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Abstract Background Low-density lipoprotein cholesterol (LDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD). Friedewald, Sampson, and Martin-Hopkins equations are used to calculate LDL-C. This study compares the impact of switching between these equations in a large geographically defined population. Materials and methods Data for individuals who had a lipid panel ordered clinically between 2010 and 2019 were included. Comparisons were made across groups using the two-sample t-test or chi-square test as appropriate. Discordances between LDL measures based on clinically actionable thresholds were summarized using contingency tables. Results The cohort included 198,166 patients (mean age 54 years, 54% female). The equations perform similarly at the lower range of triglycerides but began to diverge at a triglyceride level of 125 mg/dL. However, at triglycerides of 175 mg/dL and higher, the Martin-Hopkins equation estimated higher LDL-C values than the Samson equation. This discordance was further exasperated at triglyceride values of 400 to 800 mg/dL. When comparing the Sampson and Friedewald equations, at triglycerides are below 175 mg/dL, 9% of patients were discordant at the 70 mg/dL cutpoint, whereas 42.4% were discordant when triglycerides are between 175 and 400 mg/dL. Discordance was observed at the clinically actionable LDL-C cutpoint of 190 mg/dL with the Friedewald equation estimating lower LDL-C than the other equations. In a high-risk subgroup (ASCVD risk score > 20%), 16.3% of patients were discordant at the clinical cutpoint of LDL-C

Background Frailty is common in heart failure (HF) and is associated with death but not routinely captured clinically. Frailty is linked with inflammation and malnutrition, which can be assessed by a novel plasma multimarker score: the metabolic vulnerability index (MVX). We sought to evaluate the associations between frailty and MVX and their prognostic impact. Methods and Results In an HF community cohort (2003–2012), we measured frailty as a proportion of deficits present out of 32 physical limitations and comorbidities, MVX by nuclear magnetic resonance spectroscopy, and collected extensive longitudinal clinical data. Patients were categorized by frailty score (≤0.14, >0.14 and ≤0.27, >0.27) and MVX score (≤50, >50 and ≤60, >60 and ≤70, >70). Cox models estimated associations of frailty and MVX with death, adjusted for Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) score and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide). Uno's C‐statistic measured the incremental value of MVX beyond frailty and clinical factors. Weibull's accelerated failure time regression assessed whether MVX mediated the association between frailty and death. We studied 985 patients (median age, 77; 48% women). Frailty and MVX were weakly correlated (Spearman's ρ=0.21). The highest frailty group experienced an increased rate of death, independent of MVX, MAGGIC score, and NT‐proBNP (hazard ratio, 3.3 [95% CI, 2.5–4.2]). Frailty improved Uno's c‐statistic beyond MAGGIC score and NT‐proBNP (0.69–0.73). MVX only mediated 3.3% and 4.5% of the association between high and medium frailty groups and death, respectively. Conclusions In this HF cohort, frailty and MVX are weakly correlated. Both independently contribute to stratifying the risk of death, suggesting that they capture distinct domains of vulnerability in HF.

Background Clinical risk scores are used to identify those at high risk of atherosclerotic cardiovascular disease (ASCVD). Despite preventative efforts, residual risk remains for many individuals. Very low‐density lipoprotein cholesterol (VLDL‐C) and lipid discordance could be contributors to the residual risk of ASCVD. Methods and Results Cardiovascular disease–free residents, aged ≥40 years, living in Olmsted County, Minnesota, were identified through the Rochester Epidemiology Project. Low‐density lipoprotein cholesterol (LDL‐C) and VLDL‐C were estimated from clinically ordered lipid panels using the Sampson equation. Participants were categorized into concordant and discordant lipid pairings based on clinical cut points. Rates of incident ASCVD, including percutaneous coronary intervention, coronary artery bypass grafting, stroke, or myocardial infarction, were calculated during follow‐up. The association of LDL‐C and VLDL‐C with ASCVD was assessed using Cox proportional hazards regression. Interaction between LDL‐C and VLDL‐C was assessed. The study population (n=39 098) was primarily White race (94%) and female sex (57%), with a mean age of 54 years. VLDL‐C (per 10‐mg/dL increase) was significantly associated with an increased risk of incident ASCVD (hazard ratio, 1.07 [95% CI, 1.05–1.09]; P

Background Although VCAM‐1 (vascular cell adhesion molecule‐1) and ICAM‐1 (intercellular adhesion molecule‐1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM‐1 and ICAM‐1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM‐1, ICAM‐1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. Methods and Results In MESA (Multi‐Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM‐1 and ICAM‐1 at examination 2 (2002–2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010–2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM‐1 or ICAM‐1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM‐1 or ICAM‐1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM‐1 and ICAM‐1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2–30) of the relationship between VCAM‐1 and HFpEF and 9% (95% CI, 2–21) of the relationship between VCAM‐1 and AF. Conclusions Higher VCAM‐1 and ICAM‐1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM‐1 and ICAM‐1 may promote HFpEF and AF risk through impaired LA reservoir function.

Objective: To compare the 1-year health care utilization and mortality in persons living with heart failure (HF) before and during the coronavirus disease 2019 (COVID-19) pandemic. Patients and Methods: Residents of a 9-county area in southeastern Minnesota aged 18 years or older with a HF diagnosis on January 1, 2019; January 1, 2020; and January 1, 2021, were identified and followed up for 1-year for vital status, emergency department (ED) visits, and hospitalizations. Results: We identified 5631 patients with HF (mean age, 76 years; 53% men) on January 1, 2019, 5996 patients (mean age, 76 years; 52% men) on January 1, 2020, and 6162 patients (mean age, 75 years; 54% men) on January 1, 2021. After adjustment for comorbidities and risk factors, patients with HF in 2020 and patients with HF in 2021 experienced similar risks of mortality compared with those in 2019. After adjustment, patients with HF in 2020 and 2021 were less likely to experience all-cause hospitalizations (2020: rate ratio [RR], 0.88; 95% CI, 0.81-0.95; 2021: RR, 0.90; 95% CI, 0.83-0.97) compared with patients in 2019. Patients with HF in 2020 were also less likely to experience ED visits (RR, 0.85; 95% CI, 0.80-0.92). Conclusion: In this large population-based study in southeastern Minnesota, we observed an approximately 10% decrease in hospitalizations among patients with HF in 2020 and 2021 and a 15% decrease in ED visits in 2020 compared with those in 2019. Despite the change in health care utilization, we found no difference in the 1-year mortality between patients with HF in 2020 and those in 2021 compared with those in 2019. It is unknown whether any longer-term consequences will be observed.

BackgroundThe relationship between ketone bodies (KB) and mortality in patients with heart failure (HF) syndrome has not been well established.ObjectivesThe aim of this study is to assess the distribution of KB in HF, identify clinical correlates, and examine the associations between plasma KB and all-cause mortality in a population-based HF cohort.MethodsThe plasma KB levels were measured by nuclear magnetic resonance spectroscopy. Multivariable linear regression was used to examine associations between clinical correlates and KB levels. Proportional hazard regression was employed to examine associations between KB (represented as both continuous and categorical variables) and mortality, with adjustment for several clinical covariates.ResultsAmong the 1,382 HF patients with KB measurements, the median (IQR) age was 78 (68, 84) and 52% were men. The median (IQR) KB was found to be 180 (134, 308) μM. Higher KB levels were associated with advanced HF (NYHA class III–IV) and higher NT-proBNP levels (both P

Background: Hepatocyte growth factor (HGF) is a cytokine linked to incident heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Increases in left ventricular (LV) mass and concentric remodelling defined by increasing mass-to-volume (M:V) ratios are imaging risk markers for HFpEF. We aimed to determine if HGF is associated with adverse LV remodelling. Methods: We studied 4907 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), free of cardiovascular disease and HF at baseline, who had HGF measured and cardiac magnetic resonance imaging (CMR) performed at baseline. Of these, 2921 completed a second CMR at 10 years. We examined the cross-sectional and longitudinal associations of HGF and LV structural parameters using multivariable-adjusted linear mixed-effect models, adjusting for cardiovascular disease risk factors and N-terminal pro B-type natriuretic peptide. Results: The mean (SD) for age was 62 (10) years; 52% were female. Median (interquartile range) for HGF level was 890 pg/mL (745-1070). At baseline, the highest HGF tertile, compared to the lowest, was associated with a greater M:V ratio (relative difference 1.94 [95% confidence interval [CI]: 0.72, 3.17]) and lower LV end-diastolic volume (–2.07 mL [95% CI: –3.72, –0.42)]. In longitudinal analysis, the highest HGF tertile was associated with increasing M:V ratio (10-year difference: 4.68 [95% CI: 2.64, 6.72]) and decreasing LV end-diastolic volume (–4.74 [95% CI: –6.87, –2.62]). Conclusions: In a community-based cohort, higher HGF levels were independently associated with a concentric LV remodelling pattern of increasing M:V ratio and decreasing LV end-diastolic volume by CMR over 10 years. These associations may reflect an intermediate phenotype explaining the association of HGF with HFpEF risk. Résumé: Contexte: Le facteur de croissance des hépatocytes (hepatocyte growth factor; HGF) est une cytokine associée à l’insuffisance cardiaque (IC), particulièrement l’IC avec fraction d’éjection préservée (ICFEP). Une augmentation de la masse du ventricule gauche (VG) et un remodelage concentrique du VG, défini par une augmentation du ratio masse/volume (M:V), sont des marqueurs de risque d’ICFEP à l’examen d’imagerie. Nous souhaitions déterminer si le taux de HGF est associé à un remodelage préjudiciable du VG. Méthodologie: Nous avons étudié 4 907 participants à l’étude multiethnique sur l’athérosclérose (Multi-Ethnic Study of Atherosclerosis; MESA) qui, au départ, ne présentaient pas de maladie cardiovasculaire ni d’IC et pour qui le taux de HGF avait été mesuré et une imagerie cardiaque par résonance magnétique (IRMc) avait été réalisée. Parmi ces personnes, 2 921 ont subi une seconde IRMc à 10 ans. Nous avons examiné les associations intersectionnelles et longitudinales entre le taux de HGF et les paramètres structurels du VG à l’aide de modèles linéaires à effets mixtes multivariés, ajustés pour les facteurs de risque de maladie cardiovasculaire et les propeptides natriurétiques de type B N-terminal. Résultats: L’âge moyen des participants était de 62 ans (écart type : 10), et 52 % étaient des femmes. Le taux de HGF médian était de 890 pg/ml (écart interquartile : 745 à 1070). Au départ, comparativement au tertile inférieur du taux de HGF, le tertile supérieur était associé à un ratio M:V plus important (différence relative : 1,94; intervalle de confiance [IC] à 95 % : 0,72 à 3,17) et à un volume diastolique final du VG plus faible (-2,07 ml; IC à 95 % : -3,72 à -0,42). À l’analyse longitudinale, le tertile supérieur du taux de HGF était associé à un ratio M:V plus élevé (différence sur 10 ans : 4,68; IC à 95 % : 2,64 à 6,72) et à une réduction du volume diastolique final du VG (-4,74; IC à 95 % : -6,87 à -2,62). Conclusions: Dans une cohorte représentative de la population, un taux de HGF plus élevé était associé de manière indépendante à un schéma de remodelage concentrique du VG présentant une augmentation du ratio M:V et à une diminution du volume diastolique final du VG à l’IRMc sur 10 ans. Ces associations pourraient être représentatives d’un phénotype intermédiaire expliquant l’association entre le taux de HGF et le risque d’ICFEP.

Abstract Circulating protease inhibitors are important regulators of inflammation that are implicated in the pathophysiology of heart failure (HF). Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor which protects pulmonary tissues against inflammatory damage; however, its role in HF is not well understood. We sought to evaluate associations of circulating SLPI and genetically-mediated serum SLPI with incident HF and its subtypes in a multi-ethnic cohort of adults using clinical and genetic epidemiological approaches. Among 2,297 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), each doubling of serum SLPI was independently associated with incident HF (HR 1.77; 95% CI 1.02–3.02; P = 0.04), particularly incident HF with preserved ejection fraction (HFpEF; HR 2.44; 95% CI 1.23–4.84; P = 0.01) but not HF with reduced ejection fraction (HFrEF; HR 0.95; 95% CI 0.36–2.46; P = 0.91). Previously reported circulating SLPI protein quantitative trait loci (pQTLs) were not associated with serum SLPI levels or incident HF among MESA participants. In conclusion, baseline serum SLPI levels, but not genetically-determined serum SLPI, were significantly associated with incident HF and HFpEF over long-term follow-up in a multi-ethnic cohort. Serum circulating SLPI may be a correlate of inflammation that sheds insight on the pathobiology of HFpEF.

Abstract Background Risk factors for the pathogenesis of chronic rhinosinusitis (CRS) remain largely undetermined, which is likely due to the heterogeneity of the disease. White blood cell counts have been largely unexplored as a risk factor for CRS even though different types of white blood cells are involved in the inflammatory process of CRS. Objective To investigate causal associations between different types of white blood cells on risk of CRS utilizing a Mendelian randomization (MR) analysis. Methods A two-sample MR analysis was performed using respective GWAS summary statistics for the exposure traits (neutrophil count, eosinophil count, basophil count, lymphocyte count, and monocyte count) and outcome trait (CRS). For the exposure traits, the European Bioinformatics Institute database of complete GWAS summary data was used. For the outcome trait, summary statistics for CRS GWAS were obtained from FinnGen. Primary analysis for MR was performed using inverse-variance weighted two-sample MR. Sensitivity analyses included weighted median, MR-Egger, and MR-PRESSO (raw and outlier-corrected). Results Eosinophils were associated with CRS (OR = 1.55 [95% CI 1.38, 1.73]; p = 4.3E-14). Eosinophil results were similar across additional MR methods. MR results did not demonstrate significant causal relationships between neutrophils, lymphocytes, monocytes, or basophils with CRS. No significant pleiotropic bias was observed. Conclusions In a two-sample MR analysis, a potential causal link between blood eosinophil counts and CRS has been demonstrated. In addition, causal relationships between blood counts among other white blood cell types and CRS were not found. Further studies involving genetic variation in CRS are needed to corroborate genetic causal effects for CRS.

Abstract Background Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear. Methods In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models. Results CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3—4.1] vs. 0.4 [95% CI -0.5 – 1.3] vs. -0.1 [-95% CI -1.5—1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status. Conclusions Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.

Background Larger within‐patient variability of lipid levels has been associated with increased risk of cardiovascular disease (CVD); however, measures of lipid variability require ≥3 measurements and are not currently used clinically. We investigated the feasibility of calculating lipid variability within a large electronic health record–based population cohort and assessed associations with incident CVD. Methods and Results We identified all individuals ≥40 years of age who resided in Olmsted County, MN, on January 1, 2006 (index date), without prior CVD, defined as myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, or CVD death. Patients with ≥3 measurements of total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, or triglycerides during the 5 years before the index date were retained. Lipid variability was calculated using variability independent of the mean. Patients were followed through December 31, 2020 for incident CVD. We identified 19 652 individuals (mean age 61 years; 55% female), who were CVD‐free and had variability independent of the mean calculated for at least 1 lipid type. After adjustment, those with highest total cholesterol variability had a 20% increased risk of CVD (Q5 versus Q1 hazard ratio, 1.20 [95% CI, 1.06–1.37]). Results were similar for low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Conclusions In a large electronic health record–based population cohort, high variability in total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol was associated with an increased risk of CVD, independent of traditional risk factors, suggesting it may be a possible risk marker and target for intervention. Lipid variability can be calculated in the electronic health record environment, but more research is needed to determine its clinical utility.

Objective: To study associations between the Minnesota coronavirus disease 2019 (COVID-19) mitigation strategies on incidence rates of acute myocardial infarction (MI) or revascularization among residents of Southeast Minnesota. Methods: Using the Rochester Epidemiology Project, all adult residents of a nine-county region of Southeast Minnesota who had an incident MI or revascularization between January 1, 2015, and December 31, 2020, were identified. Events were defined as primary in-patient diagnosis of MI or undergoing revascularization. We estimated age- and sex-standardized incidence rates and incidence rate ratios (IRRs) stratified by key factors, comparing 2020 to 2015–2019. We also calculated IRRs by periods corresponding to Minnesota’s COVID-19 mitigation timeline: “Pre-lockdown” (January 1–March 11, 2020), “First lockdown” (March 12–May 31, 2020), “Between lockdowns” (June 1–November 20, 2020), and “Second lockdown” (November 21–December 31, 2020). Results: The incidence rate in 2020 was 32% lower than in 2015–2019 (24 vs 36 events/100,000 person-months; IRR, 0.68; 95% CI, 0.62-0.74). Incidence rates were lower in 2020 versus 2015–2019 during the first lockdown (IRR, 0.54; 95% CI, 0.44-0.66), in between lockdowns (IRR, 0.70; 95% CI, 0.61-0.79), and during the second lockdown (IRR, 0.54; 95% CI, 0.41-0.72). April had the lowest IRR (IRR 0.48; 95% CI, 0.34-0.68), followed by August (IRR, 0.55; 95% CI, 0.40-0.76) and December (IRR, 0.56; 95% CI, 0.41-0.77). Similar declines were observed across sex and all age groups, and in both urban and rural residents. Conclusion: Mitigation measures for COVID-19 were associated with a reduction in hospitalizations for acute MI and revascularization in Southeast Minnesota. The reduction was most pronounced during the lockdown periods but persisted between lockdowns.

The National Institutes of Health’s (NIH) K99/R00 Pathway to Independence Award offers promising postdoctoral researchers and clinician-scientists an opportunity to receive research support at both the mentored and the independent levels with the goal of facilitating a timely transition to a tenure-track faculty position. This transitional program has been generally successful, with most K99/R00 awardees successfully securing R01-equivalent funding by the end of the R00 period. However, often highly promising proposals fail because of poor grantsmanship. This overview provides guidance from the perspective of long-standing members of the National Heart, Lung, and Blood Institute’s Mentored Transition to Independence study section for the purpose of helping mentors and trainees regarding how best to assemble competitive K99/R00 applications.

Abstract Background The cellular adhesion pathway has been suggested as playing an important role in the pathogenesis of atrial fibrillation (AF). However, prior studies that have investigated the role of adhesion pathway proteins in risk of AF have been limited in the number of proteins that were studied and in the ethnic and racial diversity of the study population. Therefore we aimed to study the associations of fifteen adhesion pathway proteins with incident AF in a large, diverse population. Methods Multi-Ethnic Study of Atherosclerosis participants from four races/ethnicities (n = 2504) with protein levels measured were followed for incident AF (n = 253). HGF protein was measured on Exam 1 samples (N = 6669; AF n = 851). Cox proportional hazards regression was used to assess the association of AF with 15 adhesion pathway proteins. Bonferroni correction was applied to account for multiple comparisons. Results After adjusting for potential confounding variables (age, sex, race/ethnicity, height, body mass index, systolic blood pressure, antihypertension therapy, diabetes status, current smoker, current alcohol use, and total and HDL cholesterol), and accounting for multiple testing (P

Abstract Background The rate of decline in cardiovascular disease (CVD) mortality has lessened nationally. How these findings apply to specific states or causes of CVD deaths is not known. Examining these trends at the state level is important to plan local interventions. Methods We analyzed CVD mortality trends in Minnesota (MN) using the U.S. Centers for Disease Control and Prevention (CDC) Wide-ranging ONline Data for Epidemiologic Research (WONDER). Trends were analyzed by age, sex, type of CVD and location of death. Results CVD mortality rates in MN declined in 2000–2009 and then leveled off in 2010–2018, paralleling national rates. Age- and sex-adjusted CVD mortality decreased by 3.7% per year in 2000–2009 (average annual percent changes [AAPC]: -3.7; 95% CI: − 4.8, − 2.6) with no change observed in 2010–2018. Those aged 65–84 years had the most rapid early decline in CVD mortality (AAPC: -5.9, 95% CI: − 6.2, − 5.7) and had less improvement in 2010–2018 (AAPC: -1.8, 95% CI: − 2.2, − 1.5), and the younger age group (25–64 years) now experiences the most adverse trends (AAPC: 1.2, 95% CI: 0.7–1.8). Coronary heart disease (CHD) and cerebrovascular disease had the largest relative decreases in mortality in 2000–2009 (CHD AAPC: -5.2; 95% CI: − 6.5,-3.9; cerebrovascular disease AAPC: -4.4, 95% CI: − 5.2, − 3.6) with no change 2010–2018. Heart failure (HF)/cardiomyopathy followed similar trends with a 2.5% decrease (AAPC 95% CI: − 3.5, − 1.5) per year in 2000–2009 and no change in 2010–2018. Deaths from other CVD also decreased in the early time period (AAPC: -1.6, 95% CI: − 2.7, − 0.5) but increased in 2010–2018 (AAPC: 1.9, 95% CI: 0.5, 3.3). In- and out-of-hospital death rates improved in 2000–2009 with a slowing in improvement for in-hospital death and no further improvement for out-of-hospital death in 2010–2018. Conclusion Concerning CVD mortality trends occurred in MN. In the most recent decade (2010–2018) mortality from all CVD subtypes plateaued or even increased. CVD mortality among the younger age groups increased as well. These data are congruent with adverse national trends supporting their generalizability. These adverse trends underscore the urgent need for CVD prevention and treatment, as well as continued surveillance to assess progress at the state and national level.

Objective: To evaluate the trends in incident premature myocardial infarction (MI) and prevalence of cardiac risk factors in a population-based cohort. Methods: We studied a population-based cohort of incident premature MIs among residents (MI in men aged 18-55 years and women aged 18-65 years) in Olmsted County, Minnesota, during a 26-year period from January 1, 1987 through December 31, 2012. Recurrent MI and death after incident premature MI were enumerated through September 30, 2018. Results: Of 3276 MI cases, 850 were premature events (37.9% [322/850] women). Age-adjusted premature MI incidence rates (2012 vs 1987) declined by 39% in men (rate ratio, 0.61; 95% CI, 0.46 to 0.81]) and 61% in women (rate ratio, 0.39; 95% CI, 0.27 to 0.57). Among men with premature MI, the prevalence of hypertension, diabetes, and hyperlipidemia increased over time, whereas in women, only the prevalence of hyperlipidemia increased. During a mean follow-up of 13.3 years, there was no temporal decline in recurrent MI in men and women. Women showed 66% decreased risk for mortality (hazard ratio, 0.34; 95% CI, 0.17 to 0.68) over time, whereas men showed no change. Conclusion: The incidence of premature MI declined over a 26-year period for both men and women. The risk factor profile of persons presenting with MI worsened over time, especially in men. Death following incident MI declined only in women. These results underscore the importance of primary prevention in young adults and of sex-specific approaches.

Objective: To assess the potential impact of Pharmacogenomic (PGx) variation in cytochrome P450 2D6 (CYP2D6) enzyme function, using loss in quality-adjusted life years (QALYs) associated with treatment problems, and the willingness to pay to avoid treatment problems from patients’ and payers’ perspectives. Patients and Methods: The study included patients prescribed tramadol or codeine, or both, between January 1, 2005, and December 31, 2017. Demographic information and adverse drug events, including adverse drug events and poor pain control, were collected from the electronic health records using natural language processing techniques and review by trained abstractors. Patients’ willingness to pay and QALY estimates were based on comprehensive literature review. The CYP2D6 phenotypes were divided into 4 groups: ultra-rapid metabolizers, normal metabolizers, intermediate metabolizers, and poor metabolizers. Results: Among the 2860 identified patients, 63 (2%) were ultrarapid metabolizers, 1449 (50%) were normal metabolizers, 1155 (40%) were intermediate metabolizers, and 193 (7%) were poor metabolizers. The patients’ average estimated willingness-to-pay value to avoid treatment problems was $23 per month; poor metabolizers developed problems with the highest estimated willingness-to-pay value ($32 per month). The mean QALY loss among all patients was 0.024 QALYs (8.8 healthy days); poor metabolizers had the highest loss (0.027 QALYs, 9.9 healthy days). Conclusion: Patients with various phenotypes developed different treatment problem profiles. Poor CYP2D6 metabolizers developed problems with highest willingness to pay, and they might potentially benefit most from PGx-guided treatment and problem prevention.

Introduction: Hepatocyte growth factor (HGF) is a cytokine released in response to endothelial injury and a potential biomarker of cardiovascular disease (CVD) risk. We examined the association between cardiovascular health (CVH) and HGF in a multi-ethnic cohort of adults free from CVD at baseline.Methods: This cross-sectional study conducted between 2020 and 2021 used MESA baseline examination data (2000–2002) from 6,490 US adults aged 45–84 years. The independent variable was CVH measured by the CVH score and number of ideal metrics. The score was derived from seven 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 to 14. An inadequate score was 0–8, average, 9–10 and optimal, 11–14. The dependent variable was logarithmically transformed HGF. We used regression analyses to estimate associations between CVH and HGF adjusting for sociodemographic factors.Results: Participants' mean (SD) age was 62 (10) years. Fifty-three percent were female. A one-unit increment in the CVH score was significantly associated with 3% lower HGF levels. Average and optimal CVH scores were significantly associated with 8% and 12% lower HGF levels, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF levels.Conclusion: Favorable CVH was significantly associated with lower HGF levels in this ethnically diverse cohort. Interventions aimed at promoting and preserving favorable CVH may reduce the risk of endothelial injury as indicated by lower serum HGF levels.

Objective: To understand patient characteristics related to acceptability of returning individual research results via various modalities, focusing on electronic visits (e-visits). Patients and Methods: Twelve hundred participants from the Mayo Clinic Biobank were selected using a stratified random sampling approach based on sex, age, and education level. Mailed surveys ascertained return of results preferences for 2 disease vignettes (cystic fibrosis and hereditary breast cancer) and a pharmacogenomics vignette. The study was conducted from October 1, 2013, through March 31, 2014. Results: In all, 685 patients (57%) responded, and 60% reported liking e-visits, although the option of receiving results in an office visit was liked most frequently. Multivariable logistic models showed that the odds of liking the use of e-visits for returning results for cystic fibrosis and hereditary breast cancer were higher among those with higher education and better genetic knowledge and among those not living in proximity to the Mayo Clinic (Rochester, Minnesota). Level of genetic knowledge was not considerably associated with accepting e-visits, whereas education level remained important. For all vignettes, those who are divorced were less likely to accept e-visits. Conclusion: Researchers are faced with a difficult challenge of returning results with a method that is both acceptable to recipients and logistically feasible. This study implies that the use of e-visits may be a viable option for return of results to stratify the chasm between in-person genetic counseling and online portal receipt of results.

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.

Electronic health records (EHRs) are widely adopted with a great potential to serve as a rich, integrated source of phenotype information. Computational phenotyping, which extracts phenotypes from EHR data automatically, can accelerate the adoption and utilization of phenotype-driven efforts to advance scientific discovery and improve healthcare delivery. A list of computational phenotyping algorithms has been published but data fragmentation, i.e., incomplete data within one single data source, has been raised as an inherent limitation of computational phenotyping. In this study, we investigated the impact of diverse data sources on two published computational phenotyping algorithms, rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM), using Mayo EHRs and Rochester Epidemiology Project (REP) which links medical records from multiple health care systems. Results showed that both RA (less prevalent) and T2DM (more prevalent) case selections were markedly impacted by data fragmentation, with positive predictive value (PPV) of 91.4 and 92.4%, false-negative rate (FNR) of 26.6 and 14% in Mayo data, respectively, PPV of 97.2 and 98.3%, FNR of 5.2 and 3.3% in REP. T2DM controls also contain biases, with PPV of 91.2% and FNR of 1.2% for Mayo. We further elaborated underlying reasons impacting the performance.

Abstract Background Community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is one of the most common causes of skin and soft tissue infections in the United States, and a variety of genetic host factors are suspected to be risk factors for recurrent infection. Based on the CDC definition, we have developed and validated an electronic health record (EHR) based CA-MRSA phenotype algorithm utilizing both structured and unstructured data. Methods The algorithm was validated at three eMERGE consortium sites, and positive predictive value, negative predictive value and sensitivity, were calculated. The algorithm was then run and data collected across seven total sites. The resulting data was used in GWAS analysis. Results Across seven sites, the CA-MRSA phenotype algorithm identified a total of 349 cases and 7761 controls among the genotyped European and African American biobank populations. PPV ranged from 68 to 100% for cases and 96 to 100% for controls; sensitivity ranged from 94 to 100% for cases and 75 to 100% for controls. Frequency of cases in the populations varied widely by site. There were no plausible GWAS-significant (p

We examined the association of variation in the type 2 diabetes risk-conferring TCF7L2 gene with the risk of incident coronary heart disease (CHD) among the lean, overweight, and obese members of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Cox proportional hazard regression analyses were performed using a general model, with the major homozygote as the reference category. For 9,865 whites, a significant increase in the risk of CHD was seen only among lean ( BMI