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1.  Fibroblast Growth Factor‐23 and Incident Coronary Heart Disease, Heart Failure, and Cardiovascular Mortality: The Atherosclerosis Risk In Communities Study 
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.
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.
PMCID: PMC4309096  PMID: 24922628
Atherosclerosis Risk In Communities; cardiovascular mortality; coronary heart disease; epidemiology; fibroblast growth factor 23; heart failure
2.  Relations of the Mediterranean dietary pattern with insulin resistance and diabetes incidence in the Multi-Ethnic Study of Atherosclerosis (MESA) 
The British journal of nutrition  2012;109(8):1490-1497.
Type 2 diabetes is a highly prevalent but preventable disorder. We assessed the association between an a priori Mediterranean diet score (MeDiet) and fasting glucose and insulin at baseline and incident type 2 diabetes after 6-year follow-up in MESA. Dietary intake was measured at baseline by a 127-item food frequency questionnaire in 5,390 men and women aged 45-84 years free of prevalent diabetes and clinical CVD. A MeDiet score was created based on intake of 10 food components: vegetables, whole grains, nuts, legumes, fruits, ratio of monounsaturated to saturated fat, red and processed meat, dairy, fish and alcohol. Multivariable linear and proportional hazard models were used to estimate the association of MeDiet, categorized in quintiles, with baseline insulin and glucose, and incident diabetes, respectively. Models adjusted for demographic, physiologic and behavioral characteristics. After multivariable adjustment, individuals with a higher MeDiet score had lower baseline mean (95% CI) insulin levels [mean Q1: = 5.8 (5.6-6.0) umol/l; mean Q5: = 4.8 (4.6-5.0) umol/l; p-trend= <0.0001]. A higher MeDiet score was also associated with significantly lower glucose levels after basic adjustment, but was attenuated after adjustment for waist circumference. During follow-up, 412 incident diabetes events accrued. MeDiet was not significantly related to risk of incident diabetes (p-trend=0.64). In summary, greater consistency with a Mediterranean-style diet, reflected by a higher a priori Mediterranean diet score, was cross-sectionally associated with lower insulin levels among non-diabetics, and lower blood glucose prior to adjustment for obesity, but not with lower incidence of diabetes.
PMCID: PMC4002212  PMID: 22932232
3.  Correlates and consequences of venous thromboembolism: The Iowa Women’s Health Study Authors 
American journal of public health  2009;100(8):1506-1513.
To document the incidence, case-fatality, and recurrence of venous thromboembolism (VTE) in women, and to explore the relation of demographic, lifestyle, and anthropometric factors to VTE incidence.
In 1986 Iowa women aged 55–69 completed a mailed survey. These data were linked to Medicare data for 1986–2004 (n=40,377) to identify hospitalized VTE cases. Cox regression adjusted for age, education, smoking status, physical activity, and BMI.
2,137 women developed VTE, yielding an incidence rate of 4.04/1,000 person-years. The 28-day case-fatality was 7.7% and the 1-year recurrence, 3.4%. Educational attainment and age-at-menopause were inversely associated with VTE, as was physical activity, prior to BMI adjustment. The risk of secondary (particularly cancer-related) VTE was increased in smokers compared with never smokers. BMI, waist circumference, waist-hip-ratio height, and diabetes were positively associated with VTE risk. Hormone replacement therapy use was associated with increased risk of idiopathic VTE, while parity was unrelated.
VTE is a significant source of morbidity and mortality in older women. Risk was elevated among women who were smokers, physically inactive, overweight, and diabetic, indicating that lifestyle contributes to VTE risk.
PMCID: PMC2901301  PMID: 19910349
5.  Serum and dietary magnesium and the incidence of atrial fibrillation in whites and African Americans: the Atherosclerosis Risk in Communities (ARIC) Study 
Low serum magnesium (Mg) has been associated with an increased risk of cardiovascular disease (CVD), including ventricular arrhythmias. However, the association between serum or dietary Mg and AF has not been investigated.
Methods and Results
We studied 14,290 men and women (75% white, 53% women, mean age 54) free of AF at baseline participating in the Atherosclerosis Risk in Communities study in the United States. Incident AF cases through 2009 were ascertained from electrocardiograms, hospital discharge codes, and death certificates. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for AF associated with serum and dietary Mg quintiles. Over a median follow-up time of 20.6 years, 1,755 incident AF cases were identified. In multivariable models, lower serum Mg was associated with higher AF risk: compared to individuals in the middle quintile (≥1.60–1.65 mEq/L), the HR (95% CI) of AF in quintiles 1, 2, 4, and 5 were 1.34 (1.16–1.54), 0.99 (0.85–1.16), 1.04 (0.90–1.22), and 1.06 (0.91–1.23), respectively. There was no evidence of significant interactions between serum Mg and sex or race. No association between dietary Mg and AF risk was observed.
Lower serum Mg was associated with a higher AF risk, and this association was not different between whites and African Americans. Dietary Mg was not associated with AF risk.
PMCID: PMC4228988  PMID: 23047297
atrial fibrillation; serum magnesium; dietary magnesium
6.  Relation of Lipid Gene Scores to Longitudinal Trends in Lipid Levels and Incidence of Abnormal Lipid Levels Among Individuals of European Ancestry: The Atherosclerosis Risk in Communities (ARIC) Study 
Multiple genetic loci have been associated with blood lipid levels. We tested the hypothesis that people with an unfavorable lipid gene profile would experience a greater increase in lipid levels and a higher incidence of abnormal lipid levels, relative to those with more favorable lipid gene profiles.
Methods and Results
9,328 European-descent individuals in ARIC (ages 45–64 y) were followed for 9 years. Separate gene scores were created for each lipid phenotype based on 95 loci identified in a published GWAS of >100,000 European-descent individuals. Adjusted linear and survival models were used to estimate associations with lipid levels and incidence of lipid-lowering medication or abnormal lipid levels. Age and sex interactions were also explored. The cross-sectional difference (mg/dL) per one standard deviation (SD) was −1.89 for HDL-C, 9.5 for LDL-C, and 22.8 for triglycerides (p<5 × 10−34 for all). Longitudinally, overall triglyceride levels rose over time, and each SD greater triglyceride gene score was associated with an average increase in triglyceride levels of 0.3 mg/dL (p=0.003) over 3-years. The HDL-C, LDL-C and total cholesterol gene scores were not related to change. All lipid gene scores were positively related to incidence of abnormal lipid levels over follow-up (HRs per SD ranged from 1.15–1.36).
Associations of genetic variants with lipid levels over time are complex, with the triglyceride gene score positively related to change in triglycerides levels. Similar longitudinal results were not observed for LDL-C or HDL-C levels. Unfavorable gene scores were nevertheless related to higher incidence of abnormal levels.
PMCID: PMC3288431  PMID: 22057756
lipids; longitudinal trends; gene score; Atherosclerosis Risk in Communities (ARIC)
7.  Invited Commentary: Diet and Risk of Venous Thromboembolism—A Hard Nut to Crack 
American Journal of Epidemiology  2011;175(2):127-130.
Recently, there has been interest in determining whether diet is associated with the risk of venous thromboembolism. The article by Varraso et al. (Am J Epidemiol. 2012;175(2):114–126) published in this issue of the Journal is an important contribution to this literature. In this commentary, the author discusses the findings of Varraso et al. within the context of the existing literature and posits epidemiologic explanations for why investigators might have failed to identify strong associations between diet and venous thromboembolism.
PMCID: PMC4047293  PMID: 22180876
diet; food; pulmonary embolism; venous thrombosis
8.  Vitamin D and Subclinical Cerebrovascular Disease 
JAMA neurology  2014;71(7):863-871.
Vitamin D deficiency has been associated with hypertension, diabetes mellitus, and incident stroke. Little is known about the association between vitamin D and subclinical cerebrovascular disease.
To examine the relationship of 25-hydroxyvitamin D (25[OH]D) levels with cerebrovascular abnormalities as assessed on brain magnetic resonance imaging (MRI) among participants of the Atherosclerosis Risk in Communities (ARIC) Brain MRI study.
Participants were white and black adults aged 55 to 72 years with no history of clinical stroke who underwent a cerebral MRI at ARIC visit 3 (n = 1622) and a second cerebral MRI approximately 10 years later (n = 888).
The 25(OH)D level was measured by mass spectrometry at visit 3, with levels adjusted for calendar month and categorized using race-specific quartiles.
The cross-sectional and prospective associations of 25(OH)D levels with white matter hyperintensities (WMHs) and MRI-defined infarcts were investigated using multivariable regression models.
The mean age of the participants was 62 years, 59.6% were women, and 48.6% were black. Lower 25(OH)D levels were not significantly associated with WMH score of severity, prevalent high-grade WMH score (≥3), or prevalent infarcts in cross-sectional, multivariable-adjusted models (all P > .05). Similarly, no significant prospective associations were found for lower 25(OH)D levels with change in WMH volume, incident high WMH score (≥3), or incident infarcts on the follow-up MRI, which occurred approximately 10 years later.
A single measure of 25(OH)D was not cross-sectionally associated with WMH grade or prevalent subclinical infarcts and was not prospectively associated with WMH progression or subclinical brain infarcts seen on serial cerebral MRIs obtained approximately 10 years apart. These findings do not support optimizing vitamin D levels for brain health.
PMCID: PMC4218739  PMID: 24861877
9.  Longer legs are associated with greater risk of incident venous thromboembolism independent of total body height: The Longitudinal Study of Thromboembolism Etiology (LITE) 
Thrombosis and haemostasis  2011;106(1):113-120.
Several studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesized that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus sitting height. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height we standardized leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 yrs. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modeled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs.
PMCID: PMC3180885  PMID: 21655679
height; leg length; venous thromboembolism; Atherosclerosis Risk in Communities Study (ARIC); Cardiovascular Health Study (CHS)
10.  Interactions Between Race/Ethnicity and Anthropometry in Risk of Incident Diabetes 
American Journal of Epidemiology  2010;172(2):197-204.
This study examined how adiposity influences racial/ethnic differences in diabetes incidence by exploring whether relations between anthropometric measures and incident diabetes vary by race/ethnicity. Data from the Multi-Ethnic Study of Atherosclerosis initiated in 2000 (n = 5,446 US men and women aged 45–84 years) were analyzed by using proportional hazards and Poisson regression. The diabetes incidence rate was 2/100 person-years (n = 479 cases). Interactions were present between race and anthropometry (P-interaction(race × body mass index) = 0.002). The slope of incident diabetes per anthropometric unit was greatest for Chinese, less for whites and Hispanics, and still less for blacks. For small waist, risk of incident diabetes was <1/100 person-years for all racial/ethnic groups. At intermediate waist levels, Chinese had the highest and whites the lowest rates of incident diabetes. At the respective 95th percentiles of waist circumference, risk of incident diabetes per 100 person-years was 3.9 for Chinese (104 cm), 3.5 for whites (121 cm), 5.0 for blacks (125 cm), and 5.3 for Hispanics (121 cm). Adiposity influenced relative diabetes occurrence across racial/ethnic groups, in that Chinese had a steeper diabetes risk per unit of adiposity. However, the generally low level of adiposity in Chinese led to a relatively low diabetes occurrence.
PMCID: PMC2915488  PMID: 20570825
Asian continental ancestry group; body mass index; diabetes mellitus; waist circumference
11.  Racial and Regional Differences in Venous Thromboembolism in the United States in Three Cohorts 
Circulation  2014;129(14):1502-1509.
Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites however prior studies are limited to administrative databases that lack specific information on VTE risk factors or have limited geographic scope.
Methods and Results
We ascertained VTE from three prospective studies; the Atherosclerosis Risk in Communities study (ARIC), the Cardiovascular Health Study (CHS), and the REasons for Geographic and Racial Differences in Stroke study (REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk factors. Over 438,090 person-years, 916 incident VTE events (302 in blacks) occurred in 51,149 individuals (17,318 blacks) followed. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in CHS (HR 1.81; 95% CI 1.20, 2.73) but not ARIC (HR 1.21; 95% CI 0.96, 1.54). In REGARDS, there was a significant region by race interaction (p = 0.01); blacks in the southeast had a significantly higher rate of VTE than blacks in the rest of the US (HR 1.63; 95% CI 1.08, 2.48) which was not seen in whites (HR 0.83; 95% CI 0.61, 1.14).
The association of race with VTE differed in each cohort, which may reflect the different time periods of the studies and/or different regional rates of VTE. Further study of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.
PMCID: PMC4098668  PMID: 24508826
Venous Thrombosis; Epidemiology; Race
12.  Lipoprotein-associated phospholipase A2 and venous thromboembolism: a prospective study 
Thrombosis research  2013;132(1):44-46.
Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp-PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied.
We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3 years (from 1996–98 through 2005) for VTE occurrence (n = 226).
There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol ≥ 130 mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14).
Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk.
PMCID: PMC3742644  PMID: 23746626
lipoprotein-associated phospholipase A2; prospective study; pulmonary embolism; venous thromboembolism
13.  Peak Thrombin Generation and Subsequent Venous Thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE) 
Thrombin is an enzyme essential to the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin.
We evaluated the relation of basal peak thrombin generation to risk of future VTE, and determined whether associations were independent of other coagulation markers.
LITE ascertained VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case-control sample (434 cases, 1,004 controls). Logistic regression was used to estimate the relation of peak thrombin generation to VTE, adjusted for age, sex, race, center and BMI. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer.
Relative to the first quartile of peak thrombin generation, the odds ratio (95% CI) of VTE for those above the median was 1.74 (1.28–2.37). The association was modestly attenuated by adjustment for factor VIII and D-dimer 1.47 (1.05–2.05). Associations appeared stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with Factor V Leiden or low aPTT.
In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independent of established VTE risk factors.
PMCID: PMC2763356  PMID: 19656279
Longitudinal Investigation of Thromboembolism Etiology (LITE); thrombin generation; venous thromboembolism
14.  Diet and Incident Venous Thromboembolism: The Iowa Women’s Health Study 
American heart journal  2009;157(6):1081-1087.
Little is known about the role of diet in the development of venous thromboembolism (VTE). We explored the prospective relation of dietary patterns, food groups, and nutrients to incident VTE in older women.
In 1986, Iowa women aged 55–69 completed a mailed survey, including a 127-item food frequency questionnaire. These data were linked to Medicare data from 1986–2004, and International Classification of Disease discharge codes were used to identify hospitalized VTE cases. Cox regression analyses evaluated relations of 2 principal components-derived dietary patterns, 11 food groups, and 6 nutrients to VTE, adjusted for age, education, smoking status, physical activity, and energy intake.
Over 19 years of follow-up 1,950 of the 37,393 women developed VTE. Women consuming alcohol daily were at 26% (95% CI: 11%–38%) lower risk of VTE, as compared to nonconsumers. All alcoholic beverages types were in the direction of lower risk, however only beer and liquor were statistically significant. After basic adjustments coffee was inversely related to VTE, and diet soda and fish positively related. However, these associations were confounded, and became nonsignificant after adjustment for body mass index and diabetes. No associations were observed with consumption of ‘Western’ or ‘Prudent’ dietary patterns, fruit, vegetables, dairy, meat, refined grains, whole grains, regular soda, vitamins E, B6, B12, folate, omega-3 fatty acids, or saturated fat.
In this cohort of older women, greater intake of alcohol was associated with a lower risk of incident VTE. No other independent associations were seen between diet and VTE.
PMCID: PMC2689927  PMID: 19464420
Venous thromboembolism; Diet; Alcohol; Iowa Women’s Health Study; Medicare
15.  Statin Therapy and Levels of Hemostatic Factors in a Healthy Population: the Multi-Ethnic Study of Atherosclerosis 
HMG CoA reductase inhibitors (statins) reduce risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for reduction in VTE risk is unknown. In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk.
Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women), and major cardiovascular risk factors.
Participants using statins had lower adjusted levels of D-dimer (−9%), C-reactive protein (−21%) and factor VIII (−3%) than non-users (p<0.05). Homocysteine and von Willebrand factor were non-significantly lower with statin use. Higher fibrinogen (2%) and PAI-1 (22%) levels were observed among statin users than nonusers (p<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors by statin use.
Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and nonusers is warranted.
PMCID: PMC3702638  PMID: 23565981
statins; thrombosis; risk factor; blood coagulation; inflammation; fibrinolysis
16.  Associations of Acculturation and Socioeconomic Status with Subclinical CVD in the MultiEthnic Study of Atherosclerosis 
American journal of public health  2008;98(11):1963-1970.
To assess whether markers of acculturation (birthplace, number of U.S. generations) and socioeconomic status (SES) are associated with carotid artery plaque, internal carotid intima-media thickness (IMT), and albuminuria, in four racial/ethnic groups.
Using Multi-Ethnic Study of Atherosclerosis data (n = 6,716; age: 45-84) and race-specific binomial regression models, we computed prevalence ratios, adjusted for demographics and traditional cardiovascular risk factors.
The adjusted U.S. to foreign-born prevalence ratio (99% CI) for carotid plaque was 1.20 (0.97, 1.39) in Whites, 1.91 (0.94, 2.94) in Chinese, 1.62 (1.28, 2.06) in Blacks, and 1.23 (1.15, 1.31) in Hispanics. Greater carotid plaque prevalence was also found among Whites, Blacks, and Hispanics with more generations of US residence (p<0.001). Lower educational attainment and/or income were associated with greater carotid plaque prevalence in Whites and Blacks. Similar associations were observed with IMT. There was also some evidence of an inverse association between albuminuria and SES, in Whites and Hispanics.
Greater U.S. acculturation and lower SES were associated with a higher prevalence of carotid plaque and IMT, while little association was found with albuminuria.
PMCID: PMC2575668  PMID: 18511718
17.  Physical Activity and Cardiovascular Disease in African Americans in ARIC 
Although there is substantial evidence that physical activity reduces a person's risk of cardiovascular disease (CVD), few of these studies have included African Americans. The studies that have included African Americans offer inconclusive evidence on the association and none studied heart failure separately. We used data from the Atherosclerosis Risk in Communities study cohort to examine, in African Americans, the association of physical activity with the incidence of CVD and its major components – stroke, heart failure, and coronary heart disease.
Participants aged 45 to 64 years (3,707 African Americans and, for comparison, 10,018 Caucasians) had physical activity assessed via questionnaire in 1987 and were followed for incident CVD (n=1,039) through 2008.
After adjustment for potential confounders, physical activity was inversely related to CVD, heart failure, and coronary heart disease incidence in both races (p-values for trend <.0001), and with stroke in African Americans. Hazard ratios (95% confidence intervals) for CVD for each higher physical activity category were similar by race: 1.0, 0.65 (0.56, 0.75), and 0.59 (0.49, 0.71) for African Americans and 1.0, 0.74 (0.66, 0.83), and 0.67 (0.59, 0.75) for Caucasians (p-value for interaction = 0.38).
Our findings reinforce recommendations that regular physical activity is important for CVD risk reduction in African Americans as well as Caucasians and support the idea that some physical activity is better than none.
PMCID: PMC3622814  PMID: 23247714
exercise; stroke; coronary heart disease; heart failure; race
18.  Comparable Ascertainment of Newly-Diagnosed Atrial Fibrillation Using Active Cohort Follow-Up versus Surveillance of Centers for Medicare and Medicaid Services in the Atherosclerosis Risk in Communities Study 
PLoS ONE  2014;9(4):e94321.
Increasingly, epidemiologic studies use administrative data to identify atrial fibrillation (AF). Capture of incident AF is not well documented. We examined incidence rates and concordance of AF diagnosis based on active cohort follow-up versus surveillance of Centers for Medicare and Medicaid Services data in the Atherosclerosis Risk in Communities study.
Atherosclerosis Risk in Communities cohort participants without prevalent AF enrolled in fee-for-service Medicare, with inpatient and outpatient coverage, for at least 12 continuous months between 1991 and 2009 were included. In active Atherosclerosis Risk in Communities study follow-up, annual telephone calls captured hospitalizations and deaths with incident AF diagnosis codes. For Centers for Medicare and Medicaid Services data, incident AF was defined by billed inpatient and outpatient diagnoses.
Of 10,134 eligible cohort participants, 738 developed AF according to both Atherosclerosis Risk in Communities and Centers for Medicare and Medicaid Services data; an additional 93 and 288 incident cases were identified using only Atherosclerosis Risk in Communities and Centers for Medicare and Medicaid Services data, respectively. Incidence rates per 1,000 person-years were 10.8 (95% confidence interval: 10.1–11.6) and 13.6 (95% confidence interval: 12.8–14.4) in Atherosclerosis Risk in Communities and Centers for Medicare and Medicaid Services, respectively; agreement was 96%; kappa was 0.77 (95% confidence interval: 0.75–0.80). Earlier AF ascertainment by one system versus the other was not associated with any cardiovascular disease risk factors, after accounting for sociodemographic factors. Additional Centers for Medicare and Medicaid Services events did not alter observed associations between risk factors and AF.
Among fee-for-service enrollees, AF incidence rates were slightly lower for active cohort follow-up than for Centers for Medicare and Medicaid Services surveillance, because the latter included outpatient atrial fibrillation. Concordance was high and combining the two approaches could provide a more complete picture of newly-diagnosed AF.
PMCID: PMC3984174  PMID: 24727837
19.  Troponin T, NT-pro BNP, and Incidence of Stroke: The Atherosclerosis Risk in Communities (ARIC) Study 
Background and Purpose
Increased levels of plasma troponins and natriuretic peptides are associated with increased risk of cardiovascular disease, but only limited information exists on these biomarkers and stroke occurrence. In a prospective epidemiological study, we tested the hypothesis that high-sensitivity troponin T (TnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) are associated positively with incidence of stroke.
The Atherosclerosis Risk in Communities (ARIC) Study measured plasma TnT and NT-proBNP in 10,902 men or women initially free of stroke and followed them for a mean of 11.3 years for stroke occurrence (n=507).
Both biomarkers were associated positively with total stroke, nonlacunar ischemic, and especially, cardioembolic stroke, but not with lacunar or hemorrhagic stroke. For example, after adjustment for prevalent risk factors and cardiac diseases, the hazard ratios (95% confidence intervals) for jointly high values of TnT and NT-proBNP (versus neither biomarker high) were 2.70 (1.92, 3.79) for total stroke and 6.26 (3.40, 11.5) for cardioembolic stroke. Associations with stroke appeared somewhat stronger for NT-proBNP than TnT. Strikingly, approximately 58% of cardioembolic strokes occurred in the highest quintile of pre-stroke NT-proBNP, and 32% of cardioembolic strokes occurred in participants who had both NT-proBNP in the highest quintile and were known by ARIC to have atrial fibrillation sometime before their cardioembolic stroke occurrence.
In the general population, elevated plasma TnT and NT-proBNP concentrations are associated with increased risk of cardioembolic and other nonlacunar ischemic strokes.
PMCID: PMC3614093  PMID: 23471272
epidemiology; natriuretic peptides; risk factors; stroke; troponins
20.  Relation of Serum Phosphorus Levels to the Incidence of Atrial Fibrillation (from the Atherosclerosis Risk In Communities [ARIC] Study) 
The American journal of cardiology  2012;111(6):857-862.
High serum phosphorus levels have been linked with vascular calcification and greater cardiovascular morbidity and mortality. We assessed whether serum phosphorus was associated with the atrial fibrillation (AF) incidence in a large community-based cohort in the United States. Our analysis included 14,675 participants (25% black, 45% men) free of AF at baseline (1987 to 1989) and with measurements of fasting serum phosphorus from the Atherosclerosis Risk In Communities (ARIC) study. The incidence of AF was ascertained through the end of 2008 from study visit electrocardiograms, hospitalizations, and death certificates. Cox proportional hazard models were used to estimate the hazard ratios of AF by the serum phosphorus levels, adjusting for potential confounders. During a median follow-up of 19.7 years, we identified 1,656 incident AF cases. Greater serum phosphorus was associated with a greater AF risk: the hazard ratio of AF with a 1-mg/dl increase in serum phosphorus was 1.13 (95% confidence interval 1.02 to 1.26). No significant interaction was seen by race (p = 0.88) or gender (p = 0.51). The risk of AF was increased in association with greater serum phosphorus in those with an estimated glomerular filtration rate of ≥90 ml/min/1.72 m2 but not among those with an estimated glomerular filtration rate of <90 ml/min/1.72 m2. The total corrected calcium levels were not related to AF risk; however, greater levels of the calcium-phosphorus product were associated with greater AF risk. In conclusion, in the present large population-based study, greater levels of serum phosphorus and the related calcium-phosphorus product were associated with a greater incidence of AF.
PMCID: PMC3632319  PMID: 23273530
21.  Troponin T, B type natriuretic peptide, C-reactive protein and cause-specific mortality 
Annals of epidemiology  2012;23(2):66-73.
To evaluate the associations of high sensitivity Troponin T (Hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high sensitivity C-reactive protein (Hs-CRP) with mortality from any cause, cardiovascular disease (CVD), coronary heart disease (CHD), stroke, cancer, and respiratory disease in the Atherosclerosis Risk in Communities (ARIC) cohort.
11193 participants aged 54-74 years, initially free of the conditions being studied, had biomarkers measured and were followed for a mean of 9.9 years.
Hazard ratios (HR), adjusted for multiple risk factors, for mortality in participants in the highest Hs-TnT category compared to those with undetectable levels were: total 3.42 (95% Confidence Interval: 2.75-4.26), CVD 7.34 (4.64-11.6), CHD 6.06 (2.91-12.6), stroke 3.31 (1.26-8.66), cancer 1.60 (1.08-2.38) and respiratory 3.85 (1.39-10.7). Comparing the highest NT-proBNP quintile to those in the lowest quintile, the adjusted HRs for mortality were: total 3.05 (2.46-3.77), CVD 7.48 (4.67-12.0), CHD 4.07 (2.07-7.98) and stroke 10.4 (2.26-47.7). Comparing extreme Hs-CRP quintiles, the adjusted HRs for mortality were: total 1.61 (1.32-1.97), CVD 1.76 (1.19-2.62) and respiratory 3.36 (1.34-8.45). Having multiple markers elevated simultaneously greatly increased cause-specific mortality risks.
Greater levels of Hs-TnT, NT-proBNP and Hs-CRP are associated with increased risk of death, not just from cardiovascular disease but also from some non-cardiovascular causes.
PMCID: PMC3543509  PMID: 23228375
biomarkers; troponin T; B natriuretic peptide; C- reactive protein; mortality
22.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
23.  Vitamin D, Calcium, and Atherosclerotic Risk: Evidence from serum levels and supplementation studies 
Vitamin D and calcium have been traditionally been viewed in relation to bone health. However, recent research has suggested relations between these nutrients and cardiovascular disease (CVD). Specifically, evidence from both observational studies and clinical trials suggests that vitamin D may be related to lower risk of CVD. The picture for calcium is more complex. Dietary intake of calcium may be associated with lower CVD risk, while calcium supplementation may elevate CVD risk. In this review we summarize evidence of these relations, and comment on the recent Institute of Medicine (IOM) recommendations regarding use of vitamin D and calcium supplements.
PMCID: PMC3531793  PMID: 23232985
calcium; vitamin D; supplements; cardiovascular disease; review
24.  Association of Ideal Cardiovascular Health Metrics and Retinal Microvascular Findings: The Atherosclerosis Risk in Communities Study 
This study evaluated the prevalence of ideal cardiovascular (CV) health in the Atherosclerosis Risk in Communities Study and determined its relationship with prevalent retinopathy, wider retinal venular diameters, and narrower arteriolar diameters, which are risk markers for subclinical cerebrovascular disease and are associated with increased stroke and coronary heart disease (CHD) morbidity and mortality.
Methods and Results
We used gradings of fundus photography measurements from the Atherosclerosis Risk in Communities Study to examine the association of retinopathy and retinal arteriolar and venular calibers to the number of ideal CV health metrics. Prevalent retinopathy showed a graded relationship with the CV health categories and number of ideal CV health metrics present: retinopathy prevalence was 2.1% among those with ≥5 ideal CV health metrics compared with 13.1% among those with zero ideal CV health metrics (odds ratio [CI]), 4.8 [2.5 to 8.9]). Central retinal venule equivalent and central retinal arteriolar equivalent diameters also showed graded relationships with CV health categories and number of ideal CV health metrics: after adjustment for age, race, sex, and education, mean central retinal venular equivalent was 187.8 μm (95% CI, 186.9 to 188.6 μm) among those with ≥5 ideal CV health metrics compared with 201.1 μm (95% CI, 199.1 to 203.1 μm) among those with zero ideal CV health metrics. Mean central retinal arteriolar equivalent was 163.8 μm (95% CI, 163.0 to 164.5 μm) among those with ≥5 ideal CV health metrics compared with 157.9 μm (95% CI, 156.1 to 159.7 μm) among those with zero ideal CV health metrics.
Few adults had ideal cardiovascular health. Those with the best level of health were less likely to have retinopathy signs, wide retinal venules, and narrow retinal arterioles, which are associated with increased stroke and coronary heart disease risk.
PMCID: PMC3886782  PMID: 24252843
cardiovascular diseases; cardiovascular health metrics; cerebrovascular circulation; epidemiology; risk factors
25.  Association of Mild to Moderate Chronic Kidney Disease with Venous Thromboembolism: Pooled Analysis of Five Prospective General Population Cohorts 
Circulation  2012;126(16):1964-1971.
Recent findings suggest that chronic kidney disease (CKD) may be associated with increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.
Methods and Results
We pooled individual participant data from five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m2, HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m2. Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m2 or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE.
Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.
PMCID: PMC3520022  PMID: 22977129
chronic kidney disease; deep vein thrombosis; epidemiology; pulmonary embolism; thromboembolism

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