Weight gain increases risk of cardiovascular disease, but has not been examined extensively in relationship to venous thromboembolism (VTE). The association between weight change over 9 years and subsequent VTE among participants in the Atherosclerosis Risk in Communities (ARIC) study was examined, with a hypothesis that excess weight gain is a risk factor for VTE, relative to no weight change. Quintiles of 9-year weight change were calculated (visit 4 1996–1998 weight minus visit 1 1987–1989 weight in kg: Quintile 1: ≥−1.81 kg; Quintile 2: <−1.81 to ≤1.36 kg; Quintile 3: >1.36 to ≤4.08 kg; Quintile 4: >4.08 to ≤7.71 kg; Quintile 5: >7.71 kg). Incident VTEs from visit 4 (1996–1998) through 2015 were identified and adjudicated using medical records. Hazard ratios (HRs) were calculated using Cox models. 529 incident VTEs were identified during an average of 19 years of follow up. Compared to Quintile 2, participants in Quintile 5 of weight change had 1.46 times the rate of incident VTE (HR = 1.46 (95% CI 1.09, 1.95), adjusted for age, race, sex, income, physical activity, smoking, and prevalent CVD). The HR for Quintile 5 was modestly attenuated to 1.38 (95% CI 1.03, 1.84) when visit 1 BMI was included in the model. When examined separately, results were significant for unprovoked VTE, but not for provoked VTE. Among those obese at visit 1, both weight gain (HR 1.86 95% CI 1.27, 2.71) and weight loss (HR 2.11 95% CI 1.39, 3.19) were associated with incident VTE, compared with normal-weight participants with no weight change. Weight gain later life was associated with increased risk for unprovoked VTE. Among those with obesity, both weight gain and weight loss were associated with increased risk for VTE.

Background Cardiorenal syndrome is a well known concept, bolstered by extensive investigations of CKD as a risk factor of cardiovascular disease. However, data on whether cardiovascular disease increases long-term risk of ESKD are sparse. Methods We assessed the association of incident hospitalization with major cardiovascular diseases (heart failure, atrial fibrillation, coronary heart disease, and stroke) with subsequent risk of ESKD among individuals enrolled in the Atherosclerosis Risk in Communities study; the analysis included 9047 individuals without prevalent cardiovascular disease at their fourth study visit. Each relevant incident cardiovascular disease event was entered into multivariable Cox proportional hazard models as a timevarying exposure to estimate hazard ratios. Results During a median follow-up of 17.5 years, there were 2598 cases of hospitalization with cardiovascular disease (heart failure, n=1269; atrial fibrillation, n=1337; coronary heart disease, n=696; and stroke, n=559) and 210 cases of incident ESKD. The incidence ofmajor cardiovascular disease was associated with increased risk of ESKD, with the highest risk for heart failure (hazard ratio, 11.40; 95% confidence interval, 8.38 to 15.50), followed by coronary heart disease, atrial fibrillation, and stroke. When we analyzed heart failure with preserved ejection fraction and heart failure with reduced ejection fraction separately, the risk was nominally higher for heart failure with preserved ejection fraction. Conclusions Major incident cardiovascular disease events were associated with ESKD, independent of kidney risk factors. In particular, heart failure showed a very strong association with ESKD. Our findings highlight the importance of monitoring and managing kidney disease in patients with cardiovascular disease. The potentially distinct contribution to ESKD of heart failure with preserved versus reduced ejection fraction deserves future investigation.

OBJECTIVE: To test the hypothesis that periodontal disease would be associated with increased risk for dementia and mild cognitive impairment (MCI) by assessing dementia/MCI outcomes after a baseline periodontal examination. METHODS: Participants enrolled in the Atherosclerosis Risk in Communities study with a clinical periodontal examination (or edentulous participants) at visit 4 (1996-1998; mean ± SD age 63 ± 6 years, 55% female, 21% black) and adjudicated dementia outcomes through 2016 were included (n = 8,275). A subgroup of 4,559 participants had adjudicated dementia and MCI assessments at visit 5 (2011-2013). Participants received a full-mouth periodontal examination and were classified into periodontal profile classes (PPCs) based on the severity and extent of gingival inflammation and attachment loss. MCI and dementia were determined via neurocognitive testing, neurological examination and history, informant interviews, and brain MRI in a subset. Cox proportional hazards models regressed incident dementia on PPCs. Relative risk regression models were used for the composite of MCI/dementia. RESULTS: The cumulative incidence and incidence density of dementia during follow-up (average 18.4 years) were 19% (n = 1,569) and 11.8 cases per 1,000 person-years. Multivariable adjusted hazard ratios for incident dementia among participants with severe PPC or edentulism (vs periodontal healthy) were 1.22 (95% confidence interval [CI] 1.01-1.47) and 1.21 (95% CI 0.99-1.48), respectively. For the combined dementia/MCI outcome, adjusted risk ratios among participants with mild/intermediate PPC, severe PPC, or edentulism (vs periodontal healthy) were 1.22 (95% CI 1.00-1.48), 1.15 (95% CI 0.88-1.51), and 1.90 (95% CI 1.40-2.58). Results were stronger among younger (≤62 years) participants (p for interaction = 0.02). CONCLUSION: Periodontal disease was modestly associated with incident MCI and dementia in a community-based cohort of black and white participants.

Objective: To evaluate whether the incidence of infectious diseases increases the long-term risk for incident end-stage renal disease (ESRD) in the general population. Patients and Methods: In 10,290 participants of the Atherosclerosis Risk in Communities Study who attended visit 4 (1996-1998), we evaluated the association of incident hospitalization with major infections (pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis) with subsequent risk for ESRD through September 30, 2015. Hospitalization with major infection was entered into multivariable Cox models as a time-varying exposure to estimate the hazard ratios. Results: Mean age was 63 years, and of 10,290 individuals, 56% (n=5781) were women, 22% (n=2252) were black, and 7% (n=666) had an estimated glomerular filtration rate less than 60 mL/min/1.73 m2. During a median follow-up of 17.4 years, there were 2642 incident hospitalizations with major infection and 281 cases of ESRD (132 cases after hospitalization with major infection). The risk for ESRD was higher following major infection compared with while free of major infection (crude incidence rate, 10.9 vs 1.0 per 1000 person-years). In multivariable time-varying Cox analysis, hospitalization with major infection was associated with a 3.3-fold increased risk for ESRD (hazard ratio, 3.34; 95% CI, 2.56-4.37). The association was similar across pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis, and remained significant across subgroups of age, sex, race, diabetes, history of cardiovascular disease, and chronic kidney disease. Conclusion: Hospitalization with major infection was independently and robustly associated with subsequent risk for ESRD. Whether preventive approaches against infection have beneficial effects on kidney outcomes may deserve future investigations.

Goals: The goal of this study was to evaluate whether proton pump inhibitor (PPI) use is cross-sectionally associated with hypomagnesemia and whether hypomagnesemia mediates the prospective association between PPIs and cardiovascular disease (CVD) risk. Background: Use of PPIs has been associated with hypomagnesemia, primarily in case reports or within insurance databases. Both PPI use and low serum magnesium (Mg) have been associated with modestly higher CVD risk. Yet, the interrelation between PPI use and Mg in relation to CVD risk is unclear. Study: The 4436 Atherosclerosis Risk in Communities participants without prevalent CVD at visit 5 (baseline, 2011-2013) were included. Multivariable relative risk regression was used for cross-sectional analyses between PPI and hypomagnesemia prevalence (≤0.75 mmol/L). Incident CVD (defined by atrial fibrillation, coronary heart disease, CVD mortality, heart failure, stroke) was identified through 2017. Multivariable Cox regression was used to examine the PPI-CVD association. Results: Participants were mean±SD aged 75±5 years; 63% were women, 23% Black, and 24% were PPI users. PPI users had 1.24-fold (95% confidence interval: 1.08-1.44) higher prevalence of hypomagnesemia than nonusers. Over a median 5 years of follow-up, 684 incident CVD events occurred. PPI users had higher CVD risk [hazard ratio (95% confidence interval) 1.31 (1.10-1.57)] than nonusers. The effect estimate was largely unchanged when hypomagnesemia was added to the model as a potential mediator. Conclusions: In this elderly community-based study, PPI users had a higher prevalence of hypomagnesemia than in nonusers. PPI users also had higher CVD risk than nonusers; however, it appears unlikely that hypomagnesemia explains associations of PPIs with CVD risk.

Background: Health literacy has yet to be described in a non-clinical, racially diverse, community-based cohort. Methods: Four questions assessing health literacy were asked during annual phone encounters with Multi-Ethnic Study of Atherosclerosis (MESA) participants between 2016 and 2018 (n = 3629). We used prevalence ratios (PRs) with 95% confidence intervals (CIs) to characterize how demographic and acculturation factors related to limited health literacy. Models adjusted for age, sex, and race/ethnicity, and race/ethnicity-stratified models were also examined. Results: Limited health literacy was prevalent in 15.4% of the sample. Participants who were older, female, lower-income, or less acculturated were at greater risk for having limited health literacy. Chinese, Hispanic, and Black participants were more likely than White participants to have limited health literacy. Patterns were similar when stratified by race/ethnicity. Discussion: Within MESA limited health literacy was common, particularly among Chinese and Hispanic participants, with some of the variance explained by differences in acculturation.

Purpose: Previous studies have reported that taller people have an increased risk of colorectal cancer (CRC). We examined the association of two height components—leg length and sitting height—with CRC risk in 14,532 individuals aged 45–64 years in the Atherosclerosis Risk in Communities study. Methods: Anthropometrics were measured at baseline (1987–1989). Incident CRC cases (n = 382) were ascertained from 1987 to 2012. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard ratios for CRC and colon cancer across quintiles of sex-specific leg length and sitting height. Results: The highest (versus the lowest) quintile of leg length was associated with a 36% greater CRC risk (p-trend = 0.04), and 51% greater colon cancer risk (p-trend = 0.01). For the top four quintiles combined, risk was increased by 34% for CRC and by 45% for colon cancer versus the lowest quintile. Total height and sitting height were not significantly associated with CRC or colon cancer risk. A small number of cases (n = 57) limited our ability to conduct subgroup analyses for rectal cancer. Conclusions: A positive association of leg length with CRC and colon cancer risk suggests that biological mechanisms leading to greater leg length during puberty may explain the association between taller height and CRC.

Background We examined associations of three markers of subclinical cardiovascular disease (intimal-medial thickening, coronary artery calcification , and ankle-brachial index) with changes in self-reported walking over time. Methods Data were from 6,490 Multi-Ethnic Study of Atherosclerosis participants (aged 45-84 years), free of clinical cardiovascular disease at baseline. Outcomes, assessed four times over 11 years, included self-reported walking pace (none to striding pace; score, 0-4) and total walking time (minutes/week). Linear generalized estimating equation models estimated associations of baseline intimal-medial thickening (z-scored), coronary artery calcification (Agatston units), and ankle-brachial index (ratio of ankle-to-arm systolic blood pressure) with walking pace and walking time modeled continuously in separate analyses. Results Median follow-up was 9.2 years (maximum, 11.4). Walking pace (estimate, -0.042 points [95% CI; -0.048, -0.036], p < 0.0001) and walking time (estimate, -4.71 minutes [95% CI: -8.54, -0.88], p = 0.016) decreased yearly. Greater baseline intimal-medial thickening related to faster decline in walking pace in multivariable analyses: walking pace score decreased 0.004 points (95% CI: -0.008, -0.001) more per year for each 1-SD higher intimal-medial thickening z-score, equivalent to an additional 10% slower yearly walking. Greater coronary artery calcification was associated with slower walking but inconsistently related to decline in walking pace. Higher ankle-brachial index was associated with faster baseline walking pace (estimate, 0.043 points [95% CI: 0.027, 0.059] per 1-SD) but unrelated to changes in walking pace. Cardiovascular disease measures were unrelated to total walking time. Conclusions Greater subclinical cardiovascular disease is associated with prevalent slower self-reported walking pace in middle-aged and older adults but has limited impact on changes in walking over time.

Experiences of discrimination are associated with increased risk of adverse health outcomes; however, it is unknown whether discrimination is related to incident type 2 diabetes mellitus (diabetes). We investigated the associations of major experiences of discrimination (unfair treatment in 6 situations) and everyday discrimination (frequency of day-to-day experiences of unfair treatment) with incident diabetes among 5,310 participants from the Multi-Ethnic Study of Atherosclerosis, enrolled in 2000-2002. Using Cox proportional hazards models, we estimated hazard ratios and confidence intervals, adjusting for demographic factors, depressive symptoms, stress, smoking, alcohol, physical activity, diet, waist circumference, and body mass index. Over a median follow-up of 9.4 years, 654 diabetes cases were accrued. Major experiences of discrimination were associated with greater risk of incident diabetes when modeled continuously (for each additional experience of discrimination, hazard ratio = 1.09, 95% confidence interval: 1.01, 1.17) or categorically (for ≥2 experiences vs. 0, hazard ratio = 1.34, 95% confidence interval: 1.08, 1.66). Similar patterns were observed when evaluating discrimination attributed to race/ethnicity or to a combination of other sources. Everyday discrimination was not associated with incident diabetes. In conclusion, major experiences of discrimination were associated with increased risk of incident diabetes, independent of obesity or behavioral and psychosocial factors. Future research is needed to explore the mechanisms of the discrimination-diabetes relationship.

BACKGROUND Serum β-2 microglobulin (B2M), a major histocompatibility complex class I molecule that is a biomarker of kidney filtration and increased cell turnover, is elevated at the time of diagnosis in hematological and some solid cancers. However, serum B2M was not examined prospectively as a marker for cancer risk. We hypothesized that in a population without a prior cancer diagnosis, serum B2M is associated with risk of cancer (n = 2,436), including colorectal (n = 255), lung (n = 298), breast (n = 424), and prostate (n = 524) cancers, and hematological (n = 176) malignancies. METHODS The analytical cohort (n = 12,300) was followed for incident cancers from 1990 through 2006. B2M (range, 0.9-57.8 mg/L) was measured in stored serum collected in 1990-1992. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals for cancer incidence and mortality in relation to quartiles of B2M. RESULTS Adjusting for age, sex, race, center, education, body mass index, smoking, aspirin, and hormone therapy (in women) and comparing highest to lowest B2M quartiles, HRs were 1.25 (1.06-1.47; Ptrend = 0.002) for total cancer risk and 2.21 (1.32-3.70; Ptrend=0.001) for colorectal cancer risk, with similar HRs for colon and rectal cancers. These associations remained after adjustment for an inflammatory biomarker, C-reactive protein, and after excluding the first three years of follow-up. Significant associations were also observed for mortality from total, lung, and hematological cancers. CONCLUSIONS These findings provide the first evidence that higher serum B2M is associated with increased colorectal cancer risk. IMPACT This study supports B2M as a potential biomarker for colorectal cancer risk. Cancer Epidemiol Biomarkers Prev; 25(4); 657-64. ©2016 AACR.

Perceived discrimination is positively related to cardiovascular disease (CVD) risk factors; its relationship with incident CVD is unknown. Using data from the Multi-Ethnic Study of Atherosclerosis, a population-based multiethnic cohort study of 6,508 adults aged 45-84 years who were initially free of clinical CVD, we examined lifetime discrimination (experiences of unfair treatment in 6 life domains) and everyday discrimination (frequency of day-to-day occurrences of perceived unfair treatment) in relation to incident CVD. During a median 10.1 years of follow-up (2000-2011), 604 incident events occurred. Persons reporting lifetime discrimination in >/=2 domains (versus none) had increased CVD risk, after adjustment for race/ethnicity and sociodemographic factors, behaviors, and traditional CVD risk factors (hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.09, 1.70) and after control for chronic stress and depressive symptoms (HR = 1.28, 95% CI: 1.01, 1.60). Reported discrimination in 1 domain was unrelated to CVD (HR = 1.05, 95% CI: 0.86, 1.30). There were no differences by race/ethnicity, age, or sex. In contrast, everyday discrimination interacted with sex (P = 0.03). Stratified models showed increased risk only among men (for each 1-standard deviation increase in score, adjusted HR = 1.14, 95% CI: 1.03, 1.27); controlling for chronic stress and depressive symptoms slightly reduced this association (HR = 1.11, 95% CI: 0.99, 1.25). This study suggests that perceived discrimination is adversely related to CVD risk in middle-aged and older adults.

BACKGROUND AND PURPOSE: This study investigated chronic stress, depressive symptoms, anger, and hostility in relation to incident stroke and transient ischemic attacks in middle-aged and older adults. METHODS: Data were from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort study of 6749 adults, aged 45 to 84 years and free of clinical cardiovascular disease at baseline, conducted at 6 US sites. Chronic stress, depressive symptoms, trait anger, and hostility were assessed with standard questionnaires. The primary outcome was clinically adjudicated incident stroke or transient ischemic attacks during a median follow-up of 8.5 years. RESULTS: One hundred ninety-five incident events (147 strokes; 48 transient ischemic attacks) occurred during follow-up. A gradient of increasing risk was observed for depressive symptoms, chronic stress, and hostility (all P for trend 0.10). Hazard ratios (HRs) and 95% confidence intervals indicated significantly elevated risk for the highest-scoring relative to the lowest-scoring group for depressive symptoms (HR, 1.86; 95% confidence interval, 1.16-2.96), chronic stress (HR, 1.59; 95% confidence interval, 1.11-2.27), and hostility (HR, 2.22; 95% confidence interval, 1.29-3.81) adjusting for age, demographics, and site. HRs were attenuated but remained significant in risk factor-adjusted models. Associations were similar in models limited to stroke and in secondary analyses using time-varying variables. CONCLUSIONS: Higher levels of stress, hostility, and depressive symptoms are associated with significantly increased risk of incident stroke or transient ischemic attacks in middle-aged and older adults. Associations are not explained by known stroke risk factors.

Background: Fibroblast growth factor-23 (FGF-23) is a hormone involved in phosphorous regulation and vitamin D metabolism that may be associated with cardiovascular risk, and it is a potential target for intervention. We tested whether elevated FGF-23 is associated with incident coronary heart disease, heart failure, and cardiovascular mortality, even at normal kidney function. Methods and Results: A total of 11 638 Atherosclerosis Risk In Communities study participants, median age 57 at baseline (1990-1992), were followed through 2010. Cox regression was used to evaluate the independent association of baseline serum active FGF-23 with incident outcomes. Models were adjusted for traditional cardiovascular risk factors and estimated glomerular filtration rate. During a median follow-up of 18.6 years, 1125 participants developed coronary heart disease, 1515 developed heart failure, and 802 died of cardiovascular causes. For all 3 outcomes, there was a threshold, whereby FGF-23 was not associated with risk at < 40 pg/mL but was positively associated with risk at > 40 pg/mL. Compared with those with FGF-23 < 40 pg/mL, those in the highest FGF-23 category (≥58.8 pg/mL) had a higher risk of incident coronary heart disease (adjusted hazard ratio, 95% CIs: 1.65, 1.40 to 1.94), heart failure (1.75, 1.52 to 2.01), and cardiovascular mortality (1.65, 1.36 to 2.01). Associations were modestly attenuated but remained statistically significant after further adjustment for estimated glomerular filtration rate. In stratified analyses, similar results were observed in African Americans and among persons with normal kidney function. Conclusions: High levels of serum FGF-23 were associated with increased risk of coronary heart disease, heart failure, and cardiovascular mortality in this large, biracial, population-based cohort. This association was independent of traditional cardiovascular risk factors and kidney function.

BACKGROUND AND PURPOSE: Having a small social network and lack of social support have been associated with incident coronary heart disease; however, epidemiological evidence for incident stroke is limited. We assessed the longitudinal association of a small social network and lack of social support with risk of incident stroke and evaluated whether the association was partly mediated by vital exhaustion and inflammation. METHODS: The Atherosclerosis Risk in Communities study measured social network and social support in 13 686 men and women (mean, 57 years; 56% women; 24% black; 76% white) without a history of stroke. Social network was assessed by the 10-item Lubben Social Network Scale and social support by a 16-item Interpersonal Support Evaluation List-Short Form. RESULTS: During a median follow-up of 18.6 years, 905 incident strokes occurred. Relative to participants with a large social network, those with a small social network had a higher risk of stroke (hazard ratio [95% confidence interval], 1.44 [1.02-2.04]) after adjustment for demographics, socioeconomic variables, marital status, behavioral risk factors, and major stroke risk factors. Vital exhaustion, but not inflammation, partly mediated the association between a small social network and incident stroke. Social support was unrelated to incident stroke. CONCLUSIONS: In this sample of US community-dwelling men and women, having a small social network was associated with excess risk of incident stroke. As with other cardiovascular conditions, having a small social network may be associated with a modestly increased risk of incident stroke.