Application of Spatial Transcriptomics to the Study of Accelerated Atherosclerosis in Human Vein Grafts

<p dir="ltr">Coronary artery bypass graft (CABG) surgery is heavily utilised in the management of advanced cases of coronary artery disease (CAD), intended to facilitate revascularisation of cardiac tissue undersupplied by their native, stenosed coronary arteries. Conduits, including the reversed long saphenous vein (LSV), are commonly utilised, despite suffering from poor long-term patency rates. Initial endothelial dysfunction triggers a sustained inflammatory response in implanted vein grafts, exacerbated by arterial haemodynamics, driving a process termed “vein graft disease” (VGD). To gain greater insight into the pathophysiology of VGD, this project sought to utilise a combination of ex vivo perfusion of LSV to acute arterial haemodynamics and spatial transcriptomics to understand the spatial and temporal progression of VGD. This project also sought to identify the utility of dexamethasone pre-treatment for mitigating against the inflammatory signalling driving VGD. Investigation of the effects of ex vivo acute arterial haemodynamics on the LSV by spatial transcriptomics identified a complex interplay between pro-inflammatory stimulation and phenotypic modulation of numerous cell types, particularly endothelial-to-mesenchymal transition (EndMT), which facilitates endothelial dysfunction, adverse graft remodelling, and sustained inflammatory signalling. Investigation of EndMT onset in response to arterial haemodynamics was revealed to be under the control of transforming growth factor beta (TGFβ) signalling, to which dexamethasone, a commonly utilised anti-inflammatory medication, is sufficient to not only mitigate against these effects driving early EndMT onset, but also to vascular calcification for time periods exceeding the initial treatment period. These results provide a comprehensive overview of the transcriptomic landscape in which VGD derives, elucidating key molecular mechanisms by which this process occurs, and provide exploratory evidence for a pre-treatment approach which is easily implementable in current surgical practice, which could significantly improve outcomes for patients undergoing CABG surgery.</p>