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Background: Given the global burden of peripheral arterial disease (PAD) and the associated morbidity, continuing investigation of potential biomarkers as therapeutic targets for preventing PAD is warranted. The association of P-selectin, an endothelial cell adhesion molecule, with the ankle brachial index (ABI) and PAD is not well established. Thus, we examined the association of circulating P-selectin with prevalent and incident PAD, the ABI, and change in the ABI. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective population-based cohort including 6814 non-Hispanic white, African American, Hispanic and Chinese men and women aged 45-84 at baseline (2000-02). For this analysis, 5700 participants with both P-selectin at Exam 2 (2002-04) and the ABI at Exam 3 (2004-05) were available, with change in ABI from Exam 3 to Exam 5 (2010-12) available on 4276 participants. P-selectin was modeled per standard deviation (SD), while prevalent and incident PAD were defined as ABI ≤ 0.90 after excluding those with ABI>1.4. Linear regression was used for ABI, growth curve models for change in ABI, and logistic regression for prevalent and incident PAD. Results: In models adjusted for demographics, lifestyle factors, comorbidities, blood pressure, lipids, fasting glucose, c-reactive protein (CRP), interleukin-6 (IL-6), D-dimer, and fibrinogen, each SD (13 ng/mL) higher P-selectin was significantly associated with 0.007 lower ABI (95% CI ((-0.011, -0.004)), p<0.001), and an average change in the ABI of -0.006 ((-0.010, -0.003, p<0.001). P-selectin was also significantly associated with a 1.14-fold greater odds of prevalent PAD ((1.00, 1.28), p=0.04), and a 1.30-fold greater odds of incident PAD ((1.10, 1.55), p<0.001). There were no significant interactions of p-selectin by race/ethnicity or gender. Addition of P-selectin to models containing traditional PAD risk factors as well as CRP, IL-6, D-dimer and fibrinogen did not improve the c-statistic or net reclassification for incident PAD. Conclusions: P-selectin appears to be strongly associated with the development of PAD. However, further research is needed in population-based studies to confirm prospective associations of p-selectin with incident PAD and change in the ABI.

PR interval (PR) prolongation is a predictor of atrial fibrillation, a common cardiac arrhythmia, and is an established risk factor for pacemaker implantation, heart failure, stroke, and all-cause mortality. Previous genome-wide association studies in European (EU) and African (AA) descent populations have identified multiple loci associated with PR. However, it is unclear whether these loci are relevant in other racial groups, including Hispanic/Latinos (HL). Extending studies to include admixed populations such as HL also provides the potential to narrow regions associated with PR and identify population specific variants. Therefore, we evaluated 1,135 SNPs from four previously identified PR loci ( SCN5A, SCN10A, CAV1-CAV2, and TBX5-TBX3 ), fine-mapped on the Illumina Metabochip for association with PR. Associations were examined using linear regression assuming an additive genetic model and adjusting for global ancestry and clinical covariates (age, sex, RR interval, body mass index, height, systolic blood pressure) in 11,800 HL participants from participating studies of the Population Architecture using Genomics and Epidemiology (PAGE) consortia. Three of the four loci ( SCN5A, SCN10A, and CAV1-CAV2 ) generalized to HL populations ( P <7.1E-4 based on the number of SNPs correlated at r 2 >0.2 with EU-identified index SNPs). At each of these loci, we identified SNPs with stronger evidence of association with PR than the EU-identified index SNP when examined in the HL population ( SCN5A : rs7374540; SCN10A : rs6801957; CAV-CAV2 : rs717957). Conditional analyses also identified two additional independent SNPs at each of the three generalized loci ( SCN5A : rs3796387, rs9861242; SCN10A : rs10428132, rs7433723; CAV1-CAV2 : rs3801995, rs3807994), representing potential secondary signals. Furthermore, linkage disequilibrium (LD) patterns in Hispanics enabled the narrowing of the regions flanking the EU-identified index SNPs. For example, at the CAV1-CAV2 locus, HL LD patterns indicated that seven SNPs were in LD with rs3807989, the EU-identified index SNP, compared to 17 SNPs that were in LD with rs3807989 when applying EU LD patterns, reducing the size of the region by 71 kilobases. Finally, we examined evidence for population specific signals outside of the specific regions identified in EU populations which were associated with PR in Hispanics by focusing on SNPs uncorrelated with the EU index signals. At all four loci, multiple SNPs had evidence of association independent of the signals examined based on EU results. In conclusion, the same genetic loci that influence PR in European descent populations are also important in Hispanic populations, although we detected evidence for population specific SNPs. These results emphasize the importance of examining genetic associations in diverse populations in order to narrow the genomic interval for future functional interrogation.

Incident hypertension varies across races/ethnicities. Mechanisms implicated in the pathogenesis are endothelial dysfunction with reduction of nitric oxide and alterations of the Renin-Angiotensin-Aldosterone System (RAAS). Stromal Derived Factor 1 (SDF1) and Transforming Growth Factor β1 (TGFβ1) are essential in these processes. SDF1 is a chemotactic protein that regulates migration of endothelial progenitor cells from the bone marrow to the arterial wall to repair endothelial damage; TGFβ1 promotes extra-cellular matrix deposition within arterial vessels, inhibits nitric oxide production and stimulates renin release. In order to investigate the association of circulating levels of these proteins with incident hypertension across different ethnicities, an ethnic stratified random sample of 2,880 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) was used. Of those, 988 participants had available plasma samples and were without hypertension, defined as blood pressure ≥ 140/90 mmHg, or current use of antihypertensive medications, at baseline. During a median follow up of 8.5 years, 388 new cases of hypertension (101 in non-Hispanic whites, 94 in Chinese, 101 in African Americans and 92 in Hispanics) were observed. Time to hypertension incidence was estimated using Cox proportional hazards regression. Hazard Ratios were adjusted for age, sex, diabetes, LDL, HDL, triglycerides, BMI, smoking status and current alcohol use. The race/ethnicity by protein interaction p-values were 0.055 and 0.066 for TGFβ1 and SDF1 respectively, suggesting heterogeneity across races/ethnicities. In Chinese, a difference of one standard deviation of plasma TGFβ1 was associated with a 22% increase in incident hypertension (HR (95% CI) 1.22 (1.02, 1.47), p-value=0.03); and a difference of one standard deviation of plasma SDF1 was associated with a 31% decrease in incident hypertension (HR (95% CI) 0.69 (0.52, 0.91), p-value 0.008). No significant association was found between these proteins and incident hypertension among non-Hispanic whites, African or Hispanic Americans. In conclusion, soluble markers of endothelial integrity and of RAAS activation were associated with the incidence of hypertension among Chinese Americans. These results suggest heterogeneity in the pathophysiology of hypertension according to race/ethnicity.

L-selectin is an adhesion molecule constitutively expressed on leukocytes and mediating their interaction with the endothelium. As a member of the selectin family, it plays a crucial role in leukocyte adhesion to and migration through the endothelial wall during inflammation. A protective role of L-selectin in early atherosclerosis was demonstrated in animal models. Previous studies assessing the relationship of this protein with cardiovascular disease were inconsistent. Lower serum L-selectin levels were found in patients with coronary artery disease (CHD) and peripheral artery disease (PAD) compared to controls. In contrast, plasma levels of L-selectin were increased in patients with CHD and PAD. These inconsistencies might be due to an interaction of soluble L-selectin with clotting factors or anticoagulants present in plasma but not in serum. Also, the small number and Caucasian predominance of patients included in previous studies represent limitations that need to be addressed using a rigorous, population-based approach. Herein, we seek to investigate the association of serum L-selectin with subclinical outcomes in a large, ethnically heterogeneous population. In a randomly selected subset of 720 subjects for each of the four ethnicities included in the Multi-Ethnic Study of Atherosclerosis (MESA), serum samples were available for 2403 individuals (579 African Americans, 620 Caucasians, 600 Chinese and 604 Hispanics). Serum L-selectin levels and intima-media thickness (IMT) were measured at exam 2 and CAC was measured at exam 2 or 3 during the cohort follow up. Regression analysis and the Tobit model were used to assess the association of L-selectin levels with IMT and CAC respectively. The mean age was 63±10 years and 47% were men. The mean±SD protein levels were significantly different across ethnicities (867±192 ng/mL in African Americans, 956±215 ng/mL in Caucasians, 834±174 ng/mL in Chinese and 904±195 ng/mL in Hispanics; p<0.0001). In the univariate analysis, age was inversely correlated to the protein levels; in addition, levels were lower in males, regardless of ethnicity and in smokers, except among Hispanics. L-selectin was associated with modestly lower CAC only among Chinese (p=0.030), the association persisted after adjustment for traditional risk factors (p=0.046). No significant association was demontrated between the protein levels and IMT. In conclusion, in this large diverse population, we found that serum L-selectin was modestly associated to measures of subclinical atherosclerosis in Chinese but not in African, European or Hispanic Americans.

Pulse pressure (PP), defined as the difference between systolic and diastolic blood pressure, is considered a marker of large artery stiffness and has been shown to independently predict cardiovascular disease. Differences among ethnicities with regard to PP have been previously described, yet the underlying biological mechanisms are poorly understood. In addition, biomarkers of inflammation and matrix remodeling have been shown to be involved in the development of arterial stiffness. The aim of this study was to investigate the role of adhesion pathway components in the development of arterial stiffness measured by PP among four ethnicities. E-cadherin, HGF, L-selectin, P-selectin, 6-Ckine, MMP1, MMP2, RANTES, SDF1, SLPI, TGFβ1, TIMP2 and VCAM were measured in a random sample of 2402 participants (579 African Americans, 619 Caucasians, 600 Chinese and 604 Hispanics) in the Multi-Ethnic Study of Atherosclerosis (MESA) study at Exam 2. PP was measured concurrently and its association with each adhesion protein level was assessed via linear regression in each ethnicity. All analyses were adjusted for age, sex, and traditional cardiovascular risk factors. Mean PP was significantly different among ethnicities: 55.9±18.0 mmHg in African Americans, 52.1± 16.1 mmHg in Caucasians, 51.4±16.4 mmHg in Chinese, and 55.0±17.5 in Hispanics, p<0.001. MMP2 was positively associated with PP among African Americans (β=2.3 (0.6), p<0.001) and Caucasians (β=1.7 (0.5), p=0.001); TIMP2 among Caucasians (β=1.5 (0.5), p=0.002) and to a lesser extent among African Americans (β=1.2 (0.6) p=0.050) and Chinese (β=1.3 (0.6), p=0.034). SDF1 was associated to PP in African Americans (β=1.4 (0.6), p=0.017) and in Chinese (β=1.1 (0.5), p=0.042); finally an association existed between TGFβ1 and PP in C (β=1.1 (0.5), p=0.025). None of the studied proteins was associated with PP in Hispanics. In conclusion, components of the adhesion pathway were correlated to PP in this large multi-ethnic cohort, possibly giving new insight on the pathophysiology of arterial stiffness. In addition, heterogeneity by ethnicity suggests different mechanisms in the development of arterial stiffness.

Objectives Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone. Design Retrospective cohort study. Setting Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study. Participants The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1–Q3)=58 (47–66). Primary and secondary outcome measures Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient’s medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity. Results From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004). Conclusions These findings support the importance of sex as a biological variable to be factored into pain management studies.

Background: Prevention strategies for Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRDs) are urgently needed for reducing incidence. Intra-patient variability in lipid levels is a potentially modifiable risk factor for incident AD/ADRD. Although regular lipid measurements are a part of common clinical practice and longitudinal data routinely available in electronic health records (EHR), research examining this association between AD/ADRD and lipid variability across multiple lipid types remains scarce. Methods: All residents living in Olmsted County, MN on 1/1/2006 age ≥60 years without an AD/ADRD diagnosis were identified using Centers for Medicare & Medicaid Services diagnostic codes. Persons with ≥3 lipid measurements (total cholesterol or triglycerides) in the 5 years prior to index date were retained. Lipid variability was quantified using variability independent of the mean (VIM). Models were adjusted for traditional risk factors. Associations between lipid variability quintiles and incident AD/ADRD were assessed using Cox proportional hazards regression. Multiple imputation was used for missing covariates. Participants were followed through 2018 for incident AD/ADRD. Results: The final analysis included data on 11,551 participants with total cholesterol and 11,502 participants with triglycerides. Participants had a mean age of 71 (range 60-99) years, and were primarily white (96%). Females (54%) were also slightly more frequent than males. Median follow up was 12.9 years (range: 0-13). Participants in the highest quintile of variability for total cholesterol and triglycerides had a 20% increased risk of incident AD/ADRD. Similar results were found in the subset with complete covariate data. Conclusion: In a large EHR derived cohort, persons in the highest quintile of lipid variation had an increased risk of incident AD/ADRD. Further studies to identify the mechanisms behind this risk factor and replication of these results across a more diverse population are needed.

Background: Larger within-patient variability of lipid levels has been associated with an increased risk of cardiovascular disease (CVD). However, measures of lipid variability are not currently used clinically. We investigated the feasibility of calculating lipid variability within a large electronic health record (EHR)-based population cohort and assessed associations with incident CVD. Methods: We identified all individuals ≥40 years of age who resided in Olmsted County, MN on 1/1/2006 (index date) without prior CVD. CVD was defined as myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention or stroke. Patients with ≥3 measurements of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides during the 5 years before the index date were retained in the analyses. Lipid variability was calculated using variability independent of the mean (VIM). Patients were followed through 9/30/2017 for incident CVD (including CVD death). Cox regression was used to investigate the association between quintiles of lipid VIMs and incident CVD. Results: We identified 18,642 individuals (mean age 60; 55% female) who were free of CVD at baseline and VIM calculated for at least one lipid measurement. After adjustment, those in the highest VIM quintiles of total cholesterol had a 25% increased risk of CVD (Q5 vs. Q1 HR: 1.25, 95% CI: 1.08-1.45; Table). We observed similar results for LDL-C (Q5 vs. Q1 HR: 1.20, 95% CI: 1.04-1.39) and HDL-C (Q5 vs. Q1 HR: 1.25, 95% CI: 1.09-1.43). There was no association between triglyceride variability quintiles and CVD risk. Conclusion: In a large EHR-based population cohort, high variability in total cholesterol, HDL-C and LDL-C was associated with an increased risk of CVD, independently of traditional risk factors, suggesting it may be a target for intervention. Lipid variability can be calculated in the EHR environment but more research is needed to determine its clinical utility.

Background: Hepatocyte growth factor (HGF) is a cytokine released in response to vascular injury and a novel biomarker of cardiovascular disease (CVD) risk. However, the relationship between ideal cardiovascular health (CVH) and HGF is unknown. We examined whether ideal CVH is associated with lower HGF levels in a multi-ethnic cohort of adults free from clinical CVD at baseline. Methods: We analyzed data from the MESA study of 6,490 men and women aged 45-84 years. The independent variable was the CVH score derived from 7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose). Each metric was scored 0 points (poor), 1 point (intermediate) and 2 points (ideal). The total CVH score ranged from 0-14. An inadequate score was 0-8, average, 9-10 and optimal, 11-14. The number of ideal metrics was also counted. The dependent variable was logarithmically transformed HGF. We examined the association between the CVH score and HGF using linear regression models adjusted for age, sex, race/ethnicity, education, income, health insurance and study site. Results: The mean (SD) age of participants was 62 (10) years. Fifty-three percent were women. Participants with optimal CVH scores had the lowest HGF concentration [Median (IQR): 807 (678-962) pg/mL] compared to those with average [870 (740-1,036)] and inadequate scores [969 (821-1,159)]. A one-unit increment in the CVH score was significantly associated with a 3% lower HGF concentration (Table). Average and optimal CVH scores were also significantly associated with 8% and 12% lower HGF concentrations, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF concentrations. Interactions by age, sex and race/ethnicity were not significant. Conclusion: In this ethnically diverse cohort, optimal CVH was significantly associated with lower HGF levels. Interventions aimed at promoting ideal CVH may reduce vascular injury as indicated by lower serum HGF levels.