Laura R. Loehr

Type 2 diabetes, glucose homeostasis and incident atrial fibrillation: the Atherosclerosis Risk in Communities study

Background Type 2 diabetes has been inconsistently associated with the risk of atrial fibrillation (AF) in previous studies that have frequently been beset by methodological challenges. Design Prospective cohort study. Setting The Atherosclerosis Risk in Communities (ARIC) study. Participants Detailed medical histories were obtained from 13 025 participants. Individuals were categorised as having no diabetes, pre-diabetes or diabetes based on the 2010 American Diabetes Association criteria at study baseline (1990–2). Main outcome measures Diagnoses of incident AF were obtained to the end of 2007. Associations between type 2 diabetes and markers of glucose homeostasis and the incidence of AF were estimated using Cox proportional hazards models after adjusting for possible confounders. Results Type 2 diabetes was associated with a significant increase in the risk of AF (HR 1.35, 95% CI 1.14 to 1.60) after adjustment for confounders. There was no indication that individuals with pre-diabetes or those with undiagnosed diabetes were at increased risk of AF compared with those without diabetes. A positive linear association was observed between HbA1c and the risk of AF in those with and without diabetes (HR 1.13, 95% CI 1.07 to 1.20) and HR 1.05, 95% CI 0.96 to 1.15 per 1% point increase, respectively). There was no association between fasting glucose or insulin in those without diabetes, but a significant association with fasting glucose was found in those with the condition. The results were similar in white subjects and African-Americans. Conclusions Diabetes, HbA1c level and poor glycaemic control are independently associated with an increased risk of AF, but the underlying mechanisms governing the relationship are unknown and warrant further investigation.

Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and its ratio to forced vital capacity (FEV1/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV1/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV1 (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 × 10−8) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

Chronic Kidney Disease Is Associated With the Incidence of Atrial Fibrillation The Atherosclerosis Risk in Communities (ARIC) Study

Background— Chronic kidney disease is associated with the incidence of cardiovascular disease. Chronic kidney disease may also increase the risk of atrial fibrillation (AF), but existing studies have reported inconsistent results. Methods and Results— We estimated cystatin C–based glomerular filtration rate (eGFRcys) and measured urinary albumin-to-creatinine ratio (ACR) in 10 328 men and women free of AF from the Atherosclerosis Risk in Communities (ARIC) Study in 1996 to 1998. Incidence of AF was ascertained through the end of 2007. During a median follow-up of 10.1 years, we identified 788 incident AF cases. Compared with individuals with eGFRcys ≥90 mL · min−1 · 1.73 m−2, multivariable hazard ratios and 95% confidence intervals (CIs) of AF were 1.3 (95% CI, 1.1 to 1.6), 1.6 (95% CI, 1.3 to 2.1), and 3.2 (95% CI, 2.0 to 5.0; P for trend <0.0001) in those with eGFRcys of 60 to 89, 30 to 59, and 15 to 29 mL · min−1 · 1.73 m−2, respectively. Similarly, the presence of macroalbuminuria (ACR ≥300 mg/g; hazard ratio, 3.2; 95% CI, 2.3 to 4.5) and microalbuminuria (ACR, 30 to 299 mg/g; hazard ratio, 2.0; 95% CI, 1.6 to 2.4) was associated with higher AF risk compared with those with ACR <30 mg/g. Risk of AF was particularly elevated in those with both low eGFRcys and macroalbuminuria (hazard ratio, 13.1; 95% CI, 6.0 to 28.6, comparing individuals with ACR ≥300 mg/g and eGFRcys of 15 to 29 mL · min−1 · 1.73 m−2 and those with ACR <30 mg/g and eGFRcys ≥90 mL · min−1 · 1.73 m−2). Conclusion— In this large population-based study, reduced kidney function and presence of albuminuria were strongly associated with the incidence of AF independently of other risk factors. # Clinical Perspective {#article-title-43}Background— Chronic kidney disease is associated with the incidence of cardiovascular disease. Chronic kidney disease may also increase the risk of atrial fibrillation (AF), but existing studies have reported inconsistent results. Methods and Results— We estimated cystatin C–based glomerular filtration rate (eGFRcys) and measured urinary albumin-to-creatinine ratio (ACR) in 10 328 men and women free of AF from the Atherosclerosis Risk in Communities (ARIC) Study in 1996 to 1998. Incidence of AF was ascertained through the end of 2007. During a median follow-up of 10.1 years, we identified 788 incident AF cases. Compared with individuals with eGFRcys ≥90 mL · min−1 · 1.73 m−2, multivariable hazard ratios and 95% confidence intervals (CIs) of AF were 1.3 (95% CI, 1.1 to 1.6), 1.6 (95% CI, 1.3 to 2.1), and 3.2 (95% CI, 2.0 to 5.0; P for trend <0.0001) in those with eGFRcys of 60 to 89, 30 to 59, and 15 to 29 mL · min−1 · 1.73 m−2, respectively. Similarly, the presence of macroalbuminuria (ACR ≥300 mg/g; hazard ratio, 3.2; 95% CI, 2.3 to 4.5) and microalbuminuria (ACR, 30 to 299 mg/g; hazard ratio, 2.0; 95% CI, 1.6 to 2.4) was associated with higher AF risk compared with those with ACR <30 mg/g. Risk of AF was particularly elevated in those with both low eGFRcys and macroalbuminuria (hazard ratio, 13.1; 95% CI, 6.0 to 28.6, comparing individuals with ACR ≥300 mg/g and eGFRcys of 15 to 29 mL · min−1 · 1.73 m−2 and those with ACR <30 mg/g and eGFRcys ≥90 mL · min−1 · 1.73 m−2). Conclusion— In this large population-based study, reduced kidney function and presence of albuminuria were strongly associated with the incidence of AF independently of other risk factors.

Absolute and Attributable Risks of Atrial Fibrillation in Relation to Optimal and Borderline Risk Factors The Atherosclerosis Risk in Communities (ARIC) Study

Background— Atrial fibrillation (AF) is an important risk factor for stroke and overall mortality, but information about the preventable burden of AF is lacking. The aim of this study was to determine what proportion of the burden of AF in blacks and whites could theoretically be avoided by the maintenance of an optimal risk profile. Methods and Results— This study included 14 598 middle-aged Atherosclerosis Risk in Communities (ARIC) Study cohort members. Previously established AF risk factors, namely high blood pressure, elevated body mass index, diabetes mellitus, cigarette smoking, and prior cardiac disease, were categorized into optimal, borderline, and elevated levels. On the basis of their risk factor levels, individuals were classified into 1 of these 3 groups. The population-attributable fraction of AF resulting from having a nonoptimal risk profile was estimated separately for black and white men and women. During a mean follow-up of 17.1 years, 1520 cases of incident AF were identified. The age-adjusted incidence rates were highest in white men and lowest in black women (7.45 and 3.67 per 1000 person-years, respectively). The overall prevalence of an optimal risk profile was 5.4% but varied according to race and gender: 10% in white women versus 1.6% in black men. Overall, 56.5% of AF cases could be explained by having ≥1 borderline or elevated risk factors, of which elevated blood pressure was the most important contributor. Conclusion— As with other forms of cardiovascular disease, more than half of the AF burden is potentially avoidable through the optimization of cardiovascular risk factors levels.

Reduced Kidney Function as a Risk Factor for Incident Heart Failure: The Atherosclerosis Risk in Communities (ARIC) Study

Reduced kidney function is a risk factor for cardiovascular morbidity and mortality, and both heart failure (HF) and kidney failure incidences are increasing. This study therefore sought to determine the effect of decreased kidney function on HF incidence in a population-based study of middle-aged adults. From 1987 through 2002, 14,857 participants of the Atherosclerosis Risk in Communities (ARIC) study who were free of prevalent HF at baseline were followed for incident HF hospitalization or death (International Classification of Diseases, Ninth Revision/10th Revision 428/I50). Estimated GFR (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation, and kidney function was categorized as normal (eGFR > or =90 ml/min per 1.73 m(2); n = 7143), mildly reduced (eGFR 60 to 89 ml/min per 1.73 m(2); n = 7311), and moderately/severely reduced (eGFR <60 ml/min per 1.73 m(2); n = 403). Cox proportional hazards models were used to control for demographic and cardiovascular risk factors; analyses were stratified by the presence of coronary heart disease at baseline. During a mean follow-up of 13.2 yr, 1193 participants developed HF. The incidence of HF was three-fold higher for individuals with eGFR <60 ml/min per 1.73 m(2) compared to the reference group with eGFR > or =90 ml/min per 1.73 m(2) (18 versus 6 per 1000 person-years). The overall adjusted relative hazard of developing HF was 1.94 (1.49 to 2.53) for individuals with eGFR <60 ml/min per 1.73 m(2) compared to the reference group and was significantly increased for individuals with and without prevalent coronary heart disease at baseline. A substantially greater decline in kidney function occurred in individuals concomitant with HF hospitalization/death compared to those who did not develop HF. In summary, middle-aged adults with moderately/severely reduced kidney function are at high risk for developing HF.

Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry : A prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium

Background—Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2 478 304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Methods and Results—Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the ≈2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0×10−7. During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4×10−8), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7×10−8), which was 6.3 kb from LRIG3. Conclusions—We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.Background— Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2 478 304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Methods and Results— Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the ≈2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0×10−7. During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4×10−8), which was 58.8 kb from USP3 . Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7×10−8), which was 6.3 kb from LRIG3 . Conclusions— We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

Association Between Hospitalization for Pneumonia and Subsequent Risk of Cardiovascular Disease

IMPORTANCE The risk of cardiovascular disease (CVD) after infection is poorly understood. OBJECTIVE To determine whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD. DESIGN, SETTINGS, AND PARTICIPANTS We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989-1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15,792; enrollment age, 45-64 years; enrollment period, 1987-1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status. EXPOSURES Hospitalization for pneumonia. MAIN OUTCOMES AND MEASURES Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease). RESULTS Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. CVD risk after pneumonia was highest in the first year. CVD occurred in 54 cases and 6 controls in the first 30 days (HR, 4.07; 95% CI, 2.86-5.27); 11 cases and 9 controls between 31 and 90 days (HR, 2.94; 95% CI, 2.18-3.70); and 22 cases and 55 controls between 91 days and 1 year (HR, 2.10; 95% CI, 1.59-2.60). Additional CVD risk remained elevated into the tenth year, when 4 cases and 12 controls developed CVD (HR, 1.86; 95% CI, 1.18-2.55). In ARIC, of 680 pneumonia cases, 112 had CVD over 10 years after hospitalization. CVD occurred in 4 cases and 3 controls in the first 30 days (HR, 2.38; 95% CI, 1.12-3.63); 4 cases and 0 controls between 31 and 90 days (HR, 2.40; 95% CI, 1.23-3.47); 11 cases and 8 controls between 91 days and 1 year (HR, 2.19; 95% CI, 1.20-3.19); and 8 cases and 7 controls during the second year (HR, 1.88; 95% CI, 1.10-2.66). After the second year, the HRs were no longer statistically significant. CONCLUSIONS AND RELEVANCE Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.

Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

RATIONALE Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. OBJECTIVES Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. METHODS Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations. MEASUREMENTS AND MAIN RESULTS The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. CONCLUSIONS These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

Association of Multiple Anthropometrics of Overweight and Obesity With Incident Heart Failure The Atherosclerosis Risk in Communities Study

Background—The association of central adiposity with incident heart failure (HF) has yet to be studied in a large population-based study. Methods and Results—The Atherosclerosis Risk in Communities study is an ongoing biracial population-based cohort of those aged 45 to 64 years from 4 US communities with 16 years’ median follow-up for incident, hospitalized, or fatal HF. Waist-hip ratio, waist circumference, and body mass index (BMI) were measured at baseline (1987–1989). After exclusions, the sample size was 14 641. BMI was categorized as <25, 25 to 29.9, and ≥30 kg/m2. Waist circumference and waist-hip ratio were divided into gender-specific tertiles. A first occurrence of International Classification of Diseases, 9th Revision, Clinical Modification, codes of HF, either hospital discharge (428.0 to 428.9; n=1451) or on a death certificate (428.0 to 428.9 or I50.0 to I50.9; n=77) was considered an HF event. Cox models were adjusted for alcohol use, smoking, age, center, and educational level. The adjusted hazard ratios for the highest category (obese) compared with the lowest were well above 1.0 for all 3 anthropometric measures (hazard ratio for 3rd versus 1st tertile of waist-hip ratio: 2.27 [1.71, 3.02] for white women; 3.24 [2.25, 4.65] for black women; 2.46 [1.95, 3.09] for white men; and 2.63 [1.90, 3.65] for black men). Hazard ratios for overweight were lower in magnitude, suggesting a graded response between body size and HF. Conclusions—Obesity and overweight, as measured by 3 different anthropometrics, were associated with incident HF in the Atherosclerosis Risk in Communities cohort. The current study does not support the superiority of waist-hip ratio and waist circumference over BMI for the prediction of incident HF.

Incident Heart Failure Is Associated with Lower Whole-Grain Intake and Greater High-Fat Dairy and Egg Intake in the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND Prospective studies evaluating associations between food intake and risk of heart failure (HF) in diverse populations are needed. OBJECTIVES Relationships between incident HF (death or hospitalization) and intake of seven food categories (whole grains, fruits/vegetables, fish, nuts, high-fat dairy, eggs, red meat) were investigated in an observational cohort of 14,153 African-American and white adults, age 45 to 64 years, sampled from four US communities. METHODS Between baseline (1987-1989) and Exam 3 (1993-1995), dietary intake was based on responses to a 66-item food frequency questionnaire administered at baseline; thereafter, intake was based on averaged baseline and Exam 3 responses. Hazard ratios (HR [95% CI]) for HF were calculated per 1-daily serving difference in food group intake. RESULTS During a mean of 13 years, 1,140 HF hospitalizations were identified. After multivariable adjustment (energy intake, demographics, lifestyle factors, prevalent cardiovascular disease, diabetes, hypertension), HF risk was lower with greater whole-grain intake (0.93 [0.87, 0.99]), but HF risk was higher with greater intake of eggs (1.23 [1.08, 1.41]) and high-fat dairy (1.08 [1.01, 1.16]). These associations remained significant independent of intakes of the five other food categories, which were not associated with HF. CONCLUSIONS In this large, population-based sample of African-American and white adults, whole-grain intake was associated with lower HF risk, whereas intake of eggs and high-fat dairy were associated with greater HF risk after adjustment for several confounders.