Citations

Introduction: Increased levels of hepatocyte growth factor (HGF), active in cell growth, motility, and morphogenesis, are associated with the presence of obesity, poor metabolic health, and cardiovascular disease. Hypothesis: We assessed the hypothesis that higher baseline levels of HGF will be associated with increased risk of diabetes. Methods: We examined the association between HGF and incident diabetes in MESA, including 5395 men and women 45-84 years of age at enrollment (2000-02). Fasting serum HGF was measured at baseline and on a subsample of participants at exam 2 (n = 1915). From 2000-11, incidence of diabetes was ascertained over 4 follow-up examinations, determined by new use of insulin or oral hypoglycemic medication or fasting glucose ≥ 126 mg/dL. Cox regression was used to estimate hazard ratios (HR) for incident diabetes according to 1 standard deviation unit (SDU) of HGF (1 SDU =256 pg/mL), before and after adjustment for age, sex, race/ethnicity, education, study center, smoking status, alcohol consumption, BMI, WC, fasting glucose and insulin, CRP, and IL-6 levels. Similarly, hazard ratios for incident diabetes were estimated according to change in HGF levels from exam 1 to exam 2 in the subsample. Results: At baseline, older age, male sex, current smoking, and higher body mass index (BMI), waist circumference (WC), fasting glucose and insulin, C-reactive protein (CRP) and interleukin-6 (IL-6) levels were all associated with higher levels of HGF, while greater education and physical activity were associated with lower serum HGF. Incidence of diabetes in this analytic sample was 12% (n cases = 670). Per 1 SDU increase in baseline HGF level, unadjusted risk for diabetes increased 1.46 fold (95% CI=1.37, 1.56). After adjustment, diabetes risk per 1 SDU increase in HGF was attenuated but remained significantly increased (HR=1.22; 95% CI=1.12, 1.32). No association was found between change in HGF level between exam 1 and exam 2 and incidence of diabetes. There was no evidence of effect modification by race/ethnicity for either analysis. Conclusion: In conclusion, in this ethnically diverse U.S. adult population, higher levels of serum HGF were independently associated with increased incidence of diabetes.

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.

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.

Background: Serum levels of vascular cell adhesion molecule-1 (VCAM-1) are reflective of endothelial activation, a pathologic process that is associated with subclinical cardiac dysfunction. While VCAM-1 has been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFpEF), the prospective association of VCAM-1 with clinically overt HF is unclear. Methods: In the Multi-Ethnic Study of Atherosclerosis, we evaluated the association of VCAM-1 at Exam 2 (2002-2004) with incident HF across ejection fraction (EF) categories (HFpEF and HF with reduced EF [HFrEF]) after adjustment for cardiovascular risk factors. Incident HF was adjudicated as first hospitalization for symptomatic HF, requiring specific clinical and/or imaging criteria. Results: Of 2,298 participants (mean age: 63.0 years, female: 53%), those with higher VCAM-1 were more likely white race, had higher blood pressure, and lower renal function. Over a median of 16.0 years, there were 102 HF events (HFpEF = 65; HFrEF = 37) ( Figure ). After covariate adjustment, VCAM-1 was independently associated with incident HF ( Table ). Upon evaluation of HF subtypes, VCAM-1 was associated with incident HFpEF, and risk effect estimates were consistent for incident HFrEF. The association of VCAM-1 with incident HF was consistent across the spectrum of age, sex, and BMI. Conclusion: In a multiethnic cohort, VCAM-1 was independently associated with incident HF over long-term follow up. These findings suggest a potential role for endothelial activation in driving clinical HF. Lifestyle and pharmacologic therapies that decrease endothelial activation may prevent the progression to clinical HF.

Introduction: Hepatocyte Growth Factor (HGF) is a mesenchymal cytokine linked to incident heart failure (HF), with recent data from our group showing a strong and independent association with HF with preserved ejection fraction (HFpEF). Cardiac MRI (cMRI) allows for precise analysis of morphologic changes in left ventricular (LV) structure. Increasing LV mass and concentric remodeling (defined by an increasing mass:volume ratio) are imaging markers of HFpEF risk. Whether HGF is associated with adverse LV remodeling over time is unknown. Hypothesis: Higher HGF will be associated with increasing LV mass, decreasing LV volume and increasing mass:volume ratio over 10 yrs. Methods: We studied 4762 participants of the MESA cohort, free of cardiovascular disease (CVD) and HF at baseline, who completed both HGF measurement and cMRI at baseline. Participants with LV EF<50% were excluded. Of these, 2855 completed a 2 nd cMRI at 10 yrs. We examined the cross-sectional and longitudinal associations of HGF and LV parameters using multivariable-adjusted linear mixed effect models. Results: The mean (SD) for age was 61 (10) yrs. Median (IQR) for HGF level was 888 pg/mL (745-1066); 53% women. At baseline, the 3 rd HGF tertile, compared to the 1 st , was associated with greater mass:volume ratio [relative difference 1.66 (0.43, 2.89)] and lower LV end diastolic volume [-1.87 mL (-3.45, -0.28)], after adjustment for CVD risk factors and NT- proBNP (model 2) [Table] . In longitudinal analysis, the 3 rd HGF tertile was also associated with increasing mass:volume ratio [difference in 10-yr change: 4.79 (2.73, 6.85)] and decreasing LV end diastolic volume [-4.97 (-7.10, -2.85)]. Conclusions: In a community cohort, higher HGF levels were independently associated with a concentric LV remodeling pattern of increasing mass:volume ratio and decreasing LV end diastolic volume over 10 yrs. This association may suggest an intermediate phenotype explaining the association of HGF with HFpEF risk.

Background Serum levels of vascular cell adhesion molecule‐1 (VCAM‐1) are reflective of endothelial activation. Although VCAM‐1 has been implicated in the pathogenesis of heart failure with preserved ejection fraction (HFpEF), the prospective association of VCAM‐1 with development of clinically overt heart failure (HF) across ejection fraction categories is unclear. Methods and Results In MESA (the Multi‐Ethnic Study of Atherosclerosis), we evaluated the association of VCAM‐1 at examination 2 (2002–2004) with incident HF (HFpEF and HF with reduced ejection fraction) after adjustment for cardiovascular risk factors. Incident HF was independently adjudicated as first hospitalization for symptomatic HF. Among 2297 participants (mean age, 63 years; women, 53%), those with higher VCAM‐1 were more likely to be White race, had higher blood pressure, and had lower kidney function. Over a median of 14.4 years, there were 102 HF events (HFpEF=65; HF with reduced ejection fraction=37). After covariate adjustment, each doubling of VCAM‐1 was associated with incident HF (hazard ratio [HR], 1.94; 95% CI, 1.17–3.23; P =0.01). This association appeared stronger among current/former smokers compared with never smokers. On evaluation of HF subtypes, VCAM‐1 was associated with incident HFpEF (HR, 1.97; 95% CI, 1.04–3.72; P =0.04) but not with incident HF with reduced ejection fraction, although risk estimates were consistent (HR, 1.82; 95% CI, 0.79–4.21; P =0.16). Conclusions In a multiethnic cohort, VCAM‐1 was significantly associated with incident HF over long‐term follow‐up. These findings suggest a potential role for endothelial activation in driving clinical HF, and specifically HFpEF. Therapies that decrease endothelial activation may prevent the progression from cardiovascular risk factors to clinical HF.