Abstract / Summary
Objective Human great saphenous vein (GSV) grafts remain a mainstay of bypass surgery, but high failure rates persist, driven largely by neointimal hyperplasia. Progress on the responsible mechanisms has been limited by a lack of models that reflect human disease. We developed a humanized xenograft model to capture early molecular and cellular changes in implanted veins and to test whether veins from different indications, peripheral artery disease (PAD) vs. coronary artery disease (CAD), influence neointimal hyperplasia progression. Methods The model was developed by implanting human GSV from patients undergoing bypass surgery or amputation for either PAD or CAD into male Rowett nude rats (n = 12) via infrarenal aortic interposition grafting. Graft patency and geometric parameters were monitored via duplex ultrasound for four weeks. On day 28, vein grafts and adjacent rat aortic segments were harvested for examination using Movat pentachrome (Movat's) and immunofluorescence staining to quantify ECM components, key proteoglycans (aggrecan, versican, and decorin), and proinflammatory M1 macrophages. Results were compared with clinical revision specimens from failed PAD grafts (n = 4). Results Both NR-PAD and NR-CAD grafts developed robust neointimal hyperplasia, with increased intimal area and proteoglycan deposition, but remodeling kinetics diverged. By day 28, NR-PAD had reduced luminal area (P < .05) with a relatively stable outer diameter, whereas NR-CAD grafts increased outer diameter (P < .01) while preserving luminal area. The staining demonstrated that both groups had increased intimal aggrecan and versican, but NR-PAD grafts uniquely showed reduced decorin in the intima and media (P < .05). NR-PAD grafts displayed significantly higher densities of CD86 + proinflammatory macrophages. Clinical specimens mirrored some of the model's findings of increased aggrecan and layer-specific SMC loss, whereas versican increased only in stenotic segments. Conclusions This model effectively mimics the early response of human veins to arterial grafting, such as intimal growth and increased intimal aggrecan and versican, which are shared by NR-PAD and NR-CAD grafts. Importantly, the grafts exhibit differential remodeling kinetics between indications. The presence of versican in stenotic but not normal healing regions of clinical PAD vein grafts suggests a potential role for its prolonged presence in graft failure. Clinical Relevance The study highlights that the vein graft indication may not be biologically neutral with respect to remodeling kinetics. Understanding the differential ECM remodeling and cellular profiles between CAD and PAD vein grafts may lead to personalized therapeutic interventions to improve long-term patency of bypass grafts.