Metabolomic Association and Risk Prediction With Heart Failure in Older Adults.

BACKGROUND: Older adults have markedly increased risks of heart failure (HF), specifically HF with preserved ejection fraction (HFpEF). Identifying novel biomarkers can help in understanding HF pathogenesis and improve at-risk population identification. This study aimed to identify metabolites associated with incident HF, HFpEF, and HF with reduced ejection fraction and examine risk prediction in older adults. METHODS: Untargeted metabolomic profiling was performed in Black and White adults from the ARIC study (Atherosclerosis Risk in Communities) visit 5 (n=3719; mean age, 75 years). We applied Cox regressions to identify metabolites associated with incident HF and its subtypes. The metabolite risk score (MRS) was constructed and examined for associations with HF, echocardiographic measures, and HF risk prediction. Independent samples from visit 3 (n=1929; mean age, 58 years) were used for replication. RESULTS: Sixty metabolites (hazard ratios range, 0.79-1.49; false discovery rate, <0.05) were associated with incident HF after adjusting for clinical risk factors, eGFR, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Mannonate, a hydroxy acid, was replicated (hazard ratio, 1.36 [95% CI, 1.19-1.56]) with full adjustments. MRS was associated with an 80% increased risk of HF per SD increment, and the highest MRS quartile had 8.7× the risk of developing HFpEF than the lowest quartile. High MRS was also associated with unfavorable values of cardiac structure and function. Adding MRS over clinical risk factors and NT-proBNP improved 5-year HF risk prediction C statistics from 0.817 to 0.850 (∆C, 0.033 [95% CI, 0.017-0.047]). The association between MRS and incident HF was replicated after accounting for clinical risk factors (P<0.05). CONCLUSIONS: Novel metabolites associated with HF risk were identified, elucidating disease pathways, specifically HFpEF. An MRS was associated with HF risk and improved 5-year risk prediction in older adults, which may assist at at-risk population identification.

Longitudinal associations of blood pressure with aortic stiffness and pulsatility: the Atherosclerosis Risk in Communities Study.

OBJECTIVE: To characterize the longitudinal relationships between blood pressure measured over 24 years and arterial stiffness in late life measured as pulse wave velocity (PWV). METHODS: Carotid--femoral (cf) and femoral--ankle (fa) PWV were measured in 4166 adults at the visit 5 Atherosclerosis Risk in Communities study cohort examination (2011-2013). Participants were categorized into tertiles of PWV measurements. Blood pressure measurements were made at baseline (1987-1989), three subsequent triennial examinations, and visit 5. RESULTS: Partial correlation coefficients between visit 5 cfPWV and SBP ranged from 0.13 for visit 1 SBP to 0.32 for visit 5 SBP. For visit 5 faPWV, correlations were ∼0 for visits 1 to 4 SBP, but was 0.20 for visit 5 SBP. Over 24 years of follow-up, those with higher average SBP were more likely to fall in the middle and upper tertiles of visit 5 cfPWV. Average pulse pressure and mean arterial pressure over 24 years had similar but weaker associations with cfPWV tertiles. DBP had no clear association with cfPWV. Blood pressure measurements were positively associated with faPWV tertiles only cross-sectionally at visit 5. CONCLUSION: Adult life-course measures of SBP, more so than mean arterial and pulse pressure, were associated with later life central arterial stiffness. By contrast, only contemporaneous measures of blood pressure were associated with peripheral arterial stiffness. Although arterial stiffness was only measured at later life, these results are consistent with the notion that elevated blood pressure over time is involved in the pathogenesis of arterial stiffening.

Predictors of Mortality by Sex and Race in Heart Failure With Preserved Ejection Fraction: ARIC Community Surveillance Study.

Background Heart failure with preserved ejection fraction (HFpEF) accounts for half of heart failure hospitalizations, with limited data on predictors of mortality by sex and race. We evaluated for differences in predictors of all-cause mortality by sex and race among hospitalized patients with HFpEF in the ARIC (Atherosclerosis Risk in Communities) Community Surveillance Study. Methods and Results Adjudicated HFpEF hospitalization events from 2005 to 2013 were analyzed from the ARIC Community Surveillance Study, comprising 4 US communities. Comparisons between clinical characteristics and mortality at 1 year were made by sex and race. Of 4335 adjudicated acute decompensated heart failure cases, 1892 cases (weighted n=8987) were categorized as HFpEF. Men had an increased risk of 1-year mortality compared with women in adjusted analysis (hazard ratio [HR], 1.27; 95% CI, 1.06-1.52 [P=0.01]). Black participants had lower mortality compared with White participants in unadjusted and adjusted analyses (HR, 0.79; 95% CI, 0.64-0.97 [P=0.02]). Age, heart rate, worsening renal function, and low hemoglobin were associated with increased mortality in all subgroups. Higher body mass index was associated with improved survival in men, with borderline interaction by sex. Higher blood pressure was associated with improved survival among all groups, with significant interaction by race. Conclusions In a diverse HFpEF population, men had worse survival compared with women, and Black participants had improved survival compared with White participants. Age, heart rate, and worsening renal function were associated with increased mortality across all subgroups; high blood pressure was associated with decreased mortality with interaction by race. These insights into sex- and race-based differences in predictors of mortality may help strategize targeted management of HFpEF.

Temporal trends in validated ischaemic stroke hospitalizations in the USA.

BACKGROUND: Accurate assessment of the burden of stroke, a major cause of disability and death, is crucial. We aimed to estimate rates of validated ischaemic stroke hospitalizations in the USA during 1998-2011. METHODS: We used the Atherosclerosis Risk in Communities (ARIC) study cohort's adjudicated stroke data for participants aged ≥55 years, to construct validation models for each International Classification of Diseases (ICD)-code group and patient covariates. These models were applied to the Nationwide Inpatient Sample (NIS) data to estimate the probability of validated ischaemic stroke for each eligible hospitalization. Rates and trends in NIS using ICD codes vs estimates of validated ischaemic stroke were compared. RESULTS: After applying validation models, the estimated annual average rate of validated ischaemic stroke hospitalizations in the USA during 1998-2011 was 3.37 [95% confidence interval (CI): 3.31, 3.43) per 1000 person-years. Validated rates declined during 1998-2011 from 4.7/1000 to 2.9/1000; however, the decline was limited to 1998-2007, with no further decline subsequently through 2011. Validation models showed that the false-positive (∼23% of strokes) and false-negative rates of ICD-9-CM codes in primary position for ischaemic stroke approximately cancel. Therefore, estimates of ischaemic stroke hospitalizations did not substantially change after applying validation models. CONCLUSIONS: Overall, ischaemic stroke hospitalization rates in the USA have declined during 1998-2007, but no further decline was observed from 2007 to 2011. Validated ischaemic stroke hospitalizations estimates were similar to published estimates of hospitalizations with ischaemic stroke ICD codes in primary position. Validation of national discharge data using prospective chart review data is important to estimate the accuracy of reported burden of stroke.

Association of Peripheral Artery Disease With Incident Atrial Fibrillation: The ARIC (Atherosclerosis Risk in Communities) Study.

BACKGROUND: Although peripheral artery disease as defined by ankle-brachial index (ABI) is associated with incident atrial fibrillation (AF), questions remain about the risk of AF in borderline ABI (>0.90 to <1.0) or noncompressible arteries (>1.4). We evaluated the association of borderline ABI and ABI >1.4 in the ARIC (Atherosclerosis Risk in Communities) study, a population-based prospective cohort study. METHODS AND RESULTS: We included 14 794 participants (age, 54.2±5.8 years, 55% women, 26% blacks) with ABI measured at the baseline (1987-1989) and without AF. AF was identified from hospital records, death certificates, and ECGs. Using Cox proportional hazards, we evaluated the association between ABI and AF. During a median follow-up of 23.3 years, there were 2288 AF cases. After adjustment for cardiovascular risk factors, hazard ratio (HR) (95% confidence interval) for AF among individuals with ABI <1.0 compared with ABI 1.0 to 1.4, was 1.13 (1.01-1.27). ABI >1.4 was not associated with increased AF risk. ABI ≤0.9 and borderline ABI were associated with a higher risk of AF compared with ABI 1.0 to 1.4. Demographics-adjusted HRs (95% confidence interval) were 1.43 (1.17-1.75) and 1.32 (1.16-1.50), respectively. However, the associations of ABI ≤0.9 and borderline ABI with AF were attenuated after adjusting for cardiovascular risk factors (HR [95% confidence interval], 1.10 [0.90-1.34] and 1.14 [1.00-1.30]), respectively. CONCLUSIONS: Peripheral artery disease indicated by low ABI, including borderline ABI, is a weak risk factor for AF. ABI >1.4 is not associated with an increased AF risk. The relationship between peripheral artery disease and AF appears to be mostly explained by traditional atherosclerotic risk factors.

Association of Atrial Fibrillation With Cognitive Decline and Dementia Over 20 Years: The ARIC-NCS (Atherosclerosis Risk in Communities Neurocognitive Study).

BACKGROUND: Previous studies have reported that atrial fibrillation (AF) is associated with cognitive decline and dementia. These studies, however, had limited follow-up, were based mostly on white and highly selected populations, and did not account for attrition. We evaluated the association of incident AF with 20-year change in cognitive performance (accounting for attrition) and incident dementia in the ARIC (Atherosclerosis Risk in Communities) Study. METHODS AND RESULTS: We analyzed data from 12 515 participants (mean age, 56.9 [SD, 5.7] years in 1990-1992; 56% women and 24% black) from 1990 to 1992 through 2011 to 2013. Incident AF was ascertained from study ECGs and hospital discharge codes. Cognitive tests were performed in 1990 to 1992, 1996 to 1998, and 2011 to 2013. Incident dementia was clinician adjudicated. We used generalized estimating equations and Cox proportional hazards models to assess the association of time-dependent AF with change in Z scores of cognitive tests and incident dementia, respectively. During 20 years, 2106 participants developed AF and 1157 participants developed dementia. After accounting for cardiovascular risk factors, including ischemic stroke, the average decline over 20 years in global cognitive Z score was 0.115 (95% confidence interval, 0.014-0.215) greater in participants with AF than in those without AF. Further adjustment for attrition by multiple imputation by chained equations strengthened the association. In addition, incident AF was associated with an increased risk of dementia (hazard ratio, 1.23; 95% confidence interval, 1.04-1.45), after adjusting for cardiovascular risk factors, including ischemic stroke. CONCLUSIONS: AF is associated with greater cognitive decline and increased risk of dementia, independent of ischemic stroke. Because cognitive decline is a precursor to dementia, our findings prompt further investigation to identify specific treatments for AF that will delay the trajectory of cognitive decline and, thus, prevent dementia in patients with AF.

Trends in Hospitalizations and Survival of Acute Decompensated Heart Failure in Four US Communities (2005-2014): ARIC Study Community Surveillance.

BACKGROUND: Community trends of acute decompensated heart failure (ADHF) in diverse populations may differ by race and sex. METHODS: The ARIC study (Atherosclerosis Risk in Communities) sampled heart failure-related hospitalizations (≥55 years of age) in 4 US communities from 2005 to 2014 using International Classification of Diseases, Ninth Revision, Clinical Modification codes. ADHF hospitalizations were validated by standardized physician review and computer algorithm, yielding 40 173 events after accounting for sampling design (unweighted n=8746). RESULTS: Of the ADHF hospitalizations, 50% had reduced ejection fraction, and 39% had preserved EF (HFpEF). HF with reduced ejection fraction was more common in black men and white men, whereas HFpEF was most common in white women. Average age-adjusted rates of ADHF were highest in blacks (38.1 per 1000 black men, 30.5 per 1000 black women), with rates differing by HF type and sex. ADHF rates increased over the 10 years (average annual percentage change: black women +4.3%, black men +3.7%, white women +1.9%, white men +2.6%), mostly reflecting more acute HFpEF. Age-adjusted 28-day and 1-year case fatality proportions were ≈10% and 30%, respectively, similar across race-sex groups and HF types. Only blacks showed decreased 1-year mortality over time (average annual percentage change: black women -5.4%, black men -4.6%), with rates differing by HF type (average annual percentage change: black women HFpEF -7.1%, black men HF with reduced ejection fraction -4.7%). CONCLUSIONS: Between 2005 and 2014, trends in ADHF hospitalizations increased in 4 US communities, primarily driven by acute HFpEF. Survival at 1 year was poor regardless of EF but improved over time for black women and black men.

Predicting Risk in Patients Hospitalized for Acute Decompensated Heart Failure and Preserved Ejection Fraction: The Atherosclerosis Risk in Communities Study Heart Failure Community Surveillance.

BACKGROUND: Risk-prediction models specifically for hospitalized heart failure with preserved ejection fraction are lacking. METHODS AND RESULTS: We analyzed data from the ARIC (Atherosclerosis Risk in Communities) Study Heart Failure Community Surveillance to create and validate a risk score predicting mortality in patients ≥55 years of age admitted with acute decompensated heart failure with preserved ejection fraction (ejection fraction ≥50%). A modified version of the risk-prediction model for acute heart failure developed from patients in the EFFECT (Enhanced Feedback for Effective Cardiac Treatment) study was used as a composite predictor of 28-day and 1-year mortalities and evaluated together with other potential predictors in a stepwise logistic regression. The derivation sample consisted of 1852 hospitalizations from 2005 to 2011 (mean age, 77 years; 65% women; 74% white). Risk scores were created from the identified predictors and validated in hospitalizations from 2012 to 2013 (n=821). Mortality in the derivation and validation sample was 11% and 8% at 28 days and 34% and 31% at 1 year. The modified EFFECT score, including age, systolic blood pressure, blood urea nitrogen, sodium, cerebrovascular disease, chronic obstructive pulmonary disease, and hemoglobin, was a powerful predictor of mortality. Another important predictor for both 28-day and 1-year mortalities was hypoxia. The risk scores were well calibrated and had good discrimination in the derivation sample (area under the curve: 0.76 for 28-day and 0.72 for 1-year mortalities) and validation sample (area under the curve: 0.73 and 0.71, respectively). CONCLUSIONS: Mortality after acute decompensation in patients with heart failure with preserved ejection fraction is high, with one third of patients dying within a year. A prediction tool may allow for greater discrimination of the highest risk patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005131.

Counterclockwise and Clockwise Rotation of QRS Transitional Zone: Prospective Correlates of Change and Time-Varying Associations With Cardiovascular Outcomes.

BACKGROUND: A few studies have recently reported clockwise and counterclockwise rotations of QRS transition zone as predictors of mortality. However, their prospective correlates and associations with individual cardiovascular disease (CVD) outcomes are yet to be investigated. METHODS AND RESULTS: Among 13 567 ARIC (Atherosclerosis Risk in Communities) study participants aged 45 to 64 years, we studied key correlates of changes in the status of clockwise and counterclockwise rotation over time as well as the association of rotation status with incidence of coronary heart disease (2408 events), heart failure (2196 events), stroke (991 events), composite CVD (4124 events), 898 CVD deaths, and 3469 non-CVD deaths over 23 years of follow-up. At baseline, counterclockwise rotation was most prevalent (52.9%), followed by no (40.5%) and clockwise (6.6%) rotation. Of patients with no rotation, 57.9% experienced counterclockwise or clockwise rotation during follow-up, with diabetes mellitus and black race significantly predicting clockwise and counterclockwise conversion, respectively. Clockwise rotation was significantly associated with higher risk of heart failure (hazard ratio, 1.20; 95% confidence interval [CI], 1.02-1.41) and non-CVD death (hazard ratio, 1.28; 95% CI, 1.12-1.46) after adjusting for potential confounders including other ECG parameters. On the contrary, counterclockwise rotation was significantly related to lower risk of composite CVD (hazard ratio, 0.93; 95% CI, 0.87-0.99]), CVD mortality (hazard ratio, 0.76; 95% CI, 0.65-0.88), and non-CVD deaths (hazard ratio, 0.92; 95% CI, 0.85-0.99 [borderline significance with heart failure]). CONCLUSIONS: Counterclockwise rotation, the most prevalent QRS transition zone pattern, demonstrated the lowest risk of CVD and mortality, whereas clockwise rotation was associated with the highest risk of heart failure and non-CVD mortality. These results have implications on how to interpret QRS transition zone rotation when ECG was recorded.

Community burden and prognostic impact of reduced kidney function among patients hospitalized with acute decompensated heart failure: The Atherosclerosis Risk in Communities (ARIC) Study Community Surveillance.

BACKGROUND: Kidney dysfunction is prevalent and impacts prognosis in patients with acute decompensated heart failure (ADHF). However, most previous reports were from a single hospital, limiting their generalizability. Also, contemporary data using new equation for estimated glomerular filtration rate (eGFR) are needed. METHODS AND RESULTS: We analyzed data from the ARIC Community Surveillance for ADHF conducted for residents aged ≥55 years in four US communities between 2005-2011. All ADHF cases (n = 5, 391) were adjudicated and weighted to represent those communities (24,932 weighted cases). The association of kidney function (creatinine-based eGFR by the CKD-EPI equation and blood urea nitrogen [BUN]) during hospitalization with 1-year mortality was assessed using logistic regression. Based on worst and last serum creatinine, there were 82.5% and 70.6% with reduced eGFR (<60 ml/min/1.73m2) and 37.4% and 26.6% with severely reduced eGFR (<30 ml/min/1.73m2), respectively. Lower eGFR (regardless of last or worst eGFR), particularly eGFR <30 ml/min/1.73m2, was significantly associated with higher 1-year mortality independently of potential confounders (odds ratio 1.60 [95% CI 1.26-2.04] for last eGFR 15-29 ml/min/1.73m2 and 2.30 [1.76-3.00] for <15 compared to eGFR ≥60). The association was largely consistent across demographic subgroups. Of interest, when both eGFR and BUN were modeled together, only BUN remained significant. CONCLUSIONS: Severely reduced eGFR (<30 ml/min/1.73m2) was observed in ~30% of ADHF cases and was an independent predictor of 1-year mortality in community. For prediction, BUN appeared to be superior to eGFR. These findings suggest the need of close attention to kidney dysfunction among ADHF patients.

Cardiac Autonomic Dysfunction and Incidence of Atrial Fibrillation: Results From 20 Years Follow-Up.

BACKGROUND: Cardiac autonomic perturbations frequently antecede onset of paroxysmal atrial fibrillation (AF). Interventions that influence autonomic inputs to myocardium may prevent AF. However, whether low heart rate or heart rate variability (HRV), which are noninvasive measures of cardiac autonomic dysfunction, are associated with AF incidence is unclear. OBJECTIVES: This study sought to study the association between HRV and risk of AF. METHODS: This study included 11,715 middle-aged adults in the ARIC (Atherosclerosis Risk In Communities) cohort with heart rate and HRV measures obtained from 2-min electrocardiogram recordings performed at baseline (1987 to 1989). These measures included SD of normal-to-normal RR intervals, high-frequency (HF) (0.15 to 0.40 Hz), low-frequency (0.04 to 0.15 Hz), and the low-frequency/HF ratio (denoting a greater sympathetic to parasympathetic dominance). Incident AF cases were ascertained by electrocardiogram at ARIC follow-up visits, hospital discharge diagnosis, or death certificates through 2011. RESULTS: During an average follow-up of 19.4 years, 1,580 or 13.5% of participants developed AF. A baseline heart rate <60 beats/min was associated modestly with an increased risk of AF. Lower overall HRV as well as increased sympathetic/parasympathetic tone were associated independently with a higher risk of AF; the hazard ratio for each 1 SD lower SD of normal-to-normal RR intervals was 1.14 (95% confidence interval: 1.08 to 1.21), for HF was 1.12 (95% confidence interval: 1.06 to 1.17), and for low frequency/HF was 1.08 (95% confidence interval: 1.03 to 1.14). CONCLUSIONS: Cardiac autonomic dysfunction denoted by low resting short-term HRV was associated with higher AF incidence. A low heart rate may be associated with higher AF risk. Further studies are needed to determine whether interventions in the general population to restore autonomic balance may prevent AF.

Kidney function and sudden cardiac death in the community: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Individuals with chronic kidney disease, particularly those requiring dialysis, are at high risk of sudden cardiac death (SCD). However, comprehensive data for the full spectrum of kidney function and SCD risk in the community are sparse. Furthermore, newly developed equations for estimated glomerular filtration rate (eGFR) and novel filtration markers might add further insight to the role of kidney function in SCD. METHODS: We investigated the associations of baseline eGFRs using serum creatinine, cystatin C, or both (eGFRcr, eGFRcys, and eGFRcr-cys); cystatin C itself; and ß2-microglobulin (B2M) with SCD (205 cases through 2001) among 13,070 black and white ARIC participants at baseline during 1990-1992 using Cox regression models accounting for potential confounders. RESULTS: Low eGFR was independently associated with SCD risk: for example, hazard ratio for eGFR <45 versus ≥90mL/(min 1.73m(2)) was 3.71 (95% CI 1.74-7.90) with eGFRcr, 5.40 (2.97-9.83) with eGFRcr-cys, and 5.24 (3.01-9.11) with eGFRcys. When eGFRcr and eGFRcys were included together in a single model, the association was only significant for eGFRcys. When three eGFRs, cystatin C, and B2M were divided into quartiles, B2M demonstrated the strongest association with SCD (hazard ratio for fourth quartile vs first quartile 3.48 (2.03-5.96) vs ≤2.7 for the other kidney markers). CONCLUSIONS: Kidney function was independently and robustly associated with SCD in the community, particularly when cystatin C or B2M was used. These results suggest the potential value of kidney function as a risk factor for SCD and the advantage of novel filtration markers over eGFRcr in this context.

Trajectories of Cardiovascular Risk Factors and Incidence of Atrial Fibrillation Over a 25-Year Follow-Up: The ARIC Study (Atherosclerosis Risk in Communities).

BACKGROUND: Timing and trajectories of cardiovascular risk factor (CVRF) development in relation to atrial fibrillation (AF) have not been described previously. We assessed trajectories of CVRF and incidence of AF over 25 years in the ARIC study (Atherosclerosis Risk in Communities). METHODS: We assessed trajectories of CVRF in 2456 individuals with incident AF and 6414 matched control subjects. Subsequently, we determined the association of CVRF trajectories with the incidence of AF among 10 559 AF-free individuals (mean age, 67 years; 52% men; 20% blacks). Risk factors were measured during 5 examinations between 1987 and 2013. Cardiovascular events, including incident AF, were ascertained continuously. We modeled the prevalence of risk factors and cardiovascular outcomes in the period before and after AF diagnosis and the corresponding index date for control subjects using generalized estimating equations. Trajectories in risk factors were identified with latent mixture modeling. The risk of incident AF by trajectory group was examined with Cox models. RESULTS: The prevalence of stroke, myocardial infarction, and heart failure increased steeply during the time close to AF diagnosis. All CVRFs were elevated in AF cases compared with controls >15 years before diagnosis. We identified distinct trajectories for all the assessed CVRFs. In general, individuals with trajectories denoting long-term exposure to CVRFs had increased AF risk even after adjustment for single measurements of the CVRFs. CONCLUSIONS: AF patients have increased prevalence of CVRF many years before disease diagnosis. This analysis identified diverse trajectories in the prevalence of these risk factors, highlighting their different roles in AF pathogenesis.

Racial Differences in Atrial Fibrillation-Related Cardiovascular Disease and Mortality: The Atherosclerosis Risk in Communities (ARIC) Study.

IMPORTANCE: The adverse outcomes associated with atrial fibrillation (AF) have been studied in predominantly white cohorts. Racial differences in outcomes associated with AF merit continued investigation. OBJECTIVE: To evaluate the race-specific associations of AF with stroke, heart failure, coronary heart disease (CHD), and all-cause mortality in a community-based cohort. DESIGN, SETTING, AND PARTICIPANTS: The Atherosclerosis Risk in Communities (ARIC) Study is a prospective, observational cohort. From 1987 through 1989, the ARIC Study enrolled 15 792 men and women and conducted 4 follow-up examinations (2011-2013) with active surveillance for vital status and hospitalizations. Race was determined by self-report and categorized as white, black, or other. MAIN OUTCOMES AND MEASURES: Atrial fibrillation (adjudicated using electrocardiograms, hospital discharge codes, and death certificates), stroke, heart failure, CHD, and mortality. RESULTS: After exclusions, 15 080 participants (mean [SD] age, 54.2 [5.8] years; 8290 women [55.5%]; 3831 black individuals [25.4%]) were included in this analysis. During a mean (SD) follow-up of 20.6 (6.2) years, there were 2348 cases of incident AF. The incident rates of AF per 1000 person-years were 8.1 (95% CI, 7.7-8.5) in white individuals and 5.8 (95% CI, 5.2-6.3) in black individuals. The rates of stroke, heart failure, CHD, and mortality were higher in black individuals with AF than white individuals with AF. The association of AF with these outcomes, estimated with rate differences (rate of the end point in those with AF minus the rate in those without AF per 1000 person-years), also differed by race. The rate difference for stroke in individuals with AF was 10.2 (95% CI, 6.6-13.9) in white individuals and 21.4 (95% CI, 10.2-32.6) in black individuals. For heart failure and CHD, the rate differences were 1.5- to 2.0-fold higher in black individuals than white individuals. White individuals with AF had a rate difference of 55.9 (95% CI, 48.1-63.7) for mortality compared with black individuals, who had a rate difference of 106.0 (95% CI, 86.0-125.9). CONCLUSIONS AND RELEVANCE: In the prospective ARIC Study, the outcome of AF on the rates of stroke, heart failure, CHD, and mortality was considerably larger in black individuals than white individuals. These results indicate the vulnerability and increased risk in black individuals with AF. Continued investigation of racial differences in AF and its related adverse outcomes are essential to identify and mitigate racial disparities in the treatment of AF.

Heart Rate Variability and Incident Stroke: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: Low heart rate variability (HRV), a marker of cardiac autonomic dysfunction, has been associated with increased all-cause and cardiovascular mortality. We examined the association between reduced HRV and incident stroke in a community-based cohort. METHODS: The Atherosclerosis Risk in Communities (ARIC) study measured HRV using 2-minute ECG readings in 12 550 middle-aged adults at baseline (1987-1989). HRV indices were calculated using the SD of RR intervals (SDNN), the mean of all normal RR intervals (meanNN), the root mean square of successive differences of successive RR intervals (RMSSD), low (LF) and high (HF) frequency power, and the LF/HF ratio. All HRV measures were categorized into quintiles. Incident stroke was adjudicated through 2011. Cox regression was used to estimate hazard ratios (HRs) with the lowest HRV quintile as the reference, with and without stratification by prevalent diabetes mellitus. RESULTS: Over a median follow-up of 22 years, 816 (6.5%) participants experienced incident stroke. After covariate adjustment, there was no strong evidence of association between HRV and stroke risk. In stratified analyses, the lowest HRV quintile was associated with higher stroke risk compared with the highest quintile for SDNN (HR, 2.0, 95% confidence interval, 1.1-4.0), RMSSD (HR, 1.7; 95% confidence interval, 0.9-3.2), LF (HR, 1.5; 95% confidence interval, 0.8-3.0), and HF (HR, 1.7; 95% confidence interval, 0.9-3.0) only among people with diabetes mellitus. CONCLUSIONS: Lower HRV was associated with higher risk of incident stroke among middle-aged adults with prevalent diabetes mellitus but not among people without diabetes mellitus.

Carotid Atherosclerosis and Stroke in Atrial Fibrillation: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: Whether consideration of carotid intima-media thickness (cIMT) and carotid plaque would improve risk prediction of ischemic stroke in persons with atrial fibrillation (AF) is unknown. The purpose of this study was to assess the improvement in risk prediction of stroke by adding cIMT and carotid plaque to the CHA2DS2-VASc (variables age, heart failure, hypertension, diabetes mellitus, myocardial infarction, and peripheral arterial disease) score. METHODS: We included participants from the Atherosclerosis Risk in Communities (ARIC) study (mean age, 63 years) who developed AF within 5 years after carotid measurement, were not on warfarin, and had no prior stroke at AF diagnosis. AF was ascertained from study ECGs and diagnosis codes, and stroke was physician adjudicated. Multivariable Cox models were used to assess association between carotid indices and ischemic stroke. Improvement in 10-year risk prediction of stroke was assessed by the C-statistic, net reclassification improvement, and relative integrated discrimination improvement. RESULTS: There were 81 (11.2%) stroke events that occurred among 724 participants with AF during a mean follow-up of 8.5 years. Increased cIMT and presence of carotid plaque were significantly associated with increased stroke risk. The addition of cIMT+plaque to the CHA2DS2-VASc score marginally increased the C-statistic (95% confidence interval) from 0.685 (0.623-0.747) to 0.698 (0.638-0.759). The net reclassification improvement and integrated discrimination improvement for cIMT+plaque were 0.091 (95% confidence interval, 0.012-0.170) and 0.101 (95% confidence interval, 0.002-0.226), respectively. CONCLUSIONS: Increased cIMT and presence of carotid plaque are associated with increased risk of ischemic stroke in individuals with AF. Furthermore, they may improve risk prediction of stroke, over and above the CHA2DS2-VASc score.

Serum fibroblast growth factor-23 and incident hypertension: the Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVE: Elevated serum fibroblast growth factor-23 (FGF23), an endogenous hormone, is associated with disturbed mineral homeostasis, cardiovascular disease, and chronic kidney disease. It is unclear whether FGF23 impacts the development of incident hypertension. We examined the association between elevated FGF23 and incident hypertension in a community-based cohort. METHOD: We investigated the association of serum FGF23, measured at baseline (1990-1992), with incident hypertension at two follow-up visits (1993-1995 and 1996-1998) in 7948 middle-aged men and women without hypertension at baseline participating in the Atherosclerosis Risk in Communities Study. Incident hypertension was determined by measured blood pressure (DBP ≥ 90 mmHg or SBP ≥ 140 mmHg) and/or self-reported hypertension medication use at follow-up exams. Complementary log-log models that accounted for interval censoring were used to model the association between FGF23 and incident hypertension. RESULTS: During a median follow-up of 5.9 years, 27% (2152/7948) participants developed hypertension. A nonlinear association between serum FGF23 and incident hypertension was observed; only persons in the highest decile of serum FGF23 had an increased risk of incident hypertension. After adjustment for demographics, behaviors, and adiposity, the hazard ratio for incident hypertension was 1.24 (95% confidence interval: 1.11, 1.39) for the highest decile of FGF23 compared with the lowest quintile. The association was further attenuated in the final model after adjusting for renal function (hazard ratio: 1.21, 95% confidence interval: 1.08, 1.35). CONCLUSION: High levels (≥60.6 pg/ml) of FGF23 are associated with a modestly increased risk of incident hypertension in the general population, independent of kidney function.

Global Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies.

BACKGROUND: Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary. METHODS AND RESULTS: Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3±10.1 years; age range, 44-100 years; 56% female; 77% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (P=0.008), the risk score classified 10-year SCD risk as high (>5%) in 7.2% of participants, 10% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3%. CONCLUSIONS: Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.

Association of Lipid-Related Genetic Variants with the Incidence of Atrial Fibrillation: The AFGen Consortium.

BACKGROUND: Several studies have shown associations between blood lipid levels and the risk of atrial fibrillation (AF). To test the potential effect of blood lipids with AF risk, we assessed whether previously developed lipid gene scores, used as instrumental variables, are associated with the incidence of AF in 7 large cohorts. METHODS: We analyzed 64,901 individuals of European ancestry without previous AF at baseline and with lipid gene scores. Lipid-specific gene scores, based on loci significantly associated with lipid levels, were calculated. Additionally, non-pleiotropic gene scores for high-density lipoprotein cholesterol (HDLc) and low-density lipoprotein cholesterol (LDLc) were calculated using SNPs that were only associated with the specific lipid fraction. Cox models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of AF per 1-standard deviation (SD) increase of each lipid gene score. RESULTS: During a mean follow-up of 12.0 years, 5434 (8.4%) incident AF cases were identified. After meta-analysis, the HDLc, LDLc, total cholesterol, and triglyceride gene scores were not associated with incidence of AF. Multivariable-adjusted HR (95% CI) were 1.01 (0.98-1.03); 0.98 (0.96-1.01); 0.98 (0.95-1.02); 0.99 (0.97-1.02), respectively. Similarly, non-pleiotropic HDLc and LDLc gene scores showed no association with incident AF: HR (95% CI) = 1.00 (0.97-1.03); 1.01 (0.99-1.04). CONCLUSIONS: In this large cohort study of individuals of European ancestry, gene scores for lipid fractions were not associated with incident AF.