Faculty Bibliography

BACKGROUND:Higher physical activity (PA) is associated with lower heart failure (HF) risk; however, the effect of changes in PA on HF risk is unknown. METHODS:We evaluated 11 351 ARIC study (Atherosclerosis Risk in Communities) participants (mean age 60 years) who attended visit 3 (1993-1995) and did not have a history of cardiovascular disease. Exercise PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines as recommended, intermediate, or poor. We used Cox regression models to characterize the association of 6-year changes in PA between the first (1987-1989) and third ARIC visits and HF risk. RESULTS:During a median of 19 years of follow-up, 1750 HF events occurred. Compared with those with poor activity at both visits, the lowest HF risk was seen for those with persistently recommended activity (hazard ratio, 0.69; 95% confidence interval, 0.60-0.80). However, those whose PA increased from poor to recommended also had reduced HF risk (hazard ratio, 0.77; 95% confidence interval 0.63-0.93). Among participants with poor baseline activity, each 1 SD higher PA at 6 years (512.5 METS*minutes/week, corresponding to ≈30 minutes of brisk walking 4 times per week) was associated with significantly lower future HF risk (hazard ratio, 0.89, 95% confidence interval, 0.82-0.96). CONCLUSIONS:Although maintaining recommended activity levels is associated with the lowest HF risk, initiating and increasing PA, even in late middle age, are also linked to lower HF risk. Augmenting PA may be an important component of strategies to prevent HF.

OBJECTIVE:To investigate the association between individual and area-level socioeconomic status and hypertension risk among individuals later in life. METHODS:We used Cox proportional hazards models to examine the association of socioeconomic status with incident hypertension using race-specific neighborhood socioeconomic status, median household income, and education among 3372 participants (mean age, 61 years) from the Atherosclerosis Risk in Communities Study at Visit 4 (1996-1998). Incident hypertension was defined as self-reported diagnosis or reported use of antihypertensive medications. RESULTS:Over a median follow-up time of 9.4 years, there were 1874 new cases of hypertension (62.1 per 1000 person-years). Overall, being in high as compared with low socioeconomic status categories was associated with a lower risk of developing hypertension in late life, with hazard ratios (95% confidence intervals) of 0.87 (0.77-0.98) for high neighborhood socioeconomic status tertile, 0.79 (0.69-0.90) for high individual income, and 0.75 (0.63-0.89) for college education after adjustment for traditional risk factors. These findings were consistent and robust whenever accounting for competing risks of all-cause mortality. No significant interactions by race and age (dichotomized at age 65) were observed. CONCLUSION:Among participants free of hypertension in midlife, high neighborhood and individual socioeconomic status are associated with a decreased risk of incident hypertension. Our findings support population-level interventions, such as blood pressure screening at senior centers and faith-based organizations, that are tailored to shift the distribution of blood pressure and reduce hypertension health inequalities among older adults.

Background The role of a healthy dietary pattern in the prevention of abdominal aortic aneurysms ( AAA ) is unknown. We aimed to evaluate the relationship between adherence to a Dietary Approaches To Stop Hypertension-style dietary pattern and the risk of incident AAA s. Methods and Results Dietary intake was assessed via a 66-item food frequency questionnaire at baseline (1987-1989) and at visit 3 (1993-1995) in 13 496 participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study without clinical AAA (mean age, 54 years). A dietary scoring index based on food times was constructed to assess self-reported adherence to a dietary approaches to stop hypertension-style dietary pattern. Participants were followed for incident clinical AAA s using hospital discharge diagnoses, Medicare inpatient and outpatient diagnoses, or death certificates through December 31, 2011. Cox proportional hazards models with covariate adjustment were used to estimate hazard ratios with 95% confidence intervals. During a median follow-up of 23 years, there were 517 incident AAA cases. Individuals with a Dietary Approaches To Stop Hypertension-style diet score in the highest quintile had a 40% lower risk of hospitalization for AAA than those in the lowest quintile (hazard ratio_{Q5 vs Q1}: 0.60; 95% confidence intervals: 0.44, 0.83; P_trend=0.002). In detailed analyses, higher consumption of fruits, vegetables, whole grains, low-fat dairy, and nuts and legumes was related to a lower risk for AAA . Conclusions Greater adherence to a Dietary Approaches To Stop Hypertension-style dietary pattern was associated with lower risk for AAA . Higher consumption of fruits, vegetables, whole grains, low-fat dairy as well as nuts and legumes may help to decrease the burden of AAA s.

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:Previous studies have reported that atrial fibrillation (AF) is associated with cognitive decline and dementia. These studies, however, had limited follow-up, were based mostly on white and highly selected populations, and did not account for attrition. We evaluated the association of incident AF with 20-year change in cognitive performance (accounting for attrition) and incident dementia in the ARIC (Atherosclerosis Risk in Communities) Study. METHODS AND RESULTS:score was 0.115 (95% confidence interval, 0.014-0.215) greater in participants with AF than in those without AF. Further adjustment for attrition by multiple imputation by chained equations strengthened the association. In addition, incident AF was associated with an increased risk of dementia (hazard ratio, 1.23; 95% confidence interval, 1.04-1.45), after adjusting for cardiovascular risk factors, including ischemic stroke. CONCLUSIONS:AF is associated with greater cognitive decline and increased risk of dementia, independent of ischemic stroke. Because cognitive decline is a precursor to dementia, our findings prompt further investigation to identify specific treatments for AF that will delay the trajectory of cognitive decline and, thus, prevent dementia in patients with AF.

Fructosamine and glycated albumin are potentially useful alternatives to hemoglobin A_1c (HbA_1c) as diabetes biomarkers. The genetic determinants of fructosamine and glycated albumin, however, are unknown. We performed genome-wide association studies of fructosamine and glycated albumin among 2,104 black and 7,647 white participants without diabetes in the Atherosclerosis Risk in Communities (ARIC) Study and replicated findings in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Among whites, rs34459162, a novel missense single nucleotide polymorphism (SNP) in RCN3, was associated with fructosamine (P = 5.3 × 10^-9) and rs1260236, a known diabetes-related missense mutation in GCKR, was associated with percent glycated albumin (P = 5.9 × 10^-9) and replicated in CARDIA. We also found two novel associations among blacks: an intergenic SNP, rs2438321, associated with fructosamine (P = 6.2 × 10^-9), and an intronic variant in PRKCA, rs59443763, associated with percent glycated albumin (P = 4.1 × 10^-9), but these results did not replicate. Few established fasting glucose or HbA_1c SNPs were also associated with fructosamine or glycated albumin. Overall, we found genetic variants associated with the glycemic information captured by fructosamine and glycated albumin as well as with their nonglycemic component. This highlights the importance of examining the genetics of hyperglycemia biomarkers to understand the information they capture, including potential glucose-independent factors.

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.

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.

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.