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).

OBJECTIVES/OBJECTIVE:Cardiovascular risk factors are prevalent in the population undergoing non-cardiac surgery. Changes in perioperative cardiovascular risk factor profiles over time are unknown. The objective of this study was to evaluate national trends in cardiovascular risk factors and atherosclerotic cardiovascular disease (ASCVD) among patients undergoing non-cardiac surgery. METHODS:Adults aged ≥45 years old who underwent non-cardiac surgery were identified using the US National Inpatient Sample from 2004 to 2013. The prevalence of traditional cardiovascular risk factors (hypertension, dyslipidaemia, diabetes mellitus, obesity and chronic kidney disease) and ASCVD (coronary artery disease, peripheral artery disease and prior stroke] were evaluated over time. RESULTS:A total of 10 581 621 hospitalisations for major non-cardiac surgery were identified. Between 2008 and 2013, ≥2 cardiovascular risk factors and ASCVD were present in 44.5% and 24.3% of cases, respectively. Over time, the prevalence of multiple (≥2) cardiovascular risk factors increased from 40.5% in 2008-2009 to 48.2% in 2012-2013, P<0.001. The proportion of patients with coronary artery disease (17.2% in 2004-2005 vs 18.2% in 2012-2013, P<0.001), peripheral artery disease (6.3% in 2004-2005 vs 7.4% in 2012-2013, P<0.001) and prior stroke (3.5% in 2008-2009 vs 4.7% 2012-2013, P<0.001) also increased over time. The proportion of patients with a modified Revised Cardiac Risk Index score ≥3 increased from 6.6% in 2008-2009 to 7.7% in 2012-2013 (P<0.001). CONCLUSIONS:Among patients undergoing major non-cardiac surgery, the burden of cardiovascular risk factors and the prevalence of ASCVD increased over time. Adverse trends in risk profiles require continued attention to improve perioperative cardiovascular outcomes.

OBJECTIVES/OBJECTIVE:Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established. DESIGN, MATERIALS, METHODS/UNASSIGNED:The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss. RESULTS:In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI. CONCLUSIONS:Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822.

Systemic lupus erythematosus (SLE) is a significant risk factor for cardiovascular disease. The relationship between SLE and perioperative cardiovascular risks following non-cardiac surgery is uncertain. We investigated associations between a diagnosis of SLE and outcomes following major non-cardiac surgery in a large national database from the United States. Patients age ≥ 18 years requiring major non-cardiac surgery were identified from Healthcare Cost and Utilization Project's National Inpatient Sample data from 2004 to 2014. Systemic lupus erythematosus and perioperative major adverse cardiovascular events (MACE; myocardial infarction, ischemic stroke or death) were defined by ICD-9 diagnosis codes. Perioperative MACE were reported for SLE patients stratified by age and sex. From 2004 to 2014, a total of 17,853,194 hospitalizations for major non-cardiac surgery met study inclusion criteria. SLE was identified in 70,578 (0.4%) hospitalizations. Overall, the frequency of perioperative MACE was higher in patients with vs. without SLE [2.4 vs. 2.0%, p < 0.001; adjusted OR (aOR) 1.25; 95% CI 1.18-1.31]. Perioperative MACE associated with SLE was largely driven by increased death (aOR 1.58 95% CI 1.40-1.77) and myocardial infarction (aOR 1.32; 95% CI 1.05-1.66) in younger patients with SLE. The increased risk of perioperative MACE associated with SLE in younger patients was attenuated with increasing age. A diagnosis of SLE is associated with increased risk of perioperative MACE, particularly among younger patients. Efforts to improve the perioperative management and outcomes of patients with SLE are needed.

OBJECTIVE: High-density lipoprotein cholesterol efflux capacity (CEC) is inversely associated with incident cardiovascular events, independent of high-density lipoprotein cholesterol. Obesity is often characterized by impaired high-density lipoprotein function. However, the effects of different bariatric surgical techniques on CEC have not been compared. This study sought to determine the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on CEC. APPROACH AND RESULTS: We prospectively studied severely obese, nondiabetic, premenopausal Hispanic women not using lipid medications undergoing RYGB (n=31) or SG (n=36). Subjects were examined before and at 6 and 12 months after surgery. There were no differences in baseline characteristics between surgical groups. Preoperative CEC correlated most strongly with Apo A1 (apolipoprotein A1) concentration but did not correlate with body mass index, waist:hip, high-sensitivity C-reactive protein, or measures of insulin resistance. After 6 months, SG produced superior response in high-density lipoprotein cholesterol and Apo A1 quantity, as well as global and non-ABCA1 (ATP-binding cassette transporter A1)-mediated CEC (P=0.048, P=0.018, respectively) versus RYGB. In multivariable regression models, only procedure type was predictive of changes in CEC (P=0.05). At 12 months after SG, CEC was equivalent to that of normal body mass index control subjects, whereas it remained impaired after RYGB. CONCLUSIONS: SG and RYGB produce similar weight loss, but contrasting effects on CEC. These findings may be relevant in discussions about the type of procedure that is most appropriate for a particular obese patient. Further study of the mechanisms underlying these changes may lead to improved understanding of the factors governing CEC and potential therapeutic interventions to maximally reduce cardiovascular disease risk in both obese and nonobese patients.

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

Background/UNASSIGNED:Venous thromboembolism (VTE) is a common vascular complication of non-cardiac surgery. Methods/UNASSIGNED:We evaluated national trends in perioperative in-hospital VTE incidence, management, and outcomes using a large database of hospital admissions from the United States. Patients aged ≥ 45 years undergoing major non-cardiac surgery from 2005 to 2013 were identified from the National Inpatient Sample. In-hospital perioperative VTE was defined as lower extremity deep vein thrombosis (DVT) or pulmonary embolism (PE), and the incidence was evaluated over time. Multivariable regression models with demographics and comorbidities as covariates were generated to estimate adjusted odds ratios (aOR). Results/UNASSIGNED:Major non-cardiac surgery was performed in 9,431,442 hospitalizations that met inclusion criteria, and perioperative VTE occurred in 99,776 patients (1,057 per 100,000), corresponding to an annual incidence of ≈53,000 after applying sample weights. Over time, perioperative VTE per 100,000 surgeries increased by 135 (95% CI 107 - 163), from 925 in 2005 to 1,060 in 2013 (p for trend <0.001; aOR [for 2013 versus 2005] 1.22, 95% CI 1.19 - 1.26), due to increases in non-fatal VTE rates (from 840 [per 100,000 surgeries] in 2005 to 987 in 2013; p for trend <0.001). Perioperative VTE occurred most frequently in patients undergoing thoracic (2.0%) and vascular surgery (1.8%). Mortality was higher in patients with VTE than those without VTE (aOR 3.12, 95% CI 3.05 - 3.20). Conclusions/UNASSIGNED:Perioperative VTE occurs in approximately 1% of patients ≥45 years undergoing major non-cardiac surgery, with increasing incidence of non-fatal VTE over time.

Background: Diabetes mellitus (DM) is a significant risk factor for cardiovascular events and peripheral artery disease (PAD). Purpose: This analysis investigated the additive risk of cardiovascular events in PAD with DM compared with PAD alone by assessing the DM population in Examining Use of tiCagreLor In paD (EUCLID) trial (NCT01732822). Methods: The EUCLID trial randomized 13,885 patients with PAD to monoantithrombotic treatment with ticagrelor 90mg twice daily or clopidogrel 75mg daily. Patients with abnormal ankle-brachial index (ABI) <=0.80 or toe-brachial index (TBI) <=0.60, or prior lower extremity revascularization were enrolled and followed up for a median duration of =30 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction (MI) or ischemic stroke. The primary safety endpoint was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. This report details the risk of cardiovascular endpoints in the group of patients with DM (types 1 and 2) in EUCLID. Results: A total of 5345 patients (38.5%) enrolled in EUCLID had DM, of which 5134 (96%) had type 2 DM. At baseline, 36.5% of patients were treated with insulin (which could include other treatments), and 8.0% were treated with diet alone. The mean ABI (0.65 vs 0.65) and TBI (0.52 vs 0.55) were similar in those with and without DM. After adjustment for baseline characteristics, PAD patients with DM had significantly higher risk of the composite primary endpoint (5.0% vs. 3.7% /year, adjusted hazard ratio [HR] 1.34, 95% CI 1.14-1.57, p<0.001) but risk for major bleeding was similar (0.8% vs. 0.8% /year, HR 1.06, 95% CI 0.79-1.40, p=0.71) in comparison to PAD patients without DM. Conclusions: PAD patients with diabetes receiving potent antithrombotic therapy have a higher composite risk of cardiovascular death, MI, and stroke as compared with PAD patients without diabetes. The risk of major bleeding was similar among PAD patients with and without diabetes