Vein graft disease in a knockout mouse model of hyperhomocysteinaemia
Christina Maria Steger1, Tobias Mayr2, Nikolaos Bonaros3
1Department of Pathology, Academic Teaching Hospital Feldkirch (Affiliation of the Innsbruck Medical University), Feldkirch, Austria.
Insights
Hyperhomocysteinaemia in mice accelerated vein graft failure, increasing thrombosis and neointima formation. Further research is needed to determine if homocysteine is the primary cause of accelerated vein graft disease.
Area of Science:
- Vascular Biology
- Cardiovascular Surgery
- Metabolic Disease
Background:
- Vein graft failure after coronary artery bypass grafting is a significant clinical problem, often caused by neointimal hyperplasia and thrombosis.
- Elevated serum homocysteine (Hcy) levels are linked to cardiovascular disease and can increase post-cardiac surgery.
Purpose of the Study:
- To investigate the role of hyperhomocysteinaemia in vein graft failure using a mouse model.
- To compare vein graft outcomes in wild-type (WT) and cystathionine-beta-synthase heterozygous knockout (CBS+/-) mice.
Main Methods:
- Interposition of vena cava into the carotid artery in WT and CBS+/- mice.
- Histomorphology and immunohistochemistry analysis of vein grafts after 4 weeks.
- Measurement of serum Hcy levels before and after surgery.
Main Results:
- CBS+/- mice exhibited significantly higher thrombosis and a threefold increase in neointima formation compared to controls.
- Hyperhomocysteinaemic grafts showed altered elastic fiber and acid mucopolysaccharide content, with increased fibrosis.
- Serum Hcy levels were elevated in CBS knockout animals.
Conclusions:
- Hyperhomocysteinaemic mice serve as a valuable model for studying vein graft failure mechanisms.
- Further in vitro and in vivo studies are required to ascertain if homocysteine or related factors drive accelerated vein graft disease.
Abstract:
A major reason for vein graft failure after coronary artery bypass grafting is neointimal hyperplasia and thrombosis. Elevated serum levels of homocysteine (Hcy) are associated with higher incidence of cardiovascular disease, but homocysteine levels also tend to increase during the first weeks or months after cardiac surgery. To investigate this further, C57BL/6J mice (WT) and cystathionine-beta-synthase heterozygous knockout mice (CBS+/-), a mouse model for hyperhomocysteinaemia, underwent interposition of the vena cava of donor mice into the carotid artery of recipient mice. Two experimental groups were examined: 20 mice of each group underwent bypass surgery (group 1: WT donor and WT recipient; group 2: CBS+/- donor and CBS+/- recipient). After 4 weeks, the veins were harvested, dehydrated, paraffin-embedded, stained and analysed by histomorphology and immunohistochemistry. Additionally, serum Hcy levels in CBS knockout animals and in WT animals before and after bypass surgery were measured. At 4 weeks postoperatively, group 2 mice showed a higher percentage of thrombosis compared to controls, a threefold increase in neointima formation, higher general vascularization, a lower percentage of elastic fibres with shortage and fragmentation in the neointima, a lower percentage of acid mucopolysaccharides in the neointima and a more intense fibrosis in the neointima and media. In conclusion, hyperhomocysteinaemic cystathionine-beta-synthase knockout mice can play an important role in the study of mechanisms of vein graft failure. But further in vitro and in vivo studies are necessary to answer the question whether or not homocysteine itself or a related metabolic factor is the key aetiologic agent for accelerated vein graft disease.
