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Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients.

ABSTRACT: In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs in the treatment of congenital heart disease. We show two distinct phases of graft remodeling: an early phase distinguished by rapid changes in graft geometry and a second phase of sustained growth and decreased graft stiffness. Using clinically informed and patient-specific computational fluid dynamics (CFD) simulations, we demonstrate how changes to TEVG geometry, thickness, and stiffness affect patient hemodynamics. We show that metrics of patient hemodynamics remain within normal ranges despite clinically observed levels of graft narrowing. These insights strengthen the continued clinical evaluation of this technology while supporting recent indications that reversible graft narrowing can be well tolerated, thus suggesting caution before intervening clinically.

SUBMITTER: Schwarz EL

PROVIDER: S-EPMC8298568 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients.

Schwarz Erica L EL Kelly John M JM Blum Kevin M KM Hor Kan N KN Yates Andrew R AR Zbinden Jacob C JC Verma Aekaansh A Lindsey Stephanie E SE Ramachandra Abhay B AB Szafron Jason M JM Humphrey Jay D JD Shin'oka Toshiharu T Marsden Alison L AL Breuer Christopher K CK

NPJ Regenerative medicine 20210722 1

In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs ...[more]

PMID: 34294733

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Project description:Macrophages are a critical driver of neovessel formation in tissue-engineered vascular grafts (TEVGs), but also contribute to graft stenosis, a leading clinical trial complication. Macrophage depletion via liposomal delivery of clodronate, a first-generation bisphosphonate, mitigates stenosis, but simultaneously leads to a complete lack of tissue development in TEVGs. This result and the associated difficulty of utilizing liposomal delivery means that clodronate may not be an ideal means of preventing graft stenosis. Newer generation bisphosphonates, such as zoledronate, may have differential effects on graft development with more facile drug delivery. We sought to examine the effect of zoledronate on TEVG neotissue formation and its potential application for mitigating TEVG stenosis. Thus, mice implanted with TEVGs received zoledronate or no treatment and were monitored by serial ultrasound for graft dilation and stenosis. After two weeks, TEVGs were explanted for histological examination. The overall graft area and remaining graft material (polyglycolic-acid) were higher in the zoledronate treatment group. These effects were associated with a corresponding decrease in macrophage infiltration. In addition, zoledronate affected the deposition of collagen in TEVGs, specifically, total and mature collagen. These differences may be, in part, explained by a depletion of leukocytes within the bone marrow that subsequently led to a decrease in the number of tissue-infiltrating macrophages. TEVGs from zoledronate-treated mice demonstrated a significantly greater degree of smooth muscle cell presence. There was no statistical difference in graft patency between treatment and control groups. While zoledronate led to a decrease in the number of macrophages in the TEVGs, the severity of stenosis appears to have increased significantly. Zoledronate treatment demonstrates that the process of smooth muscle cell-mediated neointimal hyperplasia may occur separately from a macrophage-mediated mechanism.

Dataset Information

Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients.

Publications

Hemodynamic performance of tissue-engineered vascular grafts in Fontan patients.

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