hemodynamic changes associated with AVF creation. Hypothesis: In this study, we aimed to replicate the hemodynamics of murine AVF models in vitro and hypothesized that if 3D cardiac constructs were subjected to “volume overload”, they would display fibrosis and key gene expression changes seen in AVF mice. Methods: Mice underwent either AVF or sham procedure and were monitored for 28 d. Cardiac tissue constructs composed of h9c2 rat cardiac myoblasts and normal adult human dermal fibroblasts in hydrogel were seeded into devices and exposed for 96 h to 100 mmHg/10 mmHg pressure (0.4 s/0.6 s) at 1 Hz. "Systolic" pressure was generated via pneumatic pump while a hydrostatic pressure head gave rise to "diastolic" pressure. The controls were exposed to “normal” stretch while the experimental group was exposed to “volume overload”. Results and Conclusions: The in vitro model yielded similar fibrosis-related gene expression profiles (see figure) and patterns of fibrosis as the murine model.
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