Faculty Bibliography

BACKGROUND:Peripheral artery disease (PAD), a diffuse manifestation of atherothrombosis, is a major cardiovascular threat. Although platelets are primary mediators of atherothrombosis, their role in the pathogenesis of PAD remains unclear. OBJECTIVES/OBJECTIVE:The authors sought to investigate the role of platelets in a cohort of symptomatic PAD. METHODS:The authors profiled platelet activity, mRNA, and effector roles in patients with symptomatic PAD and in healthy controls. Patients with PAD and carotid artery stenosis were recruited into ongoing studies (NCT02106429 and NCT01897103) investigating platelet activity, platelet RNA, and cardiovascular disease. RESULTS:Platelet RNA sequence profiling mapped a robust up-regulation of myeloid-related protein (MRP)-14 mRNA, a potent calcium binding protein heterodimer, in PAD. Circulating activated platelets were enriched with MRP-14 protein, which augmented the expression of the adhesion mediator, P-selectin, thereby promoting monocyte-platelet aggregates. Electron microscopy confirmed the firm interaction of platelets with monocytes in vitro and colocalization of macrophages with MRP-14 confirmed their cross talk in atherosclerotic manifestations of PAD in vivo. Platelet-derived MRP-14 was channeled to monocytes, thereby fueling their expression of key PAD lesional hallmarks and increasing their directed locomotion, which were both suppressed in the presence of antibody-mediated blockade. Circulating MRP-14 was heightened in the setting of PAD, significantly correlated with PAD severity, and was associated with incident limb events. CONCLUSIONS:The authors identified a heightened platelet activity profile and unraveled a novel immunomodulatory effector role of platelet-derived MRP-14 in reprograming monocyte activation in symptomatic PAD. (Platelet Activity in Vascular Surgery and Cardiovascular Events [PACE]; NCT02106429; and Platelet Activity in Vascular Surgery for Thrombosis and Bleeding [PIVOTAL]; NCT01897103).

OBJECTIVE: Previous studies involving large administrative data sets have revealed regional variation in the demographics of patients selected for carotid endarterectomy (CEA) and carotid artery stenting (CAS) but lacked clinical granularity. This study aimed to evaluate regional variation in patient selection and operative technique for carotid artery revascularization using a detailed clinical registry. METHODS: All patients who underwent CEA or CAS from 2009 to 2015 were identified in the Vascular Quality Initiative (VQI). Deidentified regional groups were used to evaluate variation in patient selection, operative technique, and perioperative management. chi2 analysis was used to identify significant variation across regions. RESULTS: A total of 57,555 carotid artery revascularization procedures were identified. Of these, 49,179 patients underwent CEA (asymptomatic: median, 56%; range, 46%-69%; P < .01) and 8376 patients underwent CAS (asymptomatic: median, 36%; range, 29%-51%; P < .01). There was significant regional variation in the proportion of asymptomatic patients being treated for carotid stenosis <70% in CEA (3%-9%; P < .01) vs CAS (3%-22%; P < .01). There was also significant variation in the rates of intervention for asymptomatic patients older than 80 years (CEA, 12%-27% [P < .01]; CAS, 8%-26% [P < .01]). Preoperative computed tomography angiography or magnetic resonance angiography in the CAS cohort also varied widely (31%-83%; P < .01), as did preoperative medical management with combined aspirin and statin (CEA, 53%-77% [P < .01]; CAS, 62%-80% [P < .01]). In the CEA group, the use of shunt (36%-83%; P < .01), protamine (32%-89%; P < .01), and patch (87%-99%; P < .01) varied widely. Similarly, there was regional variation in frequency of CAS done without a protection device (1%-8%; P < .01). CONCLUSIONS: Despite clinical benchmarks aimed at guiding management of carotid disease, wide variation in clinical practice exists, including the proportion of asymptomatic patients being treated by CAS and preoperative medical management. Additional intraoperative variables, including the use of a patch and protamine during CEA and use of a protection device during CAS, displayed similar variation in spite of clear guidelines. Quality improvement projects could be directed toward improved adherence to benchmarks in these areas.

Background: Patients with peripheral artery disease (PAD) are at increased risk of atherothrombotic events and benefit from platelet inhibiting therapies. The EUCLID trial demonstrated no significant benefit from ticagrelor versus clopidogrel for the reduction of cardiovascular or limb events in patients with PAD. Aims: The EUCLID platelet substudy aimed to compare the antiplatelet effects of ticagrelor and clopidogrel in patients with PAD. Methods: Patients were randomized to receive either clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily). The effect of study drug was studied in 75 patients during maintenance therapy (>=6-weeks post randomization). In 42 patients, platelet inhibition was measured at baseline and after 2-and 6-weeks of study drug (=12 hrs after last dose). In all patients, pharmacodynamic assessments were made using light transmission aggregometry (in response to ADP 5 and 20uM, collagen 1ug/ml and arachidonic acid [AA] 150uM), VerifyNow P2Y12, and VASP phosphorylation. Results: During maintenance therapy, ticagrelor achieved lower platelet activity of ADP-induced platelet aggregation than clopidogrel (maximum platelet aggregation to ADP 5uM, 39% vs. 60. 5%, P< 0. 001; ADP 20uM 51% vs. 67. 5%, P=0. 004; VerifyNow, 74 vs. 165 PRU, P< 0. 001; VASP 16. 9 vs. 45. 8 PRI, P< 0. 001). High on-treatment platelet reactivity was observed more frequently in the clopidogrel treated group (P< 0. 05 for each ADP-mediated assay). The effect at 14-days and 6-weeks was consistent with a greater platelet inhibition with ticagrelor compared with clopidogrel. The inhibition of collagenor AA-induced platelet aggregation was not different between groups. Conclusions: In patients with PAD, ticagrelor achieved greater inhibition of ADP mediated platelet activity versus clopidogrel. The inhibition of non-ADP mediated platelet activity was not different between groups. Despite greater platelet inhibition, ticagrelor was not superior to clopidogrel for the reduction of cardiovascular events in patients with PAD

OBJECTIVE: Although fruit and vegetable (F&V) consumption is associated with lower risk of coronary heart disease and stroke, its association with peripheral artery disease (PAD) is less certain. We, thus, sought to characterize F&V intake and investigate the association between F&V consumption and presence of PAD in a large community sample. APPROACH AND RESULTS: Self-referred participants at >20 000 US sites who completed medical and lifestyle questionnaires were evaluated by screening ankle brachial indices for PAD (ankle brachial index /=3 servings of F&V was reported by 29.2%. Increasing age, female sex, white race, never smoking, being currently married, physical activity, increasing income, and frequent consumption of fish, nuts, and red meat were positively associated with daily consumption of F&V. After multivariable adjustment, there was a stepwise inverse association between F&V intake and PAD. Participants reporting daily intake of >/=3 servings of F&V had 18% lower odds of PAD than those reporting less than monthly consumption. In unadjusted and multivariable-adjusted models, the inverse association with F&V became stronger as ankle brachial index decreased. When stratified by smoking status, the association was present only among those subjects who currently or formerly smoked tobacco. CONCLUSIONS: Our study demonstrates an inverse association of F&V consumption with prevalent PAD and overall low F&V consumption. These observations suggest the need to further efforts to increase F&V consumption and for more rigorous evaluation of the role of F&V in PAD prevention. VISUAL OVERVIEW: An online visual overview is available for this article.