Faculty Bibliography

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.

BACKGROUND: Little is known about patterns of medication use and lifestyle counseling in patients with peripheral artery disease (PAD) in the United States. OBJECTIVES: The authors sought to evaluate trends in both medical therapy and lifestyle counseling for PAD patients in the United States from 2005 through 2012. METHODS: Data from 1,982 outpatient visits among patients with PAD were obtained from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, a nationally representative assessment of office-based and hospital outpatient department practice. Trends in the proportion of visits with medication use (antiplatelet therapy, statins, angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs], and cilostazol) and lifestyle counseling (exercise or diet counseling and smoking cessation) were evaluated. RESULTS: Over the 8-year period, the average annual number of ambulatory visits in the United States for PAD was 3,883,665. Across all visits, mean age was 69.2 years, 51.8% were female, and 56.6% were non-Hispanic white. Comorbid coronary artery disease (CAD) was present in 24.3% of visits. Medication use for cardiovascular prevention and symptoms of claudication was low: any antiplatelet therapy in 35.7% (standard error [SE]: 2.7%), statin in 33.1% (SE: 2.4%), ACEI/ARB in 28.4% (SE: 2.0%), and cilostazol in 4.7% (SE: 1.0%) of visits. Exercise or diet counseling was used in 22% (SE: 2.3%) of visits. Among current smokers with PAD, smoking cessation counseling or medication was used in 35.8% (SE: 4.6%) of visits. There was no significant change in medication use or lifestyle counseling over time. Compared with visits for patients with PAD alone, comorbid PAD and CAD were more likely to be prescribed antiplatelet therapy (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.8 to 3.9), statins (OR: 2.6; 95% CI: 1.8 to 3.9), ACEI/ARB (OR: 2.6; 95% CI: 1.8 to 3.9), and smoking cessation counseling (OR: 4.4; 95% CI: 2.0 to 9.6). CONCLUSIONS: The use of guideline-recommended therapies in patients with PAD was much lower than expected, which highlights an opportunity to improve the quality of care in these high-risk patients.

Background: Acute myocardial infarction (AMI) is a significant cardiovascular complication following non-cardiac surgery. We evaluated national trends in perioperative AMI, management, and outcomes using a large administrative database of United States hospital admissions. Methods: Patients who underwent non-cardiac surgery from 2005 to 2013 were identified using the National Inpatient Sample. Perioperative AMI was evaluated over time. Propensity score matching was used to compile cohorts of patients with perioperative AMI matched on their baseline characteristics who were managed invasively (defined as cardiac catheterization, percutaneous coronary intervention [PCI], or coronary artery bypass graft surgery [CABG]) versus conservatively. The primary outcome was in-hospital all-cause mortality. Results: Among 9,566,277 hospitalizations for major non-cardiac surgery, perioperative AMI occurred in 84,093 (0.88%). Over time, the rate of perioperative AMI per 100,000 surgeries declined by 170 (95% CI 158 - 181), from 898 in 2005 to 729 in 2013 (p for trend <0.0001). Perioperative AMI occurred most frequently in patients undergoing vascular (2.0%), transplant (1.6%), and thoracic (1.5%) surgery. In-hospital mortality was higher in patients with perioperative AMI than those without AMI (18.0% vs. 1.5%, p<0.0001; adjusted OR 5.76, 95% CI 5.65 - 5.88). Mortality associated with perioperative AMI declined over time (adjusted OR 0.86, 95% CI 0.84 - 0.88). In a propensity-matched cohort of 34,650 patients with perioperative AMI, invasive management was associated with lower mortality than conservative management (8.9% vs. 18.1%, p<0.001; OR 0.44, 95% CI 0.41-0.47). Conclusion: Perioperative AMI occurs in 0.9% of patients undergoing major non-cardiac surgery and is strongly associated with in-hospital mortality. Invasive management of such patients may mitigate some of this excess risk

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with the premature development of cardiovascular disease. The platelet-endothelium interaction is important in the pathogenesis of cardiovascular disease. In this study, we investigated the platelet phenotype from patients with SLE and matched controls, and their effect on endothelial cells. APPROACH AND RESULTS: Platelet aggregability was measured in 54 SLE subjects off antiplatelet therapy (mean age 40.1+/-12.8 years; 82% female; 37% white) with age- and sex-matched controls. Platelets were coincubated with human umbilical vein endothelial cells (HUVECs) and changes to gene expression assessed by an RNA array and quantitative reverse transcription polymerase chain reaction. SLE disease activity index ranged from 0 to 22 (mean 5.1+/-3.9). Compared with controls, patients with SLE had significantly increased monocyte and leukocyte-platelet aggregation and platelet aggregation in response to submaximal agonist stimulation. An agnostic microarray of HUVECs cocultured with SLE platelets found a platelet-mediated effect on endothelial gene pathways involved in cell activation. Sera from SLE versus control subjects significantly increased (1) activation of control platelets; (2) platelet adhesion to HUVECs; (3) platelet-induced HUVEC gene expression of interleukin-8, and ICAM-1; and (4) proinflammatory gene expression in HUVECs, mediated by interleukin-1beta-dependent pathway. Incubation of SLE-activated platelets with an interleukin-1beta-neutralizing antibody or HUVECs pretreated with interleukin-1 receptor antibodies attenuated the platelet-mediated activation of endothelial cells. CONCLUSIONS: Platelet activity measurements and subsequent interleukin-1beta-dependent activation of the endothelium are increased in subjects with SLE. Platelet-endothelial interactions may play a role in the pathogenesis of cardiovascular disease in patients with SLE.

OBJECTIVE: Low to moderate inorganic arsenic (iAs) exposure is independently associated with cardiovascular disease (CVD), particularly for patients with diabetes mellitus (DM). The mechanism of increased CVD risk from iAs exposure in DM has not been adequately characterized. We evaluated whether increasing concentrations of glucose enhance the effects of iAs on platelet and megakaryocyte activity, key steps in atherothrombosis. METHODS: Healthy donor whole blood was prepared in a standard fashion and incubated with sodium arsenite in a range from 0 to 10 microM. iAs-induced platelet activation was assessed by platelet receptor CD62P (P-selectin) expression and monocyte-platelet and leukocyte-platelet aggregation (MPA and LPA, respectively) in the presence of increasing sodium arsenite and glucose concentrations. Megakaryocyte (Meg-01) cell adhesion and gene expression was assessed after incubation with or without iAs and increasing concentrations of D-glucose. RESULTS: Platelet activity markers increased significantly with 10 vs. 0 microM iAs (P < 0.05 for all) and with higher D-glucose concentrations. Platelet activity increased significantly following co incubation of 1 and 5 microM iAs concentrations with hyperglycemic D-glucose (P < 0.01 for both) but not after incubation with euglycemic D-glucose. Megakaryocyte adhesion was more pronounced after co incubation with iAs and hyperglycemic than euglycemic D-glucose, while gene expression increased significantly to iAs only after co incubation with hyperglycemic D-glucose. CONCLUSION: We demonstrate that glucose concentrations common in DM potentiate the effect of inorganic arsenic exposure on markers of platelet and megakaryocyte activity. Our results support recent observational cohort data that DM enhances the vasculotoxic effects of arsenic exposure, and suggest that activation of the platelet-megakaryocyte hemostatic axis is a pathway through which inorganic arsenic confers atherothrombotic risk, particularly for patients with DM.

Importance: Major adverse cardiovascular and cerebrovascular events (MACCE) are a significant source of perioperative morbidity and mortality following noncardiac surgery. Objective: To evaluate national trends in perioperative cardiovascular outcomes and mortality after major noncardiac surgery and to identify surgical subtypes associated with cardiovascular events using a large administrative database of United States hospital admissions. Design, Setting, Participants: Patients who underwent major noncardiac surgery from January 2004 to December 2013 were identified using the National Inpatient Sample. Main Outcomes and Measures: Perioperative MACCE (primary outcome), defined as in-hospital, all-cause death, acute myocardial infarction (AMI), or acute ischemic stroke, were evaluated over time. Results: Among 10581621 hospitalizations (mean [SD] patient age, 65.74 [12.32] years; 5975798 female patients 56.60%]) for major noncardiac surgery, perioperative MACCE occurred in 317479 hospitalizations (3.0%), corresponding to an annual incidence of approximately 150000 events after applying sample weights. Major adverse cardiovascular and cerebrovascular events occurred most frequently in patients undergoing vascular (7.7%), thoracic (6.5%), and transplant surgery (6.3%). Between 2004 and 2013, the frequency of MACCE declined from 3.1% to 2.6% (P for trend <.001; adjusted odds ratio [aOR], 0.95; 95% CI, 0.94-0.97) driven by a decline in frequency of perioperative death (aOR, 0.79; 95% CI, 0.77-0.81) and AMI (aOR, 0.87; 95% CI, 0.84-0.89) but an increase in perioperative ischemic stroke from 0.52% in 2004 to 0.77% in 2013 (P for trend <.001; aOR 1.79; CI 1.73-1.86). Conclusions and Relevance: Perioperative MACCE occurs in 1 of every 33 hospitalizations for noncardiac surgery. Despite reductions in the rate of death and AMI among patients undergoing major noncardiac surgery in the United States, perioperative ischemic stroke increased over time. Additional efforts are necessary to improve cardiovascular care in the perioperative period of patients undergoing noncardiac surgery.

The purpose of the current study was to investigate the association between bone mineral density (BMD) scores and the prevalence of peripheral artery disease (PAD) in a large cohort of subjects who underwent arterial Doppler assessments and calcaneal bone densitometry. The study was performed using data obtained from Life Line Screening Inc. Subjects were self-selected and paid for screening tests. The prevalence of PAD was significantly higher in men with osteopenia (4.5%) and osteoporosis (10.9%) compared to men with normal BMD (3.0%) (p<0.001). Osteopenia (odds ratio (OR) 1.3) and osteoporosis (OR 2.3) were found to be independent risk factors for the presence of PAD in men. The prevalence of PAD was significantly higher in women with osteopenia (4.8%) and osteoporosis (11.8%) compared to women with normal BMD (3.3%) (p<0.001). Osteopenia (OR 1.15) and osteoporosis (OR 1.8) were found to be independent risk factors for the presence of PAD in women. The current study reports a strong association of abnormal BMD analysis with the prevalence of PAD, which persists even when controlling for age and associated atherosclerotic risk factors. Although the mechanism by which these two disease processes is related is not completely elucidated, the presence of osteoporosis should make clinicians aware of the possibility of occult PAD or associated atherosclerotic disease in appropriate patients.

Diabetes mellitus (diabetes) is associated with significantly increased risk of peripheral vascular disease. Diabetes is classified as a coronary heart disease (CHD) risk equivalent, but it is unknown whether diabetes is a CHD risk equivalent for peripheral vascular disease. The objective was to evaluate the odds of peripheral arterial disease (PAD) or carotid artery stenosis (CAS) among participants with diabetes, CHD, or both, compared with participants without diabetes or CHD, in a nationwide vascular screening database. We hypothesized that diabetes and CHD would confer similar odds of PAD and CAS. METHODS: A cross-sectional analysis of all eligible Life Line Screening Inc participants age 30 to 90 years with ankle brachial indices for PAD (ankle brachial index <0.9 in either leg) and carotid artery duplex ultrasonographic imaging for CAS (internal CAS >/=50%) was performed (N=3,522,890). RESULTS: Diabetes and CHD were present in 372,330 (10.7%) and 182,760 (5.8%) of participants, respectively; PAD and CAS were present in 155,000 (4.4%) and 130,347 (3.7%) of participants. After multivariable adjustment, PAD odds were 1.56 (95% CI 1.54-1.59) and 1.69 (95% CI 1.65-1.73) for participants with diabetes or CHD, respectively. Participants with both diabetes and CHD had 2.75-fold increased odds of PAD (95% CI 2.66-2.85). Findings were similar for CAS; compared with no diabetes or CHD, CAS odds increased for participants with diabetes alone (1.53, 95% CI 1.50-1.56), CHD alone (1.72, 95% CI 1.68-1.76), and both diabetes and CHD (2.57, 95% CI 2.49-2.66). Findings were consistent for women and men. CONCLUSION: In a large database of more than 3.5 million self-referred participants, diabetes was a CHD risk equivalent for PAD and CAS, and participants with comorbid diabetes and CHD had an especially robust association with PAD and CAS. Counseling regarding screening and prevention of peripheral vascular disease may be useful for patients with diabetes.

BACKGROUND: -In patients with symptomatic peripheral artery disease (PAD) with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown. METHODS: -The Examining Use of tiCagreLor In paD (EUCLID) trial randomized 13,885 patients with PAD to treatment with ticagrelor 90mg twice daily or clopidogrel 75mg daily. Patients were enrolled based on an abnormal ankle-brachial index (ABI)