Abstract Body (Do not enter title and authors here): Background: The efficacy of coronary artery bypass grafting (CABG) is often compromised by graft failure, particularly in elderly and female patients, who exhibit higher occlusion rates. The underlying CABG graft pathobiology leading to these phenotypes associated with graft patency remains largely elusive, hindering the development of targeted therapies for these vulnerable populations.
Hypothesis: We hypothesized that distinct age- and sex-driven molecular alterations unveil the pathobiology and are associated with phenotypes relevant to CABG graft patency.
Methods: Left internal mammary artery (LIMA) grafts from 113 patients who underwent CABG were analyzed and stratified by age (middle-aged: ≤65 vs. elderly: >65 years) and sex. Graft morphology (including intimal/medial thickness and intima-to-media ratio (IMR)) was assessed (H&E, Masson’s). RNA sequencing of LIMA/perivascular adipose tissue (PVAT) from a discovery cohort (n=3-9/group) identified differentially expressed genes associated with age- and sex-specific graft pathobiology. Bioinformatic analyses (e.g., IPA and PPI networks) identified candidate genes, which were validated by qRT-PCR. Statistical significance was set at p<0.05.
Results: We identified distinct phenotypes associated with graft patency: elderly males showed increased intimal thickness (30.35±11.85 vs. 21.81±9.05 µm, p<0.05), and elderly females showed reduced medial thickness (128.87±20.54 vs. 178.18±41.43 µm, p<0.05), indicating sex-specific remodeling. Age-related PVAT dysfunction was prominent, featuring senescent adipocytes and upregulated proinflammatory adipokines. These PVAT alterations correlated with IMR, highlighting PVAT's central role in graft pathobiology. Furthermore, we identified sex-specific transcriptomic signatures, including upregulated FMNL1 in elderly males and dysregulated CDH5 in elderly females, contributing to graft pathobiology.
Conclusions: This study unveils that age-related PVAT dysfunction and distinct sex-specific vascular molecular signatures are critical drivers of pathobiology and key phenotypes associated with CABG graft patency in elderly and female patients. The identified PVAT-derived and sex-linked vascular biomarkers are strongly associated with these pathobiological processes. These findings offer novel insights for identifying individuals at higher risk for complications related to graft patency and may inform personalized interventions aimed at improving long-term CABG success.