Abstract: TH-PO301
Cardiac Tissue Chip Model of Arteriovenous Fistula-Associated Hemodynamics Recapitulates Changes Seen in Mouse AVF Model
Session Information
- Vascular Access: From Biology to Managing Complications
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 703 Dialysis: Vascular Access
Authors
- Lee, Timmy C., The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
- Isayeva Waldrop, Tatyana, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
- Graham, Caleb, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
- Gard, William A., The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
- Ingle, Kevin Andrew, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
- Sethu, Palaniappan, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
Background
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 leads to a volume overload (VO) state. 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 constructs were subjected to “volume overload” conditions, they would display fibrosis and key gene expression changes seen in AVF mice.
Methods
Mice underwent either AVF or sham procedure and sacrificed at 28 days. Cardiac tissue constructs (Fig 1) 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 hours. Controls were exposed to “normal” stretch and experimental group exposed to “volume overload”. RT-PCR and histology were performed on the CTC and mice left ventricles (LVs), and transcriptomics of mice LVs were performed.
Results
Our CTC contructs and mice LV both demonstrated cardiac fibrosis as compared to control fibers and sham-operated mice, respectively. Our gene expression studies in our CTC 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.
Conclusion
Our CTC model yields similar fibrosis-related histology and gene expression profiles as our murine AVF model. The CTC can play a critical role in understanding cardiac pathobiology of VO states similar to what is present after AVF creation and used in evaluating therapies.
Funding
- Other NIH Support