Faculty Bibliography

BACKGROUND:Excess weight is associated with subclinical myocardial damage, as reflected by high-sensitivity cardiac troponin T (hs-cTnT) concentrations, which portends high heart failure risk. However, the association between weight history and myocardial damage is unknown. METHODS:) over all ARIC time points × follow-up duration]. We used logistic regression to estimate associations of weight history metrics with increased hs-cTnT (≥14 ng/L) at visit 4. RESULTS:Overall, 623 individuals (7%) had increased hs-cTnT at visit 4. Within each current BMI category, previous excess weight was associated with increased hs-cTnT, with the strongest associations for those with past and current obesity [odds ratio (OR), 3.85; 95% CI, 2.51-5.90 for obesity at age 25 years and visit 4]. Each 10-year longer obesity duration was associated with increased hs-cTnT (OR, 1.26; 95% CI, 1.17-1.35). Each 100 higher excess BMI-years was also progressively associated with increased hs-cTnT (OR, 1.21; 95% CI, 1.14-1.27). CONCLUSIONS:Previous obesity and greater cumulative weight from young adulthood increase the likelihood of myocardial damage, indicating long-term toxic effects of adiposity on the myocardium and the need for weight maintenance strategies targeting the entire life span.

BACKGROUND:The Dietary Approaches to Stop Hypertension (DASH) dietary pattern is recommended for cardiovascular disease risk reduction. Assessment of dietary intake has been limited to subjective measures and a few biomarkers from 24-h urine collections. OBJECTIVE:The aim of the study was to use metabolomics to identify serum compounds that are associated with adherence to the DASH dietary pattern. DESIGN:We conducted untargeted metabolomic profiling in serum specimens collected at the end of 8 wk following the DASH diet (n = 110), the fruit and vegetables diet (n = 111), or a control diet (n = 108) in a multicenter, randomized clinical feeding study (n = 329). Multivariable linear regression was used to determine the associations between the randomized diets and individual log-transformed metabolites after adjustment for age, sex, race, education, body mass index, and hypertension. Partial least-squares discriminant analysis (PLS-DA) was used to identify a panel of compounds that discriminated between the dietary patterns. The area under the curve (C statistic) was calculated as the cumulative ability to distinguish between dietary patterns. We accounted for multiple comparisons with the use of the Bonferroni method (0.05 of 818 metabolites = 6.11 × 10-5). RESULTS:Serum concentrations of 44 known metabolites differed significantly between participants randomly assigned to the DASH diet compared with both the control diet and the fruit and vegetables diet, which included an amino acid, 2 cofactors and vitamins (n = 2), and lipids (n = 41). With the use of PLS-DA, component 1 explained 29.4% of the variance and component 2 explained 12.6% of the variance. The 10 most influential metabolites for discriminating between the DASH and control dietary patterns were N-methylproline, stachydrine, tryptophan betaine, theobromine, 7-methylurate, chiro-inositol, 3-methylxanthine, methyl glucopyranoside, β-cryptoxanthin, and 7-methylxanthine (C statistic = 0.986). CONCLUSIONS:An untargeted metabolomic platform identified a broad array of serum metabolites that differed between the DASH diet and 2 other dietary patterns. This newly identified metabolite panel may be used to assess adherence to the DASH dietary pattern. This trial was registered at http://www.clinicaltrials.gov as NCT03403166.

BACKGROUND:Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG. OBJECTIVES:The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study. METHODS:Fasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored. RESULTS:). CONCLUSIONS:RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.

AIMS:Clinical heart failure (HF) guidelines recommend monitoring of creatinine and potassium throughout the initial weeks of mineralocorticoid receptor antagonists (MRAs) therapy. We here assessed the extent to which this occurs in our health care. METHODS AND RESULTS:Observational study in 2007-2010 HF patients starting MRA therapy in Stockholm, Sweden. Outcomes included potassium and creatinine laboratory testing before MRA initiation and in the early (Days 1-10) and extended (Days 11-90) post-initiation periods. Exclusion criteria considered death/hospitalization within 90 days, and lack of a second MRA dispense. Of 4036 HF patients starting on MRA, 45% were initiated from a hospital, 24% from a primary care centre, and 30% from other private centres. Overall, 89% underwent pre-initiation testing, being more common among hospital (97%) than for primary care (74%) initiations. Only 24% were adequately monitored in all three recommended intervals, being again more frequent following hospital (33%) than private (21%) or primary care (17%) initiations. In multivariable analyses, adequate monitoring was more likely for hospital [odds ratio (OR) 2.85, 95% confidence interval (95% CI) 2.34-3.56] initiations, and for patients with chronic kidney disease (OR 1.79, 95% CI 1.30-2.43) and concomitant use of angiotensin-converting enzyme (OR 1.27, 95% CI 1.05-1.52), angiotensin receptor blockers (OR 1.19, 95% CI 1.01-1.40) or beta-blockers (OR 1.65, 95% CI 1.22-2.26). Age, sex, and prescribing centre explained a small portion of adequate monitoring (c-statistic 0.63). Addition of comorbidities and medications improved prediction marginally (c-statistic 0.65). CONCLUSION:Although serum potassium and creatinine monitoring before MRA initiation for HF is frequent, rates of post-initiation monitoring remain suboptimal, especially among primary care centres.

INTRODUCTION:The interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood. METHODS:In the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45-64 years. In 2011-2013, 20-25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM. RESULTS:In 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late-life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late-life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model. DISCUSSION:Later life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition.

RATIONALE & OBJECTIVE:Determining whether a change in estimated glomerular filtration rate (eGFR) or albuminuria is clinically significant requires knowledge of short-term within-person variability of the measurements, which few studies have addressed in the setting of chronic kidney disease. STUDY DESIGN:Cross-sectional study with multiple collections over less than 4 weeks. SETTING & PARTICIPANTS:; median urinary albumin-creatinine ratio (UACR), 173mg/g). EXPOSURE:Repeat measurements from serially collected samples across 3 study visits. OUTCOMES:-microglobulin (B2M), and beta trace protein (BTP). ANALYTICAL APPROACH:) values using log-transformed measurements. RESULTS:values for UAC and UACR were comparable across the range of baseline albuminuria values. LIMITATIONS:Small sample size limits the ability to detect differences in variability across markers. Participants were recruited and followed up in a clinical and not research setting, so some preanalytical factors could not be controlled. CONCLUSIONS:eGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to be high, making it difficult to distinguish random variability from meaningful biologic changes.

BACKGROUND:Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES:The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS:Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. RESULTS:Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS:Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.

The recent Kidney Disease Improving Global Outcomes 2012 CKD guidelines recommend estimating GFR from serum creatinine (eGFR_cr) as a first-line test to assess kidney function and using cystatin C or measured glomerular filtration rate (GFR) as confirmatory tests. eGFR_cr may be inaccurate in people with variation in muscle mass or diet, and eGFR_cys is not more accurate than eGFR_cr. eGFR_crcys is more accurate than either, but it is not independent of eGFR_cr. Measured GFR is not practical and is susceptible to error due to variation in clearance methods and in the behavior of exogenous filtration markers. Over the past few years, we have hypothesized, and begun to test the hypothesis, that a panel of filtration markers (panel eGFR) from a single blood draw would require fewer demographic or clinical variables and could estimate GFR as accurately as measured GFR. In this article, we describe the conceptual background and rationale for this hypothesis and summarize our work thus far including evaluation of novel low-molecular-weight proteins and metabolites and then outline how we envision that such a panel could be used in clinical practice, research, and public health.

OBJECTIVE:There is suggestive evidence linking hypoglycemia with cardiovascular disease, but few data have been collected in a community-based setting. Information is lacking on individual cardiovascular outcomes and cause-specific mortality. RESEARCH DESIGN AND METHODS:We conducted a prospective cohort analysis of 1,209 participants with diagnosed diabetes from the Atherosclerosis Risk in Communities (ARIC) study (analytic baseline, 1996-1998). Severe hypoglycemic episodes were identified using first position ICD-9 codes from hospitalizations, emergency department visits, and ambulance calls through 2013. Cardiovascular events and deaths were captured through 2013. We used adjusted Cox regression models with hypoglycemia as a time-varying exposure. RESULTS:There were 195 participants with at least one severe hypoglycemic episode during a median fellow-up of 15.3 years. After severe hypoglycemia, the 3-year cumulative incidence of coronary heart disease was 10.8% and of mortality was 28.3%. After adjustment, severe hypoglycemia was associated with coronary heart disease (hazard ratio [HR] 2.02, 95% CI 1.27-3.20), all-cause mortality (HR 1.73, 95% CI 1.38-2.17), cardiovascular mortality (HR 1.64, 95% CI 1.15-2.34), and cancer mortality (HR 2.49, 95% CI 1.46-4.24). Hypoglycemia was not associated with stroke, heart failure, atrial fibrillation, or noncardiovascular and noncancer death. Results were robust within subgroups defined by age, sex, race, diabetes duration, and baseline cardiovascular risk. CONCLUSIONS:Severe hypoglycemia is clearly indicative of declining health and is a potent marker of high absolute risk of cardiovascular events and mortality.

BACKGROUND:The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations are recommended for glomerular filtration rate (GFR) estimation in the general population. They have not been evaluated in community-based populations, including Blacks at higher levels of GFR, but are commonly applied in such populations. METHODS:In an ancillary study of Multi-Ethnic Study of Atherosclerosis conducted at one site, we evaluated the performance of the CKD-EPI equations for creatinine (eGFRcr), cystatin C (eGFRcys) or the combination (eGFRcr-cys) compared with GFR measured as plasma clearance of iohexol. RESULTS:Among 294 participants, the mean age was 71 (SD 9) years, 47% were Black, 48% were women and the mean measured GFR (mGFR) was 72.6 (SD 18.8) mL/min/1.73 m2. The CKD-EPI equations overestimated mGFR with a larger median bias for eGFRcr and eGFRcr-cys than eGFRcys [-8.3 (95% confidence interval -9.7, -6.5), -7.8 (-9.2, -6.2) and -3.7 (-5.0, -1.8) mL/min/1.73 m2, respectively], with smaller bias for those with lower compared with higher eGFR and by race compared with sex. CONCLUSION:The small differential bias of the CKD-EPI equation between races suggests that they can be used in Blacks as well as Whites in older community-based adults. The large differential bias in women versus men in all equations is in contrast to other studies and is unexplained. Further studies are required in multiracial and multiethnic community-based cohorts, taking into account differences in GFR measurement methods.