Hyperacute Monocyte Gene Response Patterns Are Associated With Lower Extremity Vein Bypass Graft Failure

Abstract

Background Despite being the definitive treatment for lower extremity peripheral arterial disease, vein bypass grafts fail in half of all cases. Early repair mechanisms following implantation, governed largely by the immune environment, contribute significantly to long-term outcomes. The current study investigates the early response patterns of circulating monocytes as a determinant of graft outcome. Methods and Results In 48 patients undergoing infrainguinal vein bypass grafting, the transcriptomes of circulating monocytes were analyzed pre-operatively and at 1, 7 and 28 days post-operation. Dynamic clustering algorithms identified 50 independent gene response patterns. Three clusters (64 genes) were differentially expressed, with a hyperacute response pattern defining those patients with failed versus patent grafts twelve months post-operation. A second independent data set, comprised of 96 patients subjected to major trauma, confirmed the value of these 64 genes in predicting an uncomplicated versus complicated recovery. Causal network analysis identified eight upstream elements that regulate these mediator genes, and Bayesian analysis with a priori knowledge of the biological interactions were integrated to create a functional network describing the relationships among the regulatory elements and downstream mediator genes. Linear models predicted the removal of either Signal Transducer and Activator of Transcription 3 (STAT3) or Myeloid Differentiation Primary Response gene 88 (MYD88) to shift mediator gene expression levels towards those seen in successful grafts. Conclusions A novel combination of dynamic gene clustering, linear models and Bayesian network analysis has identified a core set of regulatory genes whose manipulations could migrate vein grafts towards a more favorable remodeling phenotype.

The Role of Immunomodulation in Vein Graft Remodeling and Failure

“…The expression of STAT3 or MYD88 predicted a clinically significant stenosis or thrombosis of the VG within the following year [70]. In these clusters of genes, DICER1 (a regulator gene of RNA silencing via miRNAs) was also identified [70]. Regulation of miRNAs is observed in remodeling and VGF, but needs further detailed investigation [50].…”

An omnidirectional visualization model of personalized gene regulatory networks

“…Rehfuss et al 27 reported a genomic study of infrainguinal vein bypass grafting involving 48 patients, among whom 35 succeeded and 13 failed. To investigate the genomic mechanism underlying graft outcome, transcriptomes of circulating monocytes from patients of success and failure were monitored at pre-operation and at days 1, 7, and 28 post-operation.…”

“…We validated the utility of our approach by analyzing gene expression data from surgical patients. Vein bypass grafting is an essential treatment for lower extremity arterial occlusive disease, but only with 30 – 50% success rate 27 . The biological mechanisms underlying the outcome of grafts include cue-induced differentiation of gene expression.…”

“…The implementation of variable selection helps to define and select a subset of the most significant genes that regulate a focal gene, which enables the inference of sparse but omnidirectional networks. To test and validate our approach, we analyzed genomic data of circulating monocytes from human infrainguinal vein bypass grafting, aimed at treating lower extremity arterial occlusive disease 27 , and reconstructed graft- and outcome-perturbed idopGRNs. The usefulness of our approach is further validated by a second vein graft experiment for rabbits 28 .…”

An omnidirectional visualization model of personalized gene regulatory networks

“…We test and validate the framework by analyzing genomic data of circulating monocytes from human infrainguinal vein bypass grafting, aimed at treating lower extremity arterial occlusive disease. 28 The utility of the framework is also supported by a second vein graft experiment for rabbits. 29 By reconstructing graft- and outcome-perturbed idopNetworks, we can potentially gain a mechanistic understanding of vein bypass graft success vs. failure.…”