Population Attributable Fraction of Total Stroke Associated with Modifiable Risk Factors in the United States.

Stroke is a leading cause of death in the United States across all race/ethnicity and sex groups, though disparities exist. We investigated the potential for primary prevention of total first stroke for Americans aged 20 and older, stratified by sex and race/ethnicity. Specifically, we calculated population attributable fractions (PAF) of first stroke for 7 potentially modifiable risk factors: smoking, physical inactivity, poor diet, obesity, hypertension, diabetes, and atrial fibrillation. PAFs are a function of (1) the relative risk of first stroke for people with the exposure and (2) the prevalence of the risk factor in the population. Relative risks came from recent meta-analyses and sex-race/ethnicity-specific prevalence estimates came from the 2015-2018 NHANES or Multi-Ethnic Study of Atherosclerosis (for atrial fibrillation only). Approximately 1/3 (35.7% [CI: 21.6%-49.0%]) for women, 32.7% [CI: 19.2%-45.1%] for men) of strokes were attributable to the 7 risk factors we considered. A 20% proportional reduction in stroke risk factors would result in approximately 37,000 fewer strokes annually in the United States. The estimated PAF was highest for non-Hispanic Black women (39.3% [CI: 24.8%-52.3%]) and lowest for non-Hispanic Asian men (25.5% [CI: 14.6%-36.2%]). For most groups, obesity and hypertension were the largest contributors to stroke rates.

Proteomic profiling identifies novel proteins for genetic risk of severe COVID-19: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Genome-wide association studies have identified six genetic variants associated with severe COVID-19, yet the mechanisms through which they may affect disease remains unclear. We investigated proteomic signatures related to COVID-19 risk variants rs657152 (ABO), rs10735079 (OAS1/OAS2/OAS3), rs2109069 (DPP9), rs74956615 (TYK2), rs2236757 (IFNAR2) and rs11385942 (SLC6A20/LZTFL1/CCR9/FYCO1/CXCR6/XCR1) as well as their corresponding downstream pathways that may promote severe COVID-19 in risk allele carriers and their potential relevancies to other infection outcomes. METHODS: A DNA aptamer-based array measured 4870 plasma proteins among 11 471 participants. Linear regression estimated associations between the COVID-19 risk variants and proteins with correction for multiple comparisons, and canonical pathway analysis was conducted. Cox regression assessed associations between proteins identified in the main analysis and risk of incident hospitalized respiratory infections (2570 events) over a 20.7-year follow-up. RESULTS: The ABO variant rs657152 was associated with 84 proteins in 7241 white participants with 24 replicated in 1671 Black participants. The TYK2 variant rs74956615 was associated with ICAM-1 and -5 in white participants with ICAM-5 replicated in Black participants. Of the 84 proteins identified in the main analysis, seven were significantly associated with incident hospitalized respiratory infections including Ephrin type-A receptor 4 (hazard ratio (HR): 0.87; P = 2.3 × 10-11) and von Willebrand factor type A (HR: 1.17; P = 1.6x10-13). CONCLUSIONS: Novel proteomics signatures and pathways for COVID-19-related risk variants TYK2 and ABO were identified. A subset of these proteins predicted greater risk of incident hospitalized pneumonia and respiratory infections. Further studies to examine these proteins in COVID-19 patients are warranted.

Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts.

BACKGROUND: Research suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. OBJECTIVES: We evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. METHODS: Omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. RESULTS: In the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. CONCLUSION: This study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

Anemia, Iron Deficiency, and Cause-Specific Mortality: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults. METHODS: Fasting blood was obtained from 5,070 ARIC participants (median age: 75 years) in 2011-2013. Anemia was defined by hemoglobin concentrations <12 g/dL in women and <13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. Mortality was ascertained via phone calls with proxies as part of twice-yearly cohort follow-up, surveillance of local hospital discharge indexes, state death records, and linkage to the National Death Index. RESULTS: Of the total participants, 21% had anemia at baseline. Over a median of 7.5 years, there were 1,147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer, and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality (hazard ratio 1.81 [95% CI: 1.60-2.06]), and mortality due to CVD (1.77 [1.41-2.22]), cancer (1.81 [1.41-2.33]), and respiratory disease (1.72 [1.18-2.52]) in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality (1.37 [1.19-1.58]) and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation (CRP below the median level of 1.9 mg/L) and for cancer mortality in men only. CONCLUSION: Anemia is common among older adults and is associated with all-cause mortality, as well as mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is associated with mortality in this population.

Low-dose aspirin for primary prevention of cardiovascular disease: Trends in use patterns among African American adults in Minnesota, 2015-2019.

Cardiovascular disease (CVD) disproportionately affects African Americans. Aspirin has long been recommended to reduce cardiovascular events. However, national guideline changes in 2016 limited the aspirin recommended population and several clinical trials questioning the utility of primary prevention aspirin were published in 2018. In light of the recent guidelines and study findings, we investigated primary prevention aspirin use among urban African American adults. Using three cross-sectional surveys, we collected data from self-identified African Americans with no CVD in 2015, 2017 and 2019, querying information on CVD risk factors, health behaviors and beliefs, and aspirin use. Poisson regression modeling was used to estimate age- and risk-factor adjusted aspirin prevalence, trends and associations. A total of 1491 African Americans adults, ages 45-79, were included in this analysis; 61% were women. There was no change in age- and risk factor-adjusted aspirin use over the 3 surveys for women (37%, 34% and 35% respectively) or men (27%, 25%, 30% respectively). However, fewer participants believed aspirin was helpful in 2019 compared to 2015-75% versus 84% (p < 0.001). Aspirin discussions with a health care practitioner were highly associated with aspirin use (adjusted RR 2.97, 95% CI 2.49-3.54) and aspirin use was 2.56 times higher (adjusted RR 95% CI 2.17-3.03) in respondents who agreed that people close to them thought they should take aspirin compared with those who disagreed or did not know. Despite major changes in national guidelines, overall primary prevention aspirin use did not significantly change in these African American samples from 2015 to 2019.

Aspirin Use and Awareness for Cardiovascular Disease Prevention Among Hispanics: Prevalence and Associations with Health Behavior Beliefs.

Cardiovascular disease (CVD) persists as the leading cause of death and disability in many Americans including Hispanics. Primary prevention for CVD may be achieved through regular aspirin use in high risk individuals. This study examined regular aspirin use and specific attitudes and social norms toward CVD and aspirin use within an urban Hispanic population in Minnesota. A sample of primary prevention Hispanics aged 45-79 years were surveyed about CVD history and risk factors, aspirin use, demographic characteristics, and health beliefs and social norms in relation to CVD and aspirin. Relative risk estimation using Poisson regression with robust error variance was used to examine associations with aspirin use. In this sample of 152 Hispanics (55% women), the mean age was 53 years, 70% had a regular healthcare provider, and 22% used aspirin. Aspirin discussions with a regular healthcare provider were strongly associated with aspirin use (adjusted risk ratio 3.02, 95% CI 1.20-7.60). There was a positive association between health beliefs and social norms that affirm preventive behaviors and aspirin use (adjusted linear risk ratio 1.23, 95% CI 1.04-1.45) while uncertainty about the role of aspirin for individual use and in the community was negatively associated with aspirin use (adjusted linear risk ratio 0.85, 95% CI 0.70-1.03). This growing population may benefit from health education about CVD risk and the role of aspirin in prevention.

Aspirin Use for Cardiovascular Disease Prevention in an African American Population: Prevalence and Associations with Health Behavior Beliefs.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States, disproportionately affecting African Americans. Aspirin is an effective, low cost option to reduce cardiovascular events. This study sought to describe the use of aspirin for CVD prevention in African Americans and evaluate associations with demographics, cardiovascular risk factors and health behaviors and beliefs. A total of 684 African Americans adults ages 45-79 years completed surveys and were included in this analysis. Proportions of aspirin use were stratified by primary and secondary prevention and by number of CVD risk factors in the primary prevention population. Logistic regression was used to evaluate associations with aspirin use. Secondary prevention aspirin use was 62%. Primary prevention aspirin use was 32% overall and increased to 54% in those with > 2 CVD risk factors. A history of diabetes [adjusted odds ratio (aOR) 3.42, 95% CI 2.18-5.35] and hypertension (aOR 2.25, 95% CI 1.39-3.65) were strongly associated with primary prevention aspirin use, but a conversation with a health care provider was even stronger (aOR 6.41, 95% CI 4.07-10.08). Participants who answered positively to statements about people similar to them taking aspirin or that close contacts think they should take aspirin, were much more likely to take aspirin (aOR 4.80; 95% CI 2.58-8.93 and aOR 7.45; 95% CI 4.70-11.79 respectively). These findings support a hypothesis that aspirin use may increase by encouraging conversations with health care providers and creating a supportive social environment for aspirin use. Further studies need to be done to test this hypothesis.

Plasma Metabolites Associated with Brain MRI Measures of Neurodegeneration in Older Adults in the Atherosclerosis Risk in Communities⁻Neurocognitive Study (ARIC-NCS).

BACKGROUND: Plasma metabolites are associated with cognitive and physical function in the elderly. Because cerebral small vessel disease (SVD) and neurodegeneration are common causes of cognitive and physical function decline, the primary objective of this study was to investigate the associations of six plasma metabolites (two plasma phosphatidylcholines [PCs]: PC aa C36:5 and PC aa 36:6 and four sphingomyelins [SMs]: SM C26:0, SM [OH] C22:1, SM [OH] C22:2, SM [OH] C24:1) with magnetic resonance imaging (MRI) features of cerebral SVD and neurodegeneration in older adults. METHODS: This study included 238 older adults in the Atherosclerosis Risk in Communities study at the fifth exam. Multiple linear regression was used to assess the association of each metabolite (log-transformed) in separate models with MRI measures except lacunar infarcts, for which binary logistic regression was used. RESULTS: Higher concentrations of plasma PC aa C36:5 had adverse associations with MRI features of cerebral SVD (odds ratio of 1.69 [95% confidence interval: 1.01, 2.83] with lacunar infarct, and beta of 0.16 log [cm3] [0.02, 0.30] with log [White Matter Hyperintensities (WMH) volume]) while higher concentrations of 3 plasma SM (OH)s were associated with higher total brain volume (beta of 12.0 cm3 [5.5, 18.6], 11.8 cm3 [5.0, 18.6], and 7.3 cm3 [1.2, 13.5] for SM [OH] C22:1, SM [OH] C22:2, and SM [OH] C24:1, respectively). CONCLUSIONS: This study identified associations between certain plasma metabolites and brain MRI measures of SVD and neurodegeneration in older adults, particularly higher SM (OH) concentrations with higher total brain volume.

Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization.

BACKGROUND: Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. METHODS: We identified 51 646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. RESULTS: In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. CONCLUSIONS: Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.

Sleep-disordered breathing and electrocardiographic QRS-T angle: The MESA study.

INTRODUCTION: Sleep-disordered breathing (SDB) has been linked to sudden cardiac death (SCD) but the mechanism is unclear. Abnormal QRS-T angle, a novel electrocardiographic (ECG) marker of ventricular repolarization, has been linked to adverse cardiovascular outcomes including SCD. We hypothesized that individuals with SDB have more pronounced abnormality in QRS-T angle. METHODS: We performed a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) Exam Sleep ancillary study. We calculated the odds ratio (OR) of abnormal frontal and spatial QRS-T angle (defined as >sex-specific 95th percentile thresholds) related to the apnea-hypopnea index (AHI) using logistic regression, adjusting for demographics, body habitus, cardiovascular risks, and prevalent cardiovascular disease. Linear associations between AHI and frontal and spatial QRS-T angle, separately, were also examined using multiple regression models. RESULTS: A total of 1,804 participants (mean age 67.9 (±9.0) years, 55.3% women and 64.1% non-whites) were included in the study. Sleep-disordered breathing was common among participants (median AHI 8.6 events/hr IQR [3.2-19.5/hr]). Higher AHI was associated with the odds of abnormal frontal (≥81° in men and ≥79° in women) and spatial QRS-T angle (≥129.7° in men and ≥115.9° in women; OR [95%CI]: 1.25 [1.02-1.51], p = 0.03; 1.23 [1.01-1.50], p = 0.04 respectively per 1 SD [16.8 events/hr] increase in AHI). Similarly, linear associations were observed (frontal QRS-T angle: beta coefficient: 2.30° [0.92, 3.66], p = 0.001; spatial QRS-T angle: beta coefficient: 2.16° [0.67, 3.64], p = 0.005). CONCLUSION: In a racially/ethnically diverse community cohort, severity of SDB is associated with abnormal ventricular repolarization as measured by QRS-T angle.

Sleep characteristics and risk of dementia and Alzheimer's disease: The Atherosclerosis Risk in Communities Study.

INTRODUCTION: This study tested the hypotheses that late-midlife obstructive sleep apnea (OSA) and short and long sleep duration are associated with dementia over 15 years of follow-up. METHODS: A total of 1667 Atherosclerosis Risk in Communities Study participants underwent in-home polysomnography (1996-1998) and were followed for dementia. Dementia was defined by (1) hospitalization diagnosis codes (1996-2012) and (2) a comprehensive neurocognitive examination (2011-2013) with adjudication. RESULTS: OSA and sleep duration were not associated with risk of incident dementia. When using adjudicated outcomes, severe OSA (≥30 vs. <5 apnea-hypopnea events/hour) was associated with higher risk of all-cause dementia (risk ratio [95% confidence interval], 2.35 [1.06-5.18]) and Alzheimer's disease dementia (1.66 [1.03-2.68]); associations were attenuated with cardiovascular risk factor adjustment. Sleeping <7 versus 8 to ≤9 hours was associated with higher risk of all-cause dementia (2.00 [1.03-3.86]). DISCUSSION: When adjudicated outcome definitions were used, late-midlife OSA and short sleep duration were associated with all-cause and Alzheimer's disease dementia in later life.

Accuracy of left ventricular ejection fraction by contemporary multiple gated acquisition scanning in patients with cancer: comparison with cardiovascular magnetic resonance.

BACKGROUND: Multiple gated acquisition scanning (MUGA) is a common imaging modality for baseline and serial assessment of left ventricular ejection fraction (LVEF) for cardiotoxicity risk assessment prior to, surveillance during, and surveillance after administration of potentially cardiotoxic cancer treatment. The objective of this study was to compare the accuracy of left ventricular ejection fractions (LVEF) obtained by contemporary clinical multiple gated acquisition scans (MUGA) with reference LVEFs from cardiovascular magnetic resonance (CMR) in consecutive patients with cancer. METHODS: In a cross-sectional study, we compared MUGA clinical and CMR reference LVEFs in 75 patients with cancer who had both studies within 30 days. Misclassification was assessed using the two most common thresholds of LVEF used in cardiotoxicity clinical studies and practice: 50 and 55%. RESULTS: Compared to CMR reference LVEFs, MUGA clinical LVEFs were only lower by a mean of 1.5% (48.5% vs. 50.0%, p = 0.17). However, the limits of agreement between MUGA clinical and CMR reference LVEFs were wide at -19.4 to 16.5%. At LVEF thresholds of 50 and 55%, there was misclassification of 35 and 20% of cancer patients, respectively. CONCLUSIONS: MUGA clinical LVEFs are only modestly accurate when compared with CMR reference LVEFs. These data have significant implications on clinical research and patient care of a population with, or at risk for, cardiotoxicity.

Association between sleep disordered breathing and electrocardiographic markers of atrial abnormalities: the MESA study.

AIMS: Electrocardiographic (ECG) markers of left atrial (LA) abnormalities have been linked to increased risk of atrial fibrillation (AF). Sleep disordered breathing (SDB) has been associated with increased risk of AF. We aimed to examine the association of ECG markers of LA abnormalities with SDB. METHODS AND RESULTS: 1546 participants (mean age 67.2 years, 53.4% women, and 63.3% non-whites) from the Multi-Ethnic Study of Atherosclerosis Exam 5 Sleep ancillary study were included in this analysis. ECG markers of LA abnormalities (P wave terminal force in V1 (PTFV1), maximum P wave duration, PR interval and heart rate corrected PR interval) were measured from resting standard digital ECG tracings using standardized processing. Linear and logistic regression analyses were utilized to examine the cross-sectional associations of measures of SDB (apnea hypopnea index [AHI] and % time spent with oxygen saturation <90% [%SpO290]) with each ECG marker. In a multivariable analysis adjusting for demographics, cardiovascular risk factors, and comorbidities, AHI was associated with greater PTFV1 but not with other ECG markers of LA abnormalities. A 1-SD increase of AHI (16.6/hr) was associated with higher levels of PTFV1 (175.1 µV.ms, 95% confidence interval [95%CI] 75.4, 274.7) and higher odds of abnormally elevated PTFV1 (≥4000 µV.ms) (Odds Ratio: 1.21 [95%CI 1.05, 1.39]). No association was found between %SpO290 and ECG markers of LA abnormalities. CONCLUSION: Severity of SDB, as measured by AHI, is associated with subclinical LA disease, as indicated by PTFV1. PTFV1 may be an important ECG marker linking SDB and AF.

Measurement by a Novel LC-MS/MS Methodology Reveals Similar Serum Concentrations of Vitamin D-Binding Protein in Blacks and Whites.

BACKGROUND: Vitamin D deficiency is associated with poor bone health and other adverse health outcomes; however, the associations are greatly attenuated in black vs white individuals. One possible explanation for this attenuation is different concentrations of bioavailable vitamin D metabolites in plasma, which are estimated with equations that include the total concentration of vitamin D binding globulin (VDBG) and haplotype-specific dissociation constants. METHODS: We developed a method to quantify VDBG with LC-MS/MS that could also identify the haplotypes/isoforms of VDBG present. We validated the method according to recent recommendations for publications of biomarker studies. We determined serum VDBG concentrations in samples from the Atherosclerosis Risk in Communities cohort and compared the results with a widely used monoclonal immunoassay. RESULTS: With 10 µL of serum or plasma, the lower limit of quantification for the assay (<20% CV) was 71 µg/mL. The assay was linear from 62 to 434 µg/mL, with total imprecision of 7.3-9.0% CV at approximately 250 µg/mL. Significant hemolysis interfered with quantification. The identification of isoforms was 97% concordant with genotyping (κ coefficient). Method comparison with immunoassay revealed significant isoform-specific effects in the immunoassay. Mean concentrations (SD) of VDBG by mass spectrometry were similar in whites and blacks [262 (25) vs 266 (35) µg/mL, respectively; P = 0.43]. CONCLUSIONS: Validated mass spectrometric methods for the quantification of proteins in human samples can provide additional information beyond immunoassay. Counter to prior observations by immunoassay, VDBG concentrations did not vary by race.

Short-term Variability of Vitamin D-Related Biomarkers.

BACKGROUND: Quantifying the variability of biomarkers is important, as high within-person variability can lead to misclassification of individuals. Short-term variability of important markers of vitamin D metabolism is relatively unknown. METHODS: A repeatability study was conducted in 160 Atherosclerosis Risk in Communities study participants (60% female, 28% black, mean age 76 years). Fasting serum was drawn at 2 time points, a median of 6 (range 3-13) weeks apart. Vitamin D binding protein (VDBP) and 25-hydroxyvitamin D [25(OH)D] were measured by LC-MS, fibroblast growth factor (FGF23) and parathyroid hormone (PTH) by enzyme-linked immunoassay, and calcium and phosphorus by Roche Cobas 6000. Free and bioavailable 25(OH)D were calculated. We calculated the within-person CV (CVW), intraclass correlation coefficient (ICC), Spearman rank correlation coefficient (r), and percent reclassified. RESULTS: The CVW was lowest for calcium (2.0%), albumin (3.6%), 25(OH)D (6.9%), VDBP (7.0%) and phosphorus (7.6%); intermediate for free 25(OH)D (9.0%) and bioavailable 25(OH)D (9.9%); and highest for PTH (16.7%) and FGF23 (17.8%). Reclassification was highest for PTH, VDBP, and phosphorus (all 7.5%). The ICC and r were highest (≥0.80) for 25(OH)D, free 25(OH)D, bioavailable 25(OH)D and PTH, but somewhat lower (approximately 0.60-0.75) for the other biomarkers. CONCLUSIONS: Six-week short-term variability, as assessed by CVW, was quite low for VDBP, calcium and phosphorus, but fairly high for FGF23 and PTH. As such, multiple measurements of FGF23 and PTH may be needed to minimize misclassification. These results provide insight into the extent of potential misclassification of vitamin D markers in research and clinical settings.

Biomarkers of Vitamin D Status and Risk of ESRD.

BACKGROUND: Disordered mineral metabolism is characteristic of decreased kidney function. However, the prospective associations between circulating levels of vitamin D binding protein, vitamin D, and end-stage renal disease (ESRD) have not been extensively evaluated in epidemiologic studies. STUDY DESIGN: Nested case-control study. SETTING & PARTICIPANTS: Middle-aged black and white men and women from 4 US communities. PREDICTORS: Baseline levels of vitamin D binding protein, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) were measured in blood samples collected at study visit 4 (1996-1998) of the ARIC (Atherosclerosis Risk in Communities) Study. OUTCOME: ESRD cases (n=184) were identified through hospitalization diagnostic codes from 1996 to 2008 and were frequency matched to controls (n=251) on categories of estimated glomerular filtration rate, albuminuria, diabetes mellitus, sex, and race. MEASUREMENTS: Logistic regression was used to estimate the association between mineral metabolism biomarkers (vitamin D binding protein, 25(OH)D, and 1,25(OH)2D) and incident ESRD, adjusting for age, sex, race, estimated glomerular filtration rate, albuminuria, diabetes mellitus, hypertension, education, specimen type, and serum levels of calcium, phosphate, and parathyroid hormone. RESULTS: Higher vitamin D binding protein levels were associated with elevated risk for incident ESRD (OR, 1.76; 95% CI, 1.22-2.54; P=0.003). Higher free and bioavailable 25(OH)D levels were associated with reduced risk for incident ESRD (ORs of 0.65 [95% CI, 0.46-0.92; P=0.02] and 0.63 [95% CI, 0.43-0.91; P=0.02] for free and bioavailable 25[OH]D, respectively). There was no association between ESRD and overall levels of 25(OH)D (OR, 0.83; 95% CI, 0.58-1.19; P=0.3) or 1,25(OH)2D (OR, 0.73; 95% CI, 0.48-1.13; P=0.2). LIMITATIONS: Lack of direct measurement of free and bioavailable vitamin D. CONCLUSIONS: In the general population, blood levels of vitamin D binding protein were positively associated and blood levels of free and bioavailable 25(OH)D were inversely associated with new-onset ESRD during follow-up.

Serum 25-hydroxyvitamin D and the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study.

AIMS: To assess the prospective association between circulating 25-hydroxyvitamin D [25(OH)D] and atrial fibrillation (AF) risk. METHODS AND RESULTS: We studied 12 303 participants from the Atherosclerosis Risk in Communities study without baseline AF (1990-92). Baseline serum total 25(OH)D was measured using mass spectrometry. Incident AF cases were identified from electrocardiograms, hospital discharge codes, and death certificates through 2012. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) of AF across clinical categories of serum 25(OH)D concentrations with multivariable Cox models, and tested interactions by age, race, and sex. We meta-analysed our results with those from published prospective studies that reported associations between 25(OH)D and AF risk. During a median follow-up of 21 years, we identified 1866 AF events. In multivariable models, deficient 25(OH)D status (<20 ng/mL), compared with optimal levels (≥30 ng/mL), was not associated with AF risk (HR, 95% CI: 1.10, 0.96-1.26). A significant interaction of 25(OH)D concentrations with age (P = 0.01), but not with race or sex (P > 0.40), was identified, with higher risk of AF among those with deficient 25(OH)D status in younger (HR, 95% CI: 1.35, 1.05-1.73) but not older individuals (HR, 95% CI: 1.02, 0.86-1.21). A meta-analysis of these results and four prospective studies did not support a clinically relevant association of circulating 25(OH)D with AF risk [pooled HR, 95%CI: 1.04, 1.00-1.08, per 1 SD lower 25(OH)D]. CONCLUSION: Low serum 25(OH)D was not associated with incident AF in a community-based cohort and in a meta-analysis of prospective studies. A possible association in younger individuals warrants further investigation.

Association of Dietary Protein Consumption With Incident Silent Cerebral Infarcts and Stroke: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND AND PURPOSE: The effect of dietary protein on the risk of stroke has shown inconsistent results. We aimed to evaluate the relationship of dietary protein sources with the risk of stroke and silent cerebral infarcts in a large community-based cohort. METHODS: We studied 11601 adults (age, 45-64 years at baseline in 1987-1989) enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, free of diabetes mellitus and cardiovascular disease. Dietary protein intake was assessed with validated food frequency questionnaires at baseline and after 6 years of follow-up. Incident stroke events were identified through hospital discharge codes and stroke deaths and physician-adjudicated through December 31, 2011. A subset of participants (n=653) underwent brain magnetic resonance imaging in 1993 to 1995 and in 2004 to 2006. Cox proportional hazard models and logistic regression were used for statistical analyses. RESULTS: During a median follow-up of 22.7 years, there were 699 stroke events. In multivariable analyses, total, animal, and vegetable protein consumption was not associated with risk of stroke. Red meat consumption was associated with increased stroke risk, particularly ischemic events. The hazard ratios (95% confidence interval) for risk of ischemic stroke across ascending quintiles of red meat consumption were 1 (ref), 1.13 (0.85-1.49), 1.44 (1.09-1.90), 1.33 (0.99-1.79), and 1.47 (1.06-2.05); Ptrend=0.01. No association of major dietary protein sources with silent cerebral infarcts was detected. CONCLUSIONS: This study supports the notion that consumption of red meat may increase the risk of ischemic stroke. No association between dietary protein intake and silent cerebral infarcts was found.

Parathyroid hormone concentration and risk of cardiovascular diseases: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: According to a recent meta-analysis, parathyroid hormone (PTH) excess is associated with increased cardiovascular disease (CVD) risk, but existing studies are limited. We examined in a prospective study the association of PTH with the incidence of CVD, taking into account vitamin D and other confounding variables. METHODS: The ARIC study measured PTH using a second-generation assay (Roche, Indianapolis, IN) in stored serum samples from 1990 to 1992 and related levels in 10,392 adults to incident cardiovascular outcomes (coronary heart disease [n = 808], heart failure [n = 1,294], stroke [n = 586], peripheral artery disease [n = 873], atrial fibrillation [n = 1,190], and CVD mortality [n = 647]) through 2010 (median follow-up 19 years). RESULTS: Contrary to the hypothesis, PTH level was not associated positively with any CVD outcome. The associations of incident heart failure, peripheral artery disease, and CVD mortality with PTH actually were weakly inverse (P trend = .02-.04) in the most fully adjusted models. For example, the hazard ratios across PTH quartiles were 1.00, 1.07, 1.07, and 0.96 (P trend = .74) for coronary heart disease incidence and were 1.00, 0.69, 0.74, and 0.74 (P trend = .02) for CVD mortality. Patterns were similar when restricted to participants with normal baseline kidney function. CONCLUSIONS: This large prospective study failed to support the hypothesis that elevated PTH is an independent risk marker for incident CVD. When our data were added to the previous meta-analysis, the pooled hazard ratio remained statistically significant but weakened.