Anna Kucharska-Newton

HDL-cholesterol and incidence of breast cancer in the ARIC cohort study

PURPOSE An association of low plasma HDL-cholesterol with risk of breast cancer has been suggested by multiple studies; the evidence, however, is not conclusive. We examined the possible association of low HDL-cholesterol with incidence of breast cancer using data from the Atherosclerosis Risk in Communities Study (ARIC) cohort, a prospective study of a randomly selected sample of women and men from four U.S. communities. METHODS Among 7,575 female members of the ARIC cohort, 359 cases of incident breast cancer were ascertained during the follow-up from 1987 through 2000. RESULTS In analysis adjusted for age, race, body mass index, smoking, and reproductive variables, we observed no association of low baseline HDL-cholesterol (<50mg/dL) with incident breast cancer in the total sample (hazard ratio [HR]=1.08 [95% confidence interval (CI), 0.84-1.40]) and a modest association (HR=1.67 [95% CI, 1.06-2.63]) among women who were premenopausal at baseline. No association was observed among women who were postmenopausal at baseline. Removal from analysis of the first 5 years of follow-up did not appreciably change the observed associations. CONCLUSION Results of our study suggest that low HDL-cholesterol among premenopausal women may be a marker of increased breast cancer risk.

The Population Burden of Heart Failure Attributable to Modifiable Risk Factors: The ARIC (Atherosclerosis Risk in Communities) Study

OBJECTIVES The goal of this study was to estimate the population burden of heart failure and the influence of modifiable risk factors. BACKGROUND Heart failure is a common, costly, and fatal disorder, yet few studies have evaluated the population-level influence of modifiable risk factors. METHODS From 14,709 ARIC (Atherosclerosis Risk in Communities) study participants, we estimated incidence rate differences (IRD) for the association between 5 modifiable risk factors (cigarette smoking, diabetes, elevated low-density lipoproteins, hypertension, and obesity) and heart failure. Potential impact fractions were used to measure expected changes in the heart failure incidence assuming achievement of a 5% proportional decrement in the prevalence of each risk factor. RESULTS Over an average of 17.6 years of follow-up, 1 in 3 African American and 1 in 4 Caucasian participants were hospitalized with heart failure, defined as the first hospitalization with International Classification of Diseases, Ninth Revision discharge codes of 428.x. Of the 5 modifiable risk factors, the largest IRD was observed for diabetes, which was associated with 1,058 (95% confidence interval [CI]: 787 to 1,329) and 660 (95% CI: 514 to 805) incident hospitalizations of heart failure/100,000 person-years among African-American and Caucasian participants, respectively. A 5% proportional reduction in the prevalence of diabetes would result in approximately 53 and 33 fewer incident heart failure hospitalizations per 100,000 person-years in African-American and Caucasian ARIC participants, respectively. When applied to U.S. populations, this reduction may prevent approximately 30,000 incident cases of heart failure annually. CONCLUSIONS Modest decrements in the prevalence of modifiable heart failure risk factors such as diabetes may substantially decrease the incidence of this major disease.

Use of Medicare Data to Identify Coronary Heart Disease Outcomes in the Women’s Health Initiative

Background—Data collected as part of routine clinical practice could be used to detect cardiovascular outcomes in pragmatic clinical trials or clinical registry studies. The reliability of claims data for documenting outcomes is unknown. Methods and Results—We linked records of Women’s Health Initiative (WHI) participants aged ≥65 years to Medicare claims data and compared hospitalizations that had diagnosis codes for acute myocardial infarction or coronary revascularization with WHI outcomes adjudicated by study physicians. We then compared the hazard ratios for active versus placebo hormone therapy based solely on WHI-adjudicated events with corresponding hazard ratios based solely on claims data for the same hormone trial participants. Agreement between WHI-adjudicated outcomes and Medicare claims was good for the diagnosis of myocardial infarction (&kgr;, 0.71–0.74) and excellent for coronary revascularization (&kgr;, 0.88–0.91). The hormone:placebo hazard ratio for clinical myocardial infarction was 1.31 (95% confidence interval, 1.03–1.67) based on WHI outcomes and 1.29 (95% confidence interval, 1.00–1.68) based on Medicare data. The hazard ratio for coronary revascularization was 1.09 (95% confidence interval, 0.88–1.35) based on WHI outcomes and 1.10 (95% confidence interval, 0.89–1.35) based on Medicare data. The differences between hazard ratios derived from WHI and Medicare data were not significant in 1000 bootstrap replications. Conclusions—Medicare claims may provide useful data on coronary heart disease outcomes among patients aged ≥65 years in clinical research studies. Clinical Trials Registration Information—URL: www.clinicaltrials.gov. Unique identifier: NCT00000611.

Body mass index at early adulthood, subsequent weight change and cancer incidence and mortality

Obesity later in adulthood is associated with increased risks of many cancers. However, the effect of body fatness in early adulthood, and change in weight from early to later adulthood on cancer risk later in life is less clear. We used data from 13,901 people aged 45–64 in the Atherosclerosis Risk in Communities cohort who at baseline (1987–1989) self‐reported their weight at the age of 25 and had weight and height measured. Incident cancers were identified through 2006 and cancer deaths were ascertained through 2009. Multivariable Cox proportional hazard models were used to relate body mass index (BMI) at age 25 and percent weight change from age 25 to baseline to cancer incidence and mortality. After adjusting for weight change from age 25 until baseline, a 5 kg/m2 increment in BMI at age 25 was associated with a greater risk of incidence of all cancers in women [hazard ratio (95% confidence interval): 1.10 (1.02–1.20)], but not in men. Associations with incident endometrial cancer were strong [1.83 (1.47–2.26)]. After adjusting for BMI at age 25, a 5% increment in weight from age 25 to baseline was associated with a greater risk of incident postmenopausal breast cancer [1.05 (1.02–1.07)] and endometrial cancer [1.09 (1.04–1.14)] in women and incident colorectal cancer [1.05 (1.00–1.10)] in men. Excess weight during young adulthood and weight gain from young to older adulthood may be independently associated with subsequent cancer risk. Excess weight and weight gain in early adulthood should be avoided.

Variation in Rates of Fatal Coronary Heart Disease by Neighborhood Socioeconomic Status: The Atherosclerosis Risk in Communities Surveillance (1992–2002)

PURPOSE Racial and gender disparities in out-of-hospital deaths from coronary heart disease (CHD) have been well-documented, yet disparities by neighborhood socioeconomic status (nSES) have been less systematically studied in US population-based surveillance efforts. METHODS We examined the association of nSES, classified into tertiles, with 3,743 out-of-hospital fatal CHD events, and a subset of 2,191 events classified as sudden, among persons aged 35 to 74 years in four US communities under surveillance by the Atherosclerosis Risk in Communities (ARIC). Poisson generalized linear mixed models generated age-, race- (white, black) and gender-specific standardized mortality rate ratios and 95% confidence intervals (RR, 95% CI). RESULTS Regardless of nSES measure used, inverse associations of nSES with all out-of-hospital fatal CHD and sudden fatal CHD were seen in all race-gender groups. The magnitude of these associations was larger among women than men. Further, among blacks, associations of low nSES (vs. high nSES) were stronger for sudden cardiac deaths (SCD) than for all out-of-hospital fatal CHD. CONCLUSIONS Low nSES was associated with an increased risk of out-of-hospital CHD death and SCD. Measures of the neighborhood context are useful tools in population-based surveillance efforts for documenting and monitoring socioeconomic disparities in mortality over time.

Socioeconomic Indicators and the Risk of Acute Coronary Heart Disease Events: Comparison of Population-Based Data from the United States and Finland

PURPOSE We wished to determine whether a gradient of association of low socioeconomic status with incidence of coronary heart disease was present in two population-based cohorts, one from United States and the other from Finland. METHODS Using data from the Atherosclerosis Risk in Communities (ARIC) cohort and the Finnish FINRISK cohort, we estimated, with Cox proportional hazard regression models, incidence of sudden cardiac death (SCD), non-sudden cardiac death (NSCD), and non-fatal myocardial infarction (NFMI) for strata of income and education (follow-up: 1987-2001). In both cohorts, incidence rates of the three outcomes increased across all socioeconomic status exposure categories. RESULTS Low education was associated with increased hazard of NFMI in both cohorts and with increased risk of SCD among ARIC women. Low income was significantly associated with increased hazard of all three outcomes among ARIC women and with increased hazard of cardiac death among ARIC men. In FINRISK, low income was significantly associated with increased risk of SCD only. Risk of SCD in the low income categories was similar for both cohorts. Smoking, alcohol consumption, and race (ARIC only) did not appreciably alter effect estimates in either cohort. CONCLUSIONS Indices of low SES show similar associations with increased risk of cardiac events in Finland and in United States.

HDL-cholesterol and the incidence of lung cancer in the Atherosclerosis Risk in Communities (ARIC) study

SUMMARY This study examined prospectively the association of baseline plasma HDL-cholesterol levels with incidence of lung cancer in 14,547 members of the Atherosclerosis Risk in Communities (ARIC) cohort. There were 259 cases of incident lung cancer identified during follow-up from 1987 through 2000. Results of this study indicated a relatively weak inverse association of HDL-cholesterol with lung cancer that was dependent on smoking status. The hazard ratio of lung cancer incidence in relation to low HDL-cholesterol, adjusted for race, gender, exercise, alcohol consumption, body mass index, triglycerides, age, and cigarette pack-years of smoking, was 1.45 (95% confidence interval 1.10, 1.92). This association was observed among former smokers (hazard ratio: 1.77, 95% confidence interval 1.05, 2.97), but not current smokers. The number of cases among never smokers in this study was too small (n=13) for meaningful interpretation of effect estimates. Excluding cases occurring within 5 years of baseline did not appreciably change the point estimates, suggesting lack of reverse causality. The modest association of low plasma HDL-cholesterol with greater incident lung cancer observed in this study is in agreement with existing case-control studies.

Hemostasis, Inflammation, and Fatal and Nonfatal Coronary Heart Disease. Long-Term Follow-Up of the Atherosclerosis Risk in Communities (ARIC) Cohort

Objective—This study examines the hypothesis that chronic inflammation is associated with a higher risk of cardiac death compared to the risk of nonfatal myocardial infarction. Methods and Results—Cardiac death and nonfatal MI events were identified in the ARIC cohort during follow-up from 1987 through 2001. Markers of inflammation and hemostasis were determined at baseline using standardized procedures. Cox proportional hazard regression and polytomous logistic regression were used to estimate associations. We observed a positive gradient in incidence of sudden cardiac death (SCD), nonsudden cardiac death (NSCD), and nonfatal MI in association with decreasing levels of albumin and increasing levels of white blood cell count and of markers of hemostasis (fibrinogen, von Willebrand factor, factor VIIIc). Associations for von Willebrand factor were stronger for fatal relative to nonfatal events (3rd versus 1st tertile hazard ratios: SCD 3.11 [95% CI 2.10, 4.59], NSCD 2.12 [95% CI 1.28, 3.49], nonfatal MI 1.42 [95% CI 1.19, 1.70]). For factor VIIIc those associations were strongest for sudden cardiac death: SCD 3.16 (95% CI 2.18, 4.58), NSCD 1.44 (95% CI 0.93, 2.24), nonfatal MI 1.54 (95% CI 1.29, 1.84). Gradients of association for fibrinogen and white blood cell count, examined over tertiles of distribution and per one SD increase, were similar for the 3 end points. All associations were independent of smoking status. Conclusion—von Willebrand factor and factor VIIIc are associated with an increased risk of cardiac death as compared to the risk of nonfatal MI.

Association of the platelet GPIIb/IIIa polymorphism with atherosclerotic plaque morphology: the Atherosclerosis Risk in Communities (ARIC) Study.

OBJECTIVES Platelet activation and aggregation play an important role in the pathogenesis of cardiovascular disease. We examined the association of a single nucleotide polymorphism (SNP) in the GPIIIa platelet glycoprotein (Leu33Pro) with carotid artery plaque morphology and with expression of platelet markers using data from the Atherosclerosis Risk in Communities (ARIC) Carotid MRI study. METHODS The study sample consisted of 1202 Caucasian members of the ARIC study cohort recruited in 2004-2005 to participate in the Carotid MRI Substudy under stratified sampling based on maximum carotid artery wall thickness. The Leu33Pro polymorphism was identified as SNP rs5918 in the ITGB3 gene. Plaque visualization was accomplished with contrast enhanced MRI examination of the thickest segment of the carotid artery. Expression of platelet markers was measured using fasting whole blood flow cytometry. RESULTS This cross-sectional analysis based on age and gender adjusted weighted linear regression models suggests that those homozygous for the Leu33Pro risk allele (C) have decreased mean and minimum fibrous cap thickness. We did not observe differences in plaque lipid volume or maximum carotid artery wall thickness across SNP rs5918 genotypes. Carriers of the Leu33Pro polymorphism, as compared to major allele homozygotes, had greater percent of platelets expressing P-selectin, a platelet glycoprotein indicating activation status. Prevalent coronary heart disease did not affect estimates of fibrous cap thickness or of platelet activation. CONCLUSION Our results suggest that individuals with Leu33Pro polymorphism of the GPIIIa glycoprotein may be predisposed to increased risk of atherosclerotic plaque rupture.

Electrocardiographic Predictors of Coronary Heart Disease and Sudden Cardiac Deaths in Men and Women Free From Cardiovascular Disease in the Atherosclerosis Risk in Communities Study

Background We evaluated predictors of coronary heart disease (CHD) death and sudden cardiac death (SCD) in the Atherosclerosis Risk in Communities (ARIC) study. Methods and Results The study population included 13 621 men and women 45 to 65 years of age free from manifest cardiovascular disease at entry. Hazard ratios from Cox regression with 95% confidence intervals were computed for 18 dichotomized repolarization‐related ECG variables. The average follow‐up was 14 years. Independent predictors of CHD death in men were TaVR‐ and rate‐adjusted QTend (QTea), with a 2‐fold increased risk for both, and spatial angles between mean QRS and T vectors and between Tpeak (Tp) and normal R reference vectors [θ(Rm|Tm) and θ(Tp|Tref), respectively], with a >1.5‐fold increased risk for both. In women, independent predictors of the risk of CHD death were θ(Rm|Tm), with a 2‐fold increased risk for θ(Rm|Tm), and θ(Tp|Tref), with a 1.7‐fold increased risk. Independent predictors of SCD in men were θ(Tp|Tref) and QTea, with a 2‐fold increased risk, and θ(Tinit|Tterm), with a 1.6‐fold increased risk. In women, θ(Tinit|Tterm) was an independent predictor of SCD, with a >3‐fold increased risk, and θ(Rm|Tm) and TV1 were >2‐fold for both. Conclusions θ(Rm|Tm) and θ(Tp|Tref), reflecting different aspects of ventricular repolarization, were independent predictors of CHD death and SCD, and TaVR and TV1 were also independent predictors. The risk levels for independent predictors for both CHD death and SCD were stronger in women than in men, and QTea was a significant predictor in men but not in women.