Faculty Bibliography

INTRODUCTION:Existing studies predominantly consider the association of late-life lipid levels and subsequent cognitive change. However, midlife rather than late-life risk factors are often most relevant to cognitive health. METHODS:We quantified the association between measured serum lipids in midlife and subsequent 20-year change in performance on three cognitive tests in 13,997 participants of the Atherosclerosis Risk in Communities study. RESULTS:Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides were associated with greater 20-year decline on a test of executive function, sustained attention, and processing speed. Higher total cholesterol and triglycerides were also associated with greater 20-year decline in memory scores and a measure summarizing performance on all three tests. High-density lipoprotein cholesterol was not associated with cognitive change. Results were materially unchanged in sensitivity analyses addressing informative missingness. DISCUSSION:Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides in midlife were associated with greater 20-year cognitive decline.

BACKGROUND/OBJECTIVES:We aimed to evaluate the relationship between BMI and the risk of renal disease in patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. SUBJECTS/METHODS:(obesity grade 3, n = 294); those underweight were excluded. The composite outcome "major renal event" was defined as development of new macroalbuminuria, doubling of creatinine, end stage renal disease, or renal death. These outcomes and development of new microalbuminuria were considered individually as secondary endpoints. RESULTS:increased the risk of major renal events by 4 (1-6)%. Comparable results were observed with the risk of secondary endpoints. CONCLUSIONS:Higher BMI is an independent predictor of major renal events in patients with type 2 diabetes. Our findings encourage weight loss to improve nephroprotection in these patients.

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 American Heart Association recommends focusing on 7 health factors (Life's Simple 7) for primordial prevention of cardiovascular health. However, whether greater adherence to Life's Simple 7 in midlife improves prognosis after myocardial infarction (MI) in later life is unknown. METHODS AND RESULTS:In 1277 participants who developed MI during the ARIC (Atherosclerosis Risk in Communities) Study follow-up, a 14-point score of Life's Simple 7 was constructed according to the status (2 points for ideal, 1 point for intermediate, and 0 points for poor) of each of 7 factors (smoking, adiposity, physical activity, diet, total cholesterol, blood pressure, and fasting glucose) at baseline (1987-1989). Hazard ratios for composite and individual adverse outcomes of all-cause mortality, cardiovascular mortality, recurrent MI, heart failure, and stroke were calculated according to Life's Simple 7 score. During a median follow-up of 3.3 years, 918 participants (72%) had subsequent adverse outcomes after MI. Life's Simple 7 score at middle age was inversely associated with adverse outcomes after MI (adjusted hazard ratios of composite outcome, 0.57 [95% confidence interval, 0.39-0.84] if score is ≥10, 0.78 [95% confidence interval, 0.57-1.07] if score is 7-9, and 0.82 [95% confidence interval, 0.60-1.11] if score is 4-6 versus ≤3). The association was largely independent of access to care and MI severity. Individual factors related to better prognosis after MI were ideal nonsmoking, body mass index, blood pressure, and fasting glucose. CONCLUSIONS:Optimal Life's Simple 7 at middle age was associated with better prognosis after MI in later life. Our findings suggest a secondary prevention benefit of having better cardiovascular health status in midlife.

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.

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.

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.

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.