Abstract 4366416: Polyvascular Disease Is Associated With Increased Platelet Activity, Hyperreactive Platelet Transcriptome and Cardiovascular Events

Background: Many patients with peripheral artery disease (PAD) have concomitant coronary artery disease (CAD). Patients with concomitant PAD and CAD, known as polyvascular disease, are a high-risk population. Platelets have potent mechanistic effects in the pathogenesis of cardiovascular (CV) disease. We investigated CV risk, platelet aggregation, and the platelet transcriptome in patients with polyvascular disease versus PAD alone. Methods: Patients with symptomatic PAD scheduled for lower extremity revascularization (LER) were included in the study. Patients were followed for a median of 18 months after LER for adverse clinical events. The primary endpoint was major adverse cardiovascular or limb events (MACLE), a composite of death, myocardial infarction, stroke, and major amputation. Light transmission aggregometry (LTA) was used to measure platelet aggregation in response to submaximal agonist stimulation. Platelet RNA was isolated and sequenced, and differential expression analysis was performed stratified by polyvascular disease, adjusted for age, sex, race, and ethnicity. Results: Among 289 subjects undergoing LER, 160 (55%) had polyvascular disease (mean age 70, 68% male, 68% white), and 129 (45%) had PAD alone (mean age 69, 66% male, 54% white). After multivariable adjustment of demographic and clinical risk factors, polyvascular disease patients had a higher incidence of MACLE (45.0% vs 26.4% in PAD alone, aHR 2.3, 95% CI 1.4-3.8, p=0.001; Panel A). Among 97 subjects matched for receiving both aspirin and clopidogrel, there was no difference in platelet aggregation in response to arachidonic acid (AA) and adenosine diphosphate (ADP). In contrast, platelet aggregation in response to submaximal epinephrine was higher in patients with vs without polyvascular disease (Panel B). Platelet RNA sequencing comparing groups (72 polyvascular vs 62 PAD alone) revealed 182 differentially expressed genes (p < 0.01), 77 upregulated and 105 downregulated. Gene set enrichment analysis revealed enrichment of pathways involved in platelet activation, platelet aggregation, and cell junction organization in patients with polyvascular disease compared to PAD alone (Panel C). Conclusion: Patients with polyvascular disease have a higher risk of CV events, increased platelet aggregation, and a hyperreactive platelet transcriptome. Altogether, these data suggest that platelets may mediate, in part, the heightened risk of CV events in patients with polyvascular disease.