Ronald J. Prineas

Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures.To test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures.Randomized, blinded, placebo-controlled trial.Eleven community-based clinical research centers.Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later).All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial.Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry.Alendronate increased BMD at all sites studied (P<.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (>2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects.In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.

The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.

The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study is a national, population-based, longitudinal study of 30,000 African-American and white adults aged > or =45 years. The objective is to determine the causes for the excess stroke mortality in the Southeastern US and among African-Americans. Participants are randomly sampled with recruitment by mail then telephone, where data on stroke risk factors, sociodemographic, lifestyle, and psychosocial characteristics are collected. Written informed consent, physical and physiological measures, and fasting samples are collected during a subsequent in-home visit. Participants are followed via telephone at 6-month intervals for identification of stroke events. The novel aspects of the REGARDS study allow for the creation of a national cohort to address geographic and ethnic differences in stroke.

The role of dietary antioxidant vitamins in preventing coronary heart disease has aroused considerable interest because of the knowledge that oxidative modification of low-density lipoprotein may promote atherosclerosis.We studied 34,486 postmenopausal women with no cardiovascular disease who in early 1986 completed a questionnaire that assessed, among other factors, their intake of vitamins A, E, and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease.In analyses adjusted for age and dietary energy intake, vitamin E consumption appeared to be inversely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and 0.42; P for trend 0.008). After adjustment for possible confounding variables, this inverse association remained (relative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend, 0.004). There was little evidence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementation and the duration of supplement use could not be definitely addressed. Intake of vitamins A and C did not appear to be associated with the risk of death form coronary heart disease.These results suggest that in postmenopausal women the intake of vitamin E from food is inversely associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease.

Insulin resistance may be an important cause of a constellation of cardiovascular risk factors in adults, and onset of this syndrome may occur in childhood. However, children normally experience transient insulin resistance at puberty. There were 357 normal children (159 girls, 198 boys) age 10-14 years who underwent euglycemic clamp studies to assess the effects of Tanner stage (T), sex, ethnicity, and BMI on insulin resistance. Insulin resistance increased immediately at the onset of puberty (T2), but returned to near prepubertal levels by the end of puberty (T5). Its peak occurred at T3 in both sexes, and girls were more insulin resistant than boys at all T stages. White boys appeared to be more insulin resistant than black boys; no difference was seen between white and black girls. Insulin resistance was strongly related to BMI, triceps skinfold thickness, and waist circumference, and this relationship was independent of Tanner stage or sex. Differences in BMI and adiposity did not, however, entirely explain the insulin resistance of puberty. These results demonstrate that 1) significant differences in insulin resistance are present between boys and girls; 2) insulin resistance increases significantly at T2, T3, and T4, but decreases to near prepubertal levels at T5; and 3) while insulin resistance is related to BMI and anthropometric measures of fatness, these factors do not completely explain the insulin resistance that occurs during the Tanner stages of puberty.

HomeCirculationVol. 108, No. 20Case Definitions for Acute Coronary Heart Disease in Epidemiology and Clinical Research Studies

Background: Recent clinical guidelines on the health risks of obesity use body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) and waist circumference, but the waist-hip ratio may provide independent information. Methods:To assess the joint and relative associations of BMI, waist circumference, and waist-hip ratio with multiple disease end points, we conducted a prospective cohort study of 31 702 Iowa women, aged 55 to 69 years and free of cancer, heart disease, and diabetes, assembled by random sampling and mail survey in 1986.Study end points were total and cause-specific mortality and incidence of site-specific cancers and self-reported diabetes, hypertension, and hip fracture over 11 to 12 years. Results:The waist-hip ratio was the best anthropometric predictor of total mortality, with the multivariableadjusted relative risk for quintile 5 vs 1 of 1.2 (95% confidence interval, 1.1-1.4),compared with 0.91 (95% confidence interval, 0.8-1.0)for BMI and 1.1 (95% confidence interval, 1.0-1.3)for waist circumference.The waist-hip ratio was also associated positively with mortality from coronary heart disease, other cardiovascular diseases, cancer, and other causes.The waist-hip ratio was associated less consistently than BMI or waist circumference with cancer incidence.All anthropometric indexes were associated with incidence of diabetes and hypertension.For example, women simultaneously in the highest quintiles of BMI and waist-hip ratio had a relative risk of diabetes of 29 (95% confidence interval, 18-46) vs women in the lowest combined quintiles. Conclusion:The waist-hip ratio offers additional prognostic information beyond BMI and waist circumference.

Journal Article COMPARISON OF SELF-REPORTED AND MEASURED HEIGHT AND WEIGHT Get access MARI PALTA, MARI PALTA 1Dept. of Preventive Medicine, University of IowaIowa City, LA 52242 Please send reprint requests to Dr. Palta at this address. Search for other works by this author on: Oxford Academic PubMed Google Scholar RONALD J PRINEAS, RONALD J PRINEAS 2Laboratory of Physiological Hygiene, School of Public Health, University of MinnesotaMinneapolis, MN Search for other works by this author on: Oxford Academic PubMed Google Scholar REUBEN BERMAN, REUBEN BERMAN 3Clinical Studies Center, Mount Smai HospitalMinneapolis, MN Search for other works by this author on: Oxford Academic PubMed Google Scholar PETER HANNAN PETER HANNAN 2Laboratory of Physiological Hygiene, School of Public Health, University of MinnesotaMinneapolis, MN Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, Volume 115, Issue 2, February 1982, Pages 223–230, https://doi.org/10.1093/oxfordjournals.aje.a113294 Published: 01 February 1982 Article history Received: 27 March 1981 Revision received: 25 June 1981 Published: 01 February 1982

<h3>Objective.</h3> —To test the hypothesis that both body mass index (expressed as the ratio of weight in kilograms per height in meters squared) and the ratio of waist circumference to hip circumference are positively associated with mortality risk in older women. <h3>Design.</h3> —Prospective cohort study with a 5-year follow-up period. <h3>Setting.</h3> —General community. <h3>Participants.</h3> —Random sample of 41 837 Iowa women aged 55 to 69 years. <h3>Main Outcome Measure.</h3> —Total mortality (1504 deaths). <h3>Main Results.</h3> —Body mass index, an index of relative weight, was associated with mortality in a J-shaped fashion: rates were elevated in the leanest as well as in the most obese women. In contrast, waist/hip circumference ratio was strongly and positively associated with mortality in a dose-response manner. Adjusted for age, body mass index, smoking, education level, marital status, estrogen use, and alcohol use, a 0.15-unit increase in waist/hip circumference ratio (eg, a 15-cm [6-in] increase in waist measurement in a woman with 100-cm [40-in] hips) was associated with a 60% greater relative risk of death. The observed associations were not explained to any great degree by bias from weight loss prior to baseline or higher early deaths among lean participants. <h3>Conclusions.</h3> —Waist/hip circumference ratio is a better marker than body mass index of risk of death in older women. Waist/hip circumference ratio should be measured as part of routine surveillance and risk monitoring in medical practice. <i>JAMA</i>. 1993;269:483-487)

To define the incidence and cumulative risk of atrial fibrillation (AF) in a population-based cohort of whites and African Americans. African-Americans reportedly have a lower risk of AF than whites despite their higher exposure to AF risk factors. However, precise estimates of AF incidence in African Americans have not been previously published. We studied the incidence of AF in the Atherosclerosis Risk in Communities (ARIC) study, which has followed up 15,792 men and women 45 to 65 years of age at baseline from 4 communities in the United States since 1987. Atrial fibrillation cases were identified from electrocardiograms conducted at baseline and 3 follow-up visits, and from hospitalizations and death certificates through the end of 2004. During follow-up, 1,085 new cases of AF were identified (196 in African Americans, 889 in whites). Crude incidence rates of AF were 6.7, 4.0, 3.9, and 3.0 per 1,000 persons per year in white men, white women, African-American men, and African-American women, respectively. Increasing age was exponentially associated with an elevated risk of AF. Compared to whites, African-Americans had a 41% (95% CI: 8%-62%) lower age- and sex-adjusted risk of being diagnosed with AF. The cumulative risk of AF at 80 years of age was 21% in white men, 17% in white women, and 11% in African-American men and women. In this population-based cohort, African Americans presented a lower risk of AF than whites. Still, the burden of AF among the former is substantial, with 1 in 9 receiving a diagnosis of AF before 80 years of age.

Rates of cardiovascular disease (CVD) among American Indians (AI) have been increasing. Although we have observed an association between atherosclerosis and CVD in older adults, the potential association among young AI is unclear. Therefore, we aim to describe the prevalence of atherosclerosis among young AI and determine its association with CVD and all-cause mortality.We evaluated AI participants from the Strong Heart Family Study (SHFS), who were <40 years old and CVD free at the baseline examination, 2001–2003 (n = 1376). We used carotid ultrasound to detect baseline atherosclerotic plaque. We identified CVD events and all-cause mortality through 2019, with a median follow-up of 17.8 years. We used shared frailty Cox Proportional Hazards models to assess the association between atherosclerosis and time to CVD event or all-cause mortality, while controlling for covariates.Among 1376 participants, 71 (5.2%) had atherosclerosis at baseline. During follow-up, 120 (8.7%) had CVD events and 104 (7.6%) died from any cause. CVD incidence was higher in participants who had baseline atherosclerosis (13.51/1000 person-years) than in those who did not (4.95/1000 person-years, p = 0.0003). CVD risk and all-cause mortality were higher in participants with atherosclerosis, while controlling for covariates (CVD HR = 1.85, 95%CI = 1.02–3.37, p = 0.0420; all-cause mortality HR = 2.04, 95%CI = 1.07–3.89, p = 0.0291).Among young AI, atherosclerosis was independently associated with incident CVD and all-cause mortality later in life. Thus, atherosclerosis begins early in life and interventions in adolescents and young adults to slow the progression of disease could prevent or delay CVD events later in life.

The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1(st) quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.

OBJECTIVE Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. RESEARCH DESIGN AND METHODS CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates. RESULTS During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55–2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P &amp;lt; 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (Pinteraction &amp;gt; 0.7). CONCLUSIONS Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

Problems with sexual function have been a long-standing concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. The Treatment of Mild Hypertension Study (TOMHS) provides an excellent opportunity for examination of sexual function and effects of treatment on sexual function in men and women with stage I diastolic hypertension because of the number of drug classes studied, the double-blind study design, and the long-term follow-up. TOMHS was a double-blind, randomized controlled trial of 902 hypertensive individuals (557 men, 345 women), aged 45 to 69 years, treated with placebo or one of five active drugs (acebutolol, amlodipine maleate, chlorthalidone, doxazosin maleate, or enalapril maleate). All participants received intensive lifestyle counseling regarding weight loss, dietary sodium reduction, alcohol reduction (for current drinkers), and increased physical activity. Sexual function was ascertained by physician interviews at baseline and annually during follow-up. At baseline, 14.4% of men and 4.9% of women reported a problems with sexual function. In men, 12.2% had problems obtaining and/or maintaining an erection; 2.0% of women reported a problem having an orgasm. Erection problems in men at baseline were positively related to age, systolic pressure, and previous antihypertensive drug use. The incidences of erection dysfunction during follow-up in men were 9.5% and 14.7% through 24 and 48 months, respectively, and were related to type of antihypertensive therapy. Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months than participants randomized to placebo (17.1% versus 8.1%, P = .025). Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between the chlorthalidone and placebo groups. Incidence was lowest in the doxazosin group but was not significantly different from the placebo group. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group. In many cases, erection dysfunction did not require withdrawal of medication. Disappearance of erection problems among men with problems at baseline was common in all groups but greatest in the doxazosin group. Incidence of reported sexual problems in women was low in all treatment groups. In conclusion, long-term incidence of erection problems in treated hypertensive men is relatively low but is higher with chlorthalidone treatment. Effects of erection dysfunction with chlorthalidone appear relatively early and are often tolerable, and new occurrences after 2 years are unlikely. The rate of reported sexual problems in hypertensive women is low and does not appear to differ by type of drug. Similar incidence rates of erection dysfunction in placebo and most active drug groups caution against routine attribution of erection problems to antihypertensive medication.

Dysregulation of the autonomic nervous system has been implicated in the development of hypertension. Heart rate variability is a noninvasive tool to quantitatively estimate cardiac autonomic activity and has been used to document decreased cardiac autonomic activity in hypertension. The ability of decreased heart rate variability to predict incident hypertension has not been well studied, and there are no studies of whether hypertension leads to changes in heart rate variability. We investigated the temporal sequence linking hypertension, blood pressure, and heart rate variability in a population-based cohort of 11 061 individuals aged 45 to 54 years at baseline. Individuals with hypertension had decreased heart rate variability at baseline, and this association was present across the full blood pressure range. Among 7099 individuals without hypertension at baseline, low heart rate variability predicted greater risk of incident hypertension over 9 years of follow-up. The hazard ratio (95% confidence interval [CI]) for the lowest compared with the highest quartile of the standard deviation of normal-to-normal R-R intervals was 1.24 (95% CI, 1.10-1.40), for the root mean square of successive differences in normal-to-normal R-R intervals was 1.36 (95% CI, 1.21-1.54), and for R-R interval was 1.44 (95% CI, 1.27-1.63). Over 9 years, there was no measurable difference in the rate of change in heart rate variability among those with and without hypertension, although the differences in heart rate variability at follow-up were smaller than those at baseline. These findings thus support the thesis that the autonomic nervous system is involved in the development of hypertension, yet suggest that differences in the autonomic profile of hypertensives and normotensives do not increase with time.

The epidemiology of atrial fibrillation (AF) has been mainly investigated in patients with end-stage renal disease, with limited data on less advanced chronic kidney disease (CKD) stages. A total of 3,267 adult participants (50% non-Hispanic blacks, 46% women) with CKD from the Chronic Renal Insufficiency Cohort were included in this study. None of the study participants had been on dialysis. Those with self-identified race/ethnicity other than non-Hispanic black or white (n = 323) or those without electrocardiographic data (n = 22) were excluded. Atrial fibrillation was ascertained by a 12-lead electrocardiogram and self-report. Age-, sex-, and race/ethnicity-specific prevalence rates of AF were estimated and compared between subgroups. Cross-sectional associations and correlates with prevalent AF were examined using unadjusted and multivariable-adjusted logistic regression analysis. The mean estimated glomerular filtration rate was 43.6 (±13.0) mL/(min 1.73 m2). Atrial fibrillation was present in 18% of the study population and in >25% of those ≥70 years old. In multivariable-adjusted models, 1-SD increase in age (11 years) (odds ratio 1.27, CI 95% 1.13-1.43, P < .0001), female sex (0.80, 0.65-0.98, P = .0303), smoking (former vs never) (1.34, 1.08-1.66, P = .0081), history of heart failure (3.28, 2.47-4.36, P < .001), and history of cardiovascular disease (1.94, 1.56-2.43, P < .0001) were significantly associated with AF. Race/ethnicity, hypertension, diabetes, body mass index, physical activity, education, high-sensitivity C-reactive protein, total cholesterol, and alcohol intake were not significantly associated with AF. An estimated glomerular filtration rate <45 mL/(min 1.73 m2) was associated with AF in an unadjusted model (1.35, 1.13-1.62, P = .0010), but not after multivariable adjustment (1.12, 0.92-1.35, P = .2710). Nearly 1 in 5 participants in Chronic Renal Insufficiency Cohort, a national study of CKD, had evidence of AF at study entry, a prevalence similar to that reported among patients with end-stage renal disease and 2 to 3 times of that reported in the general population. Risk factors for AF in this CKD population do not mirror those reported in the general population.

It has been recommended that body mass index (BMI) (weight in kilograms/height in meter2) be used routinely to evaluate obesity in children and adolescents. This report describes the distribution of BMI in children and adolescents in the United States.Standardized measurements of height and weight from 9 large epidemiologic studies including 66,772 children age 5 to 17 years were used to develop tables for the distributions of BMI that are age, race, and gender specific.The mean BMI increases with age and is slightly higher for girls than boys. Mean BMI for black and Hispanic girls was noticeably higher than for white girls. The percentiles of BMI are consistently higher than those based on the NHANES I measures, particularly for the 95th percentile. The proportion of obese children compared with NHANES I standards is higher and is highest for Hispanic boys and black and Hispanic girls.The tables and figures will allow pediatricians to determine the relative ranking of BMI for patients compared with values derived from a large sample of healthy children and adolescents. The identified gender and ethnic differences may be guides to understanding the cause and prevention of obesity.

Weight gain is of concern during early development because adult obesity and its cardiovascular consequences appear to have their origins during childhood. Insulin resistance is known to be related to obesity. Thus, weight gain beginning in childhood may influence the development of insulin-induced cardiovascular risk during adulthood.We monitored 679 individuals from 7.7+/-0.1 years of age with repeated measures of height, weight, and systolic blood pressure (SBP) until 23.6+/-0.2 years of age, when blood samples were obtained for measurements of insulin and lipids. Initial childhood weight, body mass index (BMI), and height were significantly correlated with young adult weight, BMI, and height and with fasting insulin, lipids, and SBP. The increases in weight and BMI but not height during childhood were significantly related to the young adult levels of insulin, lipids, and SBP.These data suggest that weight gain in excess of normal growth during childhood is a determinant of adult cardiovascular risk. The finding in multiple linear regression analysis that weight gain during childhood rather than the childhood weight at 7.7 years of age is significantly related to young adult risk factors suggests that a reduction in weight gain could reduce subsequent levels of cardiovascular risk.

Arne Pfeufer, Aravinda Chakravarti and colleagues from the QTSCD consortium report genetic associations influencing the QT interval duration, a measure of cardiac repolarization which is a risk factor for sudden cardiac death, in five genome-wide association studies. The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10−8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.

Epidemiologic studies have established that increased body weight is associated with a greater incidence of breast cancer in postmenopausal women. The authors hypothesized that abdominal adiposity further increases risk of postmenopausal breast cancer. They therefore investigated the waist-to-hip circumference ratio in relation to breast cancer incidence in a nested case-control study of 41,837 postmenopausal Iowa women aged 55-69 years. Women were recruited through a mail survey in January 1986 and were asked to have someone measure their body circumferences using a paper tape measure and written instructions. Cancer incidence was ascertained using a statewide cancer registry. A total of 229 incident breast cancers occurred among at-risk women during the first 2 years of follow-up (1986-1987). Compared with randomly selected controls (n = 1,839), women with incident breast cancer had a higher age-adjusted mean waist-to-hip ratio (by 0.013 units, p = 0.030), as well as greater mean weight (by 1.7 kg, p = 0.07), body mass index (by 0.6 kg/m2, p = 0.08), and weight gain since age 18 (by 2.7 kg, p less than 0.01). In multiple logistic regression models, age and current body mass index were significant effect modifiers of the association between the waist-to-hip ratio and breast cancer. A two-standard deviation increase in the waist-to-hip ratio (0.168 units) was associated with no increase in the relative risk of breast cancer in younger and lighter postmenopausal women. However, in older, heavier postmenopausal women, the same increase in the waist-to-hip ratio carried greater than a twofold excess relative risk. Adjustment for other breast cancer risk factors did not materially alter this finding. Two plausible explanations for elevated breast cancer incidence in women with abdominal adiposity include 1) increased concentrations of non-protein-bound estrogens due to reduced sex hormone binding globulin, or 2) increased conversion of adrenal androgens to estrone with abdominal adiposity.

ContextIt is unknown whether long-standing disparities in incidence of coronary heart disease (CHD) among US blacks and whites persist.Objective To examine incident CHD by black and white race and by sex. Design, Setting, and Participants Prospective cohort study of 24 443 participants without CHD at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, who resided in the continental United States and were enrolled between 2003 and 2007 with follow-up through December 31, 2009.Main Outcome Measure Expert-adjudicated total (fatal and nonfatal) CHD, fatal CHD, and nonfatal CHD (definite or probable myocardial infarction [MI]; very small non-ST-elevation MI [NSTEMI] had peak troponin level Ͻ0.5 µg/L).Results Over a mean (SD) of 4.2 (1.5) years of follow-up, 659 incident CHD events occurred (153 in black men, 138 in black women, 254 in white men, and 114 in white women).Among men, the age-standardized incidence rate per 1000 person-years for total CHD was 9.0 (95% CI, 7.5-10.8)for blacks vs 8.1 (95% CI, 6.9-9.4) for whites; fatal CHD: 4.0 (95% CI, 2.9-5.3)vs 1.9 (95% CI, 1.4-2.6),respectively; and nonfatal CHD: 4.9 (95% CI, 3.8-6.2) vs 6.2 (95% CI, 5.2-7.4).Among women, the age-standardized incidence rate per 1000 person-years for total CHD was 5.0 (95% CI, 4.2-6.1)for blacks vs 3.4 (95% CI, 2.8-4.2) for whites; fatal CHD: 2.0 (95% CI, 1.5-2.7)vs 1.0 (95% CI, 0.7-1.5),respectively; and nonfatal CHD: 2.8 (95% CI, 2.2-3.7)vs 2.2 (95% CI, 1.7-2.9).Age-and regionadjusted hazard ratios for fatal CHD among blacks vs whites was near 2.0 for both men and women and became statistically nonsignificant after multivariable adjustment.The multivariable-adjusted hazard ratio for incident nonfatal CHD for blacks vs whites was 0.68 (95% CI, 0.51-0.91)for men and 0.81 (95% CI, 0.58-1.15)for women.Of the 444 nonfatal CHD events, 139 participants (31.3%) had very small NSTEMIs. ConclusionsThe higher risk of fatal CHD among blacks compared with whites was associated with cardiovascular disease risk factor burden.These relationships may differ by sex.

Background and Purpose— The paradox of the reported low prevalence of atrial fibrillation (AF) in blacks compared with whites despite higher stroke rates in the former could be related to limitations in the current methods used to diagnose AF in population-based studies. Hence, this study aimed to use the ethnic distribution of ECG predictors of AF as measures of AF propensity in different ethnic groups. Methods— The distribution of baseline measures of P-wave terminal force, P-wave duration, P-wave area, and PR duration (referred to as AF predictors) were compared by ethnicity in 15 429 participants (27% black) from the Atherosclerosis Risk in Communities (ARIC) study by unpaired t test, χ 2 , and logistic-regression analysis, as appropriate. Cox proportional-hazards analysis was used to separately examine the association of AF predictors with incident AF and ischemic stroke. Results— Whereas AF was significantly less common in blacks compared with whites (0.24% vs 0.95%, P &lt;0.0001), similar to what has been reported in previous studies, blacks had significantly higher and more abnormal values of AF predictors ( P &lt;0.0001 for all comparisons). Black ethnicity was significantly associated with abnormal AF predictors compared with whites; odds ratios for different AF predictors ranged from 2.1 to 3.1. AF predictors were significantly and independently associated with AF and ischemic stroke with no significant interaction between ethnicity and AF predictors, findings that further justify using AF predictors as an earlier indicator of future risk of AF and stroke. Conclusions— There is a disconnect between the ethnic distribution of AF predictors and the ethnic distribution of AF, probably because the former, unlike the latter, do not suffer from low sensitivity. These results raise the possibility that blacks might actually have a higher prevalence of AF that might have been missed by previous studies owing to limited methodology, a difference that could partially explain the greater stroke risk in blacks.

Childhood cardiovascular risk factors predict subclinical adult cardiovascular disease, but links to clinical events are unclear.In a prospective cohort study involving participants in the International Childhood Cardiovascular Cohort (i3C) Consortium, we evaluated whether childhood risk factors (at the ages of 3 to 19 years) were associated with cardiovascular events in adulthood after a mean follow-up of 35 years. Body-mass index, systolic blood pressure, total cholesterol level, triglyceride level, and youth smoking were analyzed with the use of i3C-derived age- and sex-specific z scores and with a combined-risk z score that was calculated as the unweighted mean of the five risk z scores. An algebraically comparable adult combined-risk z score (before any cardiovascular event) was analyzed jointly with the childhood risk factors. Study outcomes were fatal cardiovascular events and fatal or nonfatal cardiovascular events, and analyses were performed after multiple imputation with the use of proportional-hazards regression.In the analysis of 319 fatal cardiovascular events that occurred among 38,589 participants (49.7% male and 15.0% Black; mean [±SD] age at childhood visits, 11.8±3.1 years), the hazard ratios for a fatal cardiovascular event in adulthood ranged from 1.30 (95% confidence interval [CI], 1.14 to 1.47) per unit increase in the z score for total cholesterol level to 1.61 (95% CI, 1.21 to 2.13) for youth smoking (yes vs. no). The hazard ratio for a fatal cardiovascular event with respect to the combined-risk z score was 2.71 (95% CI, 2.23 to 3.29) per unit increase. The hazard ratios and their 95% confidence intervals in the analyses of fatal cardiovascular events were similar to those in the analyses of 779 fatal or nonfatal cardiovascular events that occurred among 20,656 participants who could be evaluated for this outcome. In the analysis of 115 fatal cardiovascular events that occurred in a subgroup of 13,401 participants (31.0±5.6 years of age at the adult measurement) who had data on adult risk factors, the adjusted hazard ratio with respect to the childhood combined-risk z score was 3.54 (95% CI, 2.57 to 4.87) per unit increase, and the mutually adjusted hazard ratio with respect to the change in the combined-risk z score from childhood to adulthood was 2.88 (95% CI, 2.06 to 4.05) per unit increase. The results were similar in the analysis of 524 fatal or nonfatal cardiovascular events.In this prospective cohort study, childhood risk factors and the change in the combined-risk z score between childhood and adulthood were associated with cardiovascular events in midlife. (Funded by the National Institutes of Health.).

Background— Race and sex differences in silent myocardial infarction (SMI) are not well established. Methods and Results— The analysis included 9498 participants from the Atherosclerosis Risk in Communities (ARIC) study who were free of cardiovascular disease at baseline (visit 1, 1987–1989). Incident SMI was defined as ECG evidence of MI without clinically documented MI (CMI) after the baseline until ARIC visit 4 (1996–1998). Coronary heart disease and all-cause deaths were ascertained starting from ARIC visit 4 until 2010. During a median follow-up of 8.9 years, 317 participants (3.3%) developed SMI and 386 (4.1%) developed CMI. The incidence rates of both SMI and CMI were higher in men (5.08 and 7.96 per 1000-person years, respectively) than in women (2.93 and 2.25 per 1000-person years, respectively; P &lt;0.0001 for both). Blacks had a nonsignificantly higher rate of SMI than whites (4.45 versus 3.69 per 1000-person years; P =0.217), but whites had higher rate of CMI than blacks (5.04 versus 3.24 per 1000-person years; P =0.002). SMI and CMI (compared with no MI) were associated with increased risk of coronary heart disease death (hazard ratio, 3.06 [95% confidence interval, 1.88–4.99] and 4.74 [95% confidence interval, 3.26–6.90], respectively) and all-cause mortality (hazard ratio, 1.34 [95% confidence interval, 1.09–1.65] and 1.55 [95% confidence interval, 1.30–1.85], respectively). However, SMI and CMI were associated with increased mortality among both men and women, with potentially greater increased risk among women (interaction P =0.089 and 0.051, respectively). No significant interactions by race were detected. Conclusions— SMI represents &gt;45% of incident MIs and is associated with poor prognosis. Race and sex differences in the incidence and prognostic significance of SMI exist that may warrant considering SMI in personalized assessments of coronary heart disease risk.

It is unknown whether atrial fibrillation (AF) is associated with an increased risk of sudden cardiac death (SCD) in the general population. This association was examined in 2 population-based cohorts.In the Atherosclerosis Risk in Communities (ARIC) Study, we analyzed data from 15 439 participants (baseline age, 45-64 years; 55.2% women; and 26.6% black) from baseline (1987-1989) through December 31, 2001. In the Cardiovascular Health Study (CHS), we analyzed data from 5479 participants (baseline age, ≥65 years; 58.2% women; and 15.4% black) from baseline (first cohort, 1989-1990; second cohort, 1992-1993) through December 31, 2006. The main outcome was physician-adjudicated SCD, defined as death from a sudden, pulseless condition presumed to be due to a ventricular tachyarrhythmia. The secondary outcome was non-SCD (NSCD), defined as coronary heart disease death not meeting SCD criteria. We used Cox proportional hazards models to assess the association between AF and SCD/NSCD, adjusting for baseline demographic and cardiovascular risk factors.In the ARIC Study, 894 AF, 269 SCD, and 233 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 2.89 per 1000 person-years (with AF) and 1.30 per 1000 person-years (without AF). The multivariable hazard ratios (HRs) (95% CIs) of AF for SCD and NSCD were 3.26 (2.17-4.91) and 2.43 (1.60-3.71), respectively. In the CHS, 1458 AF, 292 SCD, and 581 NSCD events occurred during follow-up (median, 13.1 years). The crude incidence rates of SCD were 12.00 per 1000 person-years (with AF) and 3.82 per 1000 person-years (without AF). The multivariable HRs (95% CIs) of AF for SCD and NSCD were 2.14 (1.60-2.87) and 3.10 (2.58-3.72), respectively. The meta-analyzed HRs (95% CIs) of AF for SCD and NSCD were 2.47 (1.95-3.13) and 2.98 (2.52-3.53), respectively.Incident AF is associated with an increased risk of SCD and NSCD in the general population. Additional research to identify predictors of SCD in patients with AF is warranted.

Because height is a more appropriate index of maturation than weight for use with normative blood pressure (BP) data, we developed normative BP levels for children, by sex, while accounting for age and height simultaneously. Eight U.S. studies used in the Report of the Second Task Force on Blood Pressure Control in Children and one additional study of BP in U.S. children were reanalyzed to develop age-sex-height-specific values for normative BP values among 56,108 children, aged 1 to 17 years, seen at 76,018 visits. Height percentiles were computed on the basis of standard National Center for Health Statistics growth charts. When height is taken into account, more short children (10th age-sex-specific height percentile) and fewer tall children (90th age-sex-specific height percentile) are likely to be classified as hypertensive than when the current age-sex-specific percentiles of BP alone are used. Tables are provided for boys and girls separately, by single year of age (1 to 17 years) and by the 90th and 95th percentiles of systolic blood pressure and diastolic blood pressure (fifth phase of Korotkoff sounds) for selected age-sex-specific height percentiles based on standard U.S. growth charts.

Increased left ventricular mass (LVM) by echocardiography is associated with increased risk of cardiovascular disease. Thus, it is of interest to compare the effects of both pharmacological and nonpharmacological approaches to the treatment of hypertension on reduction of LVM.Changes in LV structure were assessed by M-mode echocardiograms in a double-blind, placebo-controlled clinical trial of 844 mild hypertensive participants randomized to nutritional-hygienic (NH) intervention plus placebo or NH plus one of five classes of antihypertensive agents: (1) diuretic (chlorthalidone), (2) beta-blocker (acebutolol), (3) alpha-antagonist (doxazosin mesylate), (4) calcium antagonist (amlodipine maleate), or (5) angiotensin-converting enzyme inhibitor (enalapril maleate). Echocardiograms were performed at baseline, at 3 months, and annually for 4 years. Changes in blood pressure averaged 16/12 mm Hg in the active treatment groups and 9/9 mm Hg in the NH only group. All groups showed significant decreases (10% to 15%) in LVM from baseline that appeared at 3 months and continued for 48 months. The chlorthalidone group experienced the greatest decrease at each follow-up visit (average decrease, 34 g), although the differences from other groups were modest (average decrease among 5 other groups, 24 to 27 g). Participants randomized to NH intervention only had mean changes in LVM similar to those in the participants randomized to NH intervention plus pharmacological treatment. The greatest difference between groups was seen at 12 months, with mean decreases ranging from 35 g (chlorthalidone group) to 17 g (acebutolol group) (P = .001 comparing all groups). Within-group analysis showed that changes in weight, urinary sodium excretion, and systolic BP were moderately correlated with changes in LVM, being statistically significant in most analyses.NH intervention with emphasis on weight loss and reduction of dietary sodium is as effective as NH intervention plus pharmacological treatment in reducing echocardiographically determined LVM, despite a smaller decrease in blood pressure in the NH intervention only group. A possible exception is that the addition of diuretic (chlorthalidone) may have a modest additional effect on reducing LVM.

To describe the progression of autonomic impairment among individuals with diabetes and pre-diabetic metabolic impairments.We investigated the consequence of diabetes and pre-diabetic metabolic impairments on the 9-year change in heart rate variability (HRV) in a population-based cohort of 6,245 individuals aged 45-64 years at baseline and cross-sectional associations among 9,940 individuals.Diabetic subjects had a more rapid temporal decrease in HRV conditional on baseline HRV than nondiabetic subjects. Adjusted mean annual changes (95% CI) (ms/year) in the SD of all normal-to-normal R-R intervals were -0.65 (-0.69 to -0.61) for those with normal fasting glucose vs. -0.95 (-1.09 to -0.81) for diabetic subjects, in root mean square of successive differences in normal-to-normal R-R intervals -0.35 (-0.39 to -0.30) vs. -0.66 (-0.82 to -0.51), and in R-R interval 6.70 (6.37-7.04) vs. 3.89 (2.72-5.05). While we found cross-sectional associations between decreased HRV and diabetes and nondiabetic hyperinsulinemia and a weak inverse association with fasting glucose, neither impaired fasting glucose nor nondiabetic hyperinsulimenia was associated with a measurably more rapid decline in HRV than normal.Cardiac autonomic impairment appears to be present at early stages of diabetic metabolic impairment, and progressive worsening of autonomic cardiac function over 9 years was observed in diabetic subjects. The degree to which pre-diabetic metabolic impairments in insulin and glucose metabolism contribute to decreases in cardiac autonomic function remains to be determined.

No large national studies of ethnic differences in blood pressure among children accounting for body size differences have been published, to the author's knowledge. This report details the similarities and differences in systolic and diastolic blood pressures betweenn Black children and White children in the United States and examines the effects of age, sex, and body size on ethnic differences in blood pressure levels. Standardized measurements of seated systolic and diastolic pressures from eight large epidemiologic studies published between 1978 and 1991 that included measurements of 47, 196 children on 68, 556 occasions for systolic pressure and for 38, 184 children on 52, 053 occasions for diastolic pressure were used; 51 percent (24, 048 children) were boys and 37 percent (17, 466 children) were Black. Overall, there appear to be few substantive ethnic differences in either systolic or diastolic pressure during childhood and adolescence. The differences that were observed were small, inconsistent, and often expalained by differences in body size. There was an ethnic group-body mass index (BMI) interaction that resulted in these findings that at lower levels of BMI Blacks have higher blood pressure and more hypertension than do Whites, but that at the highest levels of BMI, Whites have more hypertension (systolic or diastolic pressure) than do Blacks. Am J Epidemiol 2000: 151: 1007-19.

The incidence of ESRD is increasing rapidly. Limited information exists regarding early markers for the development of ESRD. This study aimed to determine over 25 yr the risk for ESRD associated with proteinuria, estimated GFR (eGFR), and hematocrit in men who did not have identified kidney disease and were randomly assigned into the Multiple Risk Factor Intervention Study (MRFIT). A total of 12,866 men who were at high risk for heart disease were enrolled (1973 to 1975) and followed through 1999. Renal replacement therapy was ascertained by matching identifiers with the United States Renal Data System's data; vital status was from the National Death Index. Men who initiated renal replacement therapy or died as a result of kidney disease were deemed to have developed ESRD. Dipstick urine for proteinuria, eGFR, and hematocrit were related to development of ESRD. During 25 yr, 213 (1.7%) men developed ESRD. Predictors of ESRD were dipstick proteinuria of 1+ or > or =2+ (hazard ratio [HR] 3.1 [95% confidence interval (CI) 1.8 to 5.4] and 15.7 [95% CI 10.3 to 23.9] respectively) and an eGFR of <60 ml/min per 1.73 m(2) (HR 2.4; 95% CI 1.5 to 3.8). Correlation between eGFR and serum creatinine was 0.9; the risk for ESRD with a 1-SD difference of each was identical (HR 1.21). Bivariate analysis demonstrated a 41-fold increase in ESRD risk in those with an eGFR <60 ml/min per 1.73 m(2) and > or =2+ proteinuria (95% CI 15.2 to 71.1). There was no association between hematocrit and ESRD. Other baseline measures that independently predicted ESRD included age, cigarette smoking, BP, low HDL cholesterol, and fasting glucose. Among middle-aged men who were at high risk for cardiovascular disease but had no clinical evidence of cardiovascular disease or significant kidney disease, dipstick proteinuria and an eGFR value <60 ml/min per 1.73 m(2) were strong predictors of long-term development of ESRD. It remains unknown whether intervention for proteinuria or early identification of those with chronic kidney disease reduces the risk for ESRD.

This study assessed the relation of fatness and insulin resistance and their interaction with cardiovascular risk factors, inflammatory factors, and oxidative stress in thin and heavy adolescents.Euglycemic insulin clamp studies were performed on 295 (169 male, 126 female) adolescents (mean+/-SE age, 15+/-0.1 years). Comparisons were made between (1) heavy and thin adolescents; (2) insulin-sensitive and insulin-resistant adolescents; and (3) thin insulin-sensitive (T-IS), thin insulin-resistant (T-IR), heavy insulin-sensitive (H-IS), and heavy insulin-resistant (H-IR) adolescents. Summed z scores were used to determine clustering of risk factors (fasting insulin, triglycerides, HDL-C, and systolic blood pressure [SBP]) among the groups. SBP, triglycerides, and fasting insulin were significantly higher and HDL-C significantly lower in the heavy adolescents. Fasting insulin and triglycerides were significantly higher and HDL-C significantly lower in the insulin-resistant adolescents. Among the 4 groups, the risk factors and cluster score followed a pattern of risk as follows: T-IS<T-IR<H-IS<H-IR, with H-IR significantly greater than the other groups and showing an interaction between fatness and insulin resistance.These results show the significant association of both fatness and insulin resistance and their significant interaction with cardiovascular risk factors in adolescence. The finding that insulin resistance may be acting interactively with fatness suggests that interventions directed at insulin resistance in addition to weight loss may be required to alter early development of cardiovascular risk.

The associations of body mass and body fat distribution, as measured by waist-to-hip circumference ratio, with serum concentrations of sex hormones and sex hormone binding globulin were examined in 88 postmenopausal women. Body mass index (BMI) was significantly and negatively associated with sex hormone binding globulin (SHBG) (r = -0.41), luteinizing hormone (LH) (r = -0.40) and follicle stimulating hormone (FSH) (r = -0.38) and was also significantly positively associated with both total and free oestradiol (r = 0.40 and 0.45, respectively). Waist-to-hip circumference ratio was significantly negatively correlated with SHBG (r = -0.53), LH (r = -0.35), and FSH (r = -0.35). After adjustment for BMI and other related factors, waist-to-hip circumference ratio was significantly and negatively associated with SHBG, LH, and FSH, and demonstrated a significant curvilinear relationship with free testosterone. These results suggest that in postmenopausal women, abdominal adiposity is associated with a relatively more androgenic sex hormone profile.

Drug treatment of high blood pressure has been shown to reduce the associated cardiovascular risk. Stroke represents the type of event more strongly linked with high blood pressure, responsible for a high rate of death or invalidity, and with the highest proportion of events that can be avoided by treatment. Hypertensive patients with a history of cerebrovascular accident are at particularly high risk of recurrence. Specific trials of blood pressure lowering drugs in stroke survivors showed inconclusive results in the past.We performed a meta-analysis using all available randomized controlled clinical trials assessing the effect of blood pressure lowering drugs on clinical outcomes (recurrence of stroke, coronary events, cause-specific, and overall mortality) in patients with prior stroke or transient ischemic attack.We identified 9 trials, including a total of 6752 patients: 2 trials included 551 hypertensive stroke survivors; 6 trials of hypertensive patients included a small proportion of stroke survivors (536 patients); 1 trial included stroke survivors, whether hypertensive or not (5665 patients). The recurrence of stroke, fatal and nonfatal, was significantly reduced in active groups compared with control groups consistently across the different sources of data (relative risk of 0.72, 95% confidence interval: 0.61 to 0.85). There was no evidence that this intervention induced serious adverse effect.Blood pressure lowering drug interventions reduced the risk of stroke recurrence in stroke survivors. Available data did not allow to verify whether such benefit depends on initial blood pressure level. More data are needed before considering antihypertensive therapy in normotensive patients at high cerebrovascular risk.

The SMART trial found a raised risk of cardiovascular disease (CVD) events in patients undergoing CD4+ T cell-count guided intermittent antiretroviral therapy (ART) compared with patients on continuous ART. Exploratory analyses were performed to better understand the reasons for this observation.A total of 5,472 patients with CD4+ T-cell counts >350 cells/mm3 were recruited and randomized to either continuous ART (the viral suppression arm; VS) or CD4+ T-cell count-guided use of ART (the drug conservation arm; DC).Major CVD events developed in 79 patients. The hazard ratio (HR) for risk of CVD events for DC versus VS was 1.57 (95% confidence interval 1.00-2.46; P=0.05). There was no evidence that being off ART or a higher current HIV viral load were associated with increased CVD risk. Total cholesterol and low-density lipoprotein cholesterol were reduced as a result of ART interruption in DC patients but so was high-density lipoprotein (HDL) cholesterol, leading to a net unfavourable change in the total/HDL cholesterol ratio.Reasons for the higher risk of CVD for DC compared with VS patients remain unclear. There was no clear evidence to suggest that ART interruption per se or a higher HIV viral load were associated with an increased CVD risk in the DC group. Lipid changes were less favourable among DC compared with VS patients, which could offer a partial explanation.

Objective: Our objective was to describe in children the relation of fatness and insulin resistance to the risk factors associated with the insulin resistance syndrome and to compare fasting insulin with the euglycemic insulin clamp as a measure of insulin resistance in children. Study design: This was a random selection of participants after blood pressure screening of 12,043 students in the fifth through eighth grades. Euglycemic insulin clamp studies with an insulin infusion rate of 1 mU/kg/min and a variable infusion of 20% glucose to maintain euglycemia, that is, plasma glucose at 5.6 mmol/L. Insulin sensitivity (Mlbm) is defined as the amount of glucose required to maintain euglycemia (milligrams of glucose infused per kilogram lean body mass per minute). Results: Body mass index was significantly correlated with fasting insulin and significantly inversely correlated with Mlbm. Fasting insulin was significantly correlated with systolic blood pressure in both sexes, all lipids, except high-density lipoprotein-cholesterol in males and triglycerides and high-density lipoprotein-cholesterol in females, but after adjustment was done for body mass index, it was significantly related only to triglycerides. Mlbm was significantly correlated only with triglycerides and high-density lipoprotein-cholesterol, and this did not change after adjustment was done for body mass index. A clustering effect for the risk factors was seen in children in the lowest quartile of Mlbm (highest degree of insulin resistance) compared with children in the highest quartile of Mlbm (lowest degree of insulin resistance). Conclusions: As defined by Mlbm, there is an early association of insulin resistance, independent of body fat, with the risk factors. There is a significant relation between fasting insulin, as an estimate of insulin resistance, and the risk factors, but this is significantly influenced by body fatness. The clustering of risk factors according to level of Mlbm suggests that adult cardiovascular disease is more likely to develop in children with the greatest degree of insulin resistance. (J Pediatr 2001;139:700–7)

Echocardiography provides a noninvasive means of assessing left ventricular (LV) structure and evidence of LV wall remodeling in hypertensive persons. The relation of demographic, biological, and other factors with LV structure can be assessed.LV structure was assessed by M-mode echocardiograms for 511 men and 333 women with mild hypertension (average blood pressure, 140/91 mm Hg). Measurements of LV wall thicknesses and internal dimensions were made, and estimates of LV mass indexes and other derivations of structure were calculated. LV hypertrophy criteria were based on previously reported echocardiographic population studies of normal subjects. These measures were compared by age, sex, race, body mass index, systolic blood pressure, antihypertensive drug use, physical activity, alcohol intake, cigarette smoking, and urinary sodium excretion. Despite virtual absence of ECG-determined LV hypertrophy, 13% of men and 20% of women had echocardiographically determined LV hypertrophy indexed by body surface area (g/m2), and 24% of men and 45% of women had LV hypertrophy indexed by height (g/m). Black participants had slightly higher mean levels of wall thickness than nonblack participants but similar LV mass. Systolic blood pressure and urinary sodium excretion were significantly and independently associated with LV mass index and LV hypertrophy using both g/m2 and g/m. Body mass index was significantly related to LV mass index and LV hypertrophy using g/m. Smoking was significantly associated with LV mass index, i.e., using continuous measurement but not using the dichotomy for LV hypertrophy.This study of a large population of men and women with mild primary hypertension, largely without ECG evidence of LV hypertrophy, showed a substantial percentage of participants with echocardiographically determined LV hypertrophy. LV mass indexes correlated positively with systolic blood pressure, body mass index, urinary sodium excretion, and smoking.

The relation between body fat distribution, as measured by the waist-to-hip circumference ratio, and the 2-year incidences of hypertension and stroke were examined in a cohort of 41,837 women aged 55-69 years. Women who developed hypertension were 2.1 (95% confidence interval 1.7-2.6) times more likely to be in the upper tertile of waist-to-hip ratio than those who did not. Adjustment for age, body mass index (kilograms per meter squared), cigarette smoking, physical activity, alcohol intake, and education level reduced this odds ratio to 1.6 (95% confidence interval 1.3-2.1). Women who developed a stroke were also 2.1 (95% confidence interval 1.5-2.9) times more likely to be in the upper tertile of waist-to-hip ratio than those who did not. Adjustment for the same covariates also lowered this odds ratio to 1.6 (95% confidence interval 1.1-2.4). Further adjustment for hypertension and diabetes mellitus reduced the estimated risk of stroke due to elevated waist-to-hip ratio to 1.3 (95% confidence interval 0.8-2.1). Hypertension, diabetes mellitus, and cigarette smoking remained significantly associated with stroke incidence in the multivariate model. These results indicate that abdominal adiposity, as measured by an increased waist-to-hip ratio, increases the risks of hypertension and stroke, even after accounting for overall body mass. The association of abdominal adiposity with risk of stroke is related, in part, to the association of abdominal adiposity with hypertension and diabetes.

Autonomic nervous system dysfunction, a correlate of obesity and poor cardiorespiratory fitness, is associated with the development of diabetes. We tested whether estimates of autonomic nervous system function improved in the intensive lifestyle versus metformin or placebo arms of the Diabetes Prevention Program (DPP) and whether baseline or a change in autonomic nervous system function was associated with the development of diabetes over 3.2 years.In 2,980 DPP participants, 12-lead electrocardiograms were measured at baseline and annually. Heart rate, heart rate variability (HRV), and QT duration were used to estimate fitness and autonomic nervous system function.In the lifestyle arm, heart rate and QT indexes decreased, and HRV increased over time. The magnitude of decline in heart rate and QT duration was substantially smaller in the other arms, whereas HRV did not increase. Baseline heart rate was the only index significantly (P < 0.05) associated with incident diabetes after adjustment for demographics and weight change (hazard ratio for lifestyle and metformin arms = 1.19 and 1.17 per 10.6 beats/min, respectively). Decreases in heart rate and QT indexes and increases in HRV over time were associated with a lower risk of developing diabetes. The protective association between decreased heart rate and incident diabetes in the lifestyle arm remained significant after accounting for change in weight and physical activity.Indexes that reflect autonomic function and fitness improved (i.e., heart rate decreased and HRV increased) in the lifestyle modification arm of the DPP. Improvements in these indexes are inversely associated with the development of diabetes independent of weight change.

Elevated blood pressure (EBP) in children and adolescents increases future risk of cardiovascular disease. Among children and adolescents, increased weight is associated with EBP.National cross-sectional data for children and adolescents aged 8-17 years from the National Health and Nutrition Examination Surveys (NHANESs): 1988-1994, 1999-2002, and 2003-2006. The main outcome measures were EBP and pre-EBP estimates.Overweight boys (odds ratio (OR) 1.54, confidence interval (CI) 1.11-2.13) and both obese boys and girls were significantly more likely to be classified as pre-EBP (boys, OR 2.81, CI 2.13-3.71; girls, OR 2.55, CI 1.75-3.73) and having EBP (boys aged 8-12 years, OR 6.06, CI 2.73-13.44, boys aged 13-17, OR 9.62 CI 4.86-19.06; girls, OR 2.33, CI 1.31-4.13) when compared to the reference weight and controlling for all other covariates.During 2003-2006, 13.6% (s.e. = 1.2) of boys aged 8-17 years and 5.7% (s.e. = 0.7) of the girls aged 8-17 years were classified as pre-EBP and 2.6% (s.e. = 0.5) of the boys aged 8-17 and 3.4% (s.e. = 0.7) of the girls aged 8-17 were having EBP. After controlling for age, race/ethnicity, and body mass index (BMI), girls only were significantly more likely to have EBP during 2003-2006 than during 1988-1994 (OR 2.17, CI 1.05-4.49). In contrast, adolescent boys aged 13-17 years were significantly less likely to be having EBP during 2003-2006 than during 1988-1994 (OR 0.32, CI 0.13-0.81).Obesity is strongly, positively, and independently associated with EBP and pre-EBP among youths. However, controlling for all covariates including BMI, EBP has increased among girls but decreased among adolescent boys aged 13-17, during 2003-2006 when compared with 1988-1994.

To determine the prevalence of cognitive impairment and dementia in a multi-ethnic community, we examined a population sample of 2,759 elderly (65 years of age and older) African American, Hispanic-Cuban and white non-Hispanic men and women of Dade County, Florida. The Short Portable Mental Status Questionnaire (SPMSQ) was used as a screening test. The prevalence of cognitive impairment for African American men was 17.0% and women 16.7%; Cuban men 9.4% and women 11.4%; and white non-Hispanic men 9.0% and women 8.5%. Participants with cognitive impairment were referred to two Memory Disorder Clinics for diagnosis of dementia/Alzheimer's disease (AD). SPMSQ cutpoints took account of race and education. The prevalence of dementia/AD was adjusted for sensitivity and specificity of the SPMSQ in each sex/ethnic group. The prevalence of dementia among African American men (20.9%) was twice that among white non-Hispanic men (11.6%). White non-Hispanic and Cuban women had a similar prevalence of dementia (12.1% vs. 12.9%). Low SPMSQ specificity for Cuban men and African American women gave unstable dementia prevalence estimates. More than two thirds of all dementia cases had AD, and among white non-Hispanics, women had double the prevalence of AD among men (10.9% vs. 5.4%). The prevalence of AD among African American men was more than two and a half times greater than the prevalence among white non-Hispanic men (14.4% vs. 5.4%). Age (p = 0.001), family history of AD (p = 0.02) and African American (p = 0.0001) or Cuban (p = 0.006) ethnic group were directly and independently associated with the prevalence of AD.

The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) found a higher risk of stroke after carotid artery stenting and a higher risk of myocardial infarction (MI) after carotid endarterectomy.Cardiac biomarkers and ECGs were performed before and 6 to 8 hours after either procedure and if there was clinical evidence of ischemia. In CREST, MI was defined as biomarker elevation plus either chest pain or ECG evidence of ischemia. An additional category of biomarker elevation with neither chest pain nor ECG abnormality was prespecified (biomarker+ only). Crude mortality and risk-adjusted mortality for MI and biomarker+ only were assessed during follow-up. Among 2502 patients, 14 MIs occurred in carotid artery stenting and 28 MIs in carotid endarterectomy (hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.94; P=0.032) with a median biomarker ratio of 40 times the upper limit of normal. An additional 8 carotid artery stenting and 12 carotid endarterectomy patients had biomarker+ only (hazard ratio, 0.66; 95% confidence interval, 0.27 to 1.61; P=0.36), and their median biomarker ratio was 14 times the upper limit of normal. Compared with patients without biomarker elevation, mortality was higher over 4 years for those with MI (hazard ratio, 3.40; 95% confidence interval, 1.67 to 6.92) or biomarker+ only (hazard ratio, 3.57; 95% confidence interval, 1.46 to 8.68). After adjustment for baseline risk factors, both MI and biomarker+ only remained independently associated with increased mortality.In patients randomized to carotid endarterectomy versus carotid artery stenting, both MI and biomarker+ only were more common with carotid endarterectomy. Although the levels of biomarker elevation were modest, both events were independently associated with increased future mortality and remain an important consideration in choosing the mode of carotid revascularization or medical therapy.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00004732.

Recent clinical trials have found that the combination of conjugated equine oestrogen (CEO) and medroxyprogesterone has a protective effect on the incidence of type 2 diabetes. To determine the effect of CEO alone on the incidence of diabetes mellitus in postmenopausal women, we analysed the results of the Women's Health Initiative oestrogen-alone trial.The Women's Health Initiative is a randomised, double-masked trial comparing the effect of daily 0.625 mg CEO with placebo during 7.1 years of follow-up of 10,739 postmenopausal women who were aged 50-79 years and had previously had a hysterectomy. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin and lipoproteins were measured in an 8.6% random sample of study participants, at baseline and at 1, 3 and 6 years.The cumulative incidence of treated diabetes was 8.3% in the oestrogen-alone group and 9.3% in the placebo group (hazard ratio 0.88, 95% CI 0.77-1.01, p=0.072). During the first year of follow-up, a significant fall in insulin resistance (homeostasis model assessment of insulin resistance) in actively treated women compared with the control subjects (Year 1 baseline between-group difference -0.53) was seen. However, there was no difference in insulin resistance at the 3- or 6-year follow-up.Postmenopausal therapy with oestrogen alone may reduce the incidence of treated diabetes. The effect is smaller than that seen with oestrogen plus progestin. CEO should not, however, be used with the intention of preventing diabetes, as its well-described adverse effects preclude long-term use for primary prevention.

<h3>Objectives:</h3> To compare 5 antihypertensive drugs and placebo for changes in quality of life (QL). To assess the relationship of lifestyle factors and change in lifestyle factors to QL in participants with stage I diastolic hypertension. <h3>Methods:</h3> The Treatment of Mild Hypertension Study (TOMHS) was a randomized, double-blind, placebocontrolled clinical trial with minimum participant follow-up of 4 years. It was conducted at 4 hypertension screening and treatment academic centers in the United States. The cohort consisted of 902 men and women with hypertension, aged 45 to 69 years, with diastolic blood pressures less than 100 mm Hg. Informed consent was obtained from each participant after the nature of the procedures had been fully explained. Sustained nutritional-hygienic intervention was administered to all participants to reduce weight, to reduce dietary sodium and alcohol intake, and to increase physical activity. Participants were randomized to take (1) acebutolol (n=132); (2) amlodipine maleate (n=131); (3) chlorthalidone (n=126); (4) doxazosin mesylate (n=134); (5) enalapril maleate (n=135); or placebo (n=234). Changes in 7 QL indexes were assessed based on a 35-item questionnaire: (1) general health; (2) energy or fatigue; (3) mental health; (4) general functioning; (5) satisfaction with physical abilities; (6) social functioning; and (7) social contacts. <h3>Results:</h3> At baseline, higher QL was associated with older age, more physical activity, lower obesity level, male gender, non-African American race, and higher educational level. Improvements in QL were observed in all randomized groups, including the placebo group during follow-up; greater improvements were observed in the acebutolol and chlorthalidone groups and were evident throughout follow-up. The amount of weight loss, increase in physical activity, and level of attained blood pressure control during follow-up were related to greater improvements in QL. <h3>Conclusions:</h3> In patients with stage I hypertension, antihypertensive treatment with any of 5 agents used in TOMHS does not impair QL. The diuretic chlorthalidone and the cardioselective β-blocker acebutolol appear to improve QL the most. Success with lifestyle changes affecting weight loss and increase in physical activity relate to greater improvements in QL and show that these interventions, in addition to contributing to blood pressure control, have positive effects on the general well-being of the individual. Arch Intern Med. 1997;157:638-648

To test the hypothesis that the relative insulin resistance of puberty is associated with changes in IGF-I levels, we compared IGF-I, IGF binding protein-3 (IGFBP-3), and IGFBP-1 levels to insulin resistance [M(lbm), milligrams glucose used per kilogram of lean body mass (LBM) per minute] measured during euglycemic, hyperinsulinemic clamp studies in 342 children and adolescents. IGF-I levels rose and fell during the Tanner stages of puberty in a pattern that closely followed the rise and fall of insulin resistance. IGF-I levels were significantly related to M(lbm) in boys (P = 0.0006) and girls (P = 0.02). IGF-I was significantly related to fasting insulin levels only in girls (P = 0.006; boys, P = 0.26), and this relation was significantly influenced in girls by body fat (P = 0.007), with the strongest association between IGF-I and fasting insulin seen in thin girls. IGFBP-1 correlated negatively with insulin resistance in both boys (P = 0.0004) and girls (P = 0.04), whereas IGFBP-3 correlated positively with insulin resistance in boys (P = 0.0004) but not girls (P = 0.85). These data suggest that the GH/IGF-I axis is an important contributor to the insulin resistance of puberty.

The relation between central adiposity, measured by the waist/hip circumference ratio (WHR), and 4-year risk of fatal coronary artery disease was examined in a large cohort (n = 32,898) of women aged 55 to 69 years. The age-adjusted relative risk of death from coronary artery disease (115 deaths) was 3.3 for women in the highest tertile of WHR compared to the lowest tertile (95% confidence interval: 2.0, 5.6). After adjustment for age, body mass, smoking, physical activity, estrogen use, marital status, and alcohol intake, the relative risk o f coronary death for women in the middle and highest tertiles versus those in the lowest tertile of WHR were 1.3 and 2.8, respectively (P for linear trend < 0.001). Further adjustment for hypertension and diabetes mellitus reduced the estimates slightly to 1.2 and 2.0, but the trend in relative risk remained statistically significant (P = 0.03). In contrast, body mass index showed no independent association with coronary death. Hypertension, diabetes mellitus, cigarette smoking, estrogen nonuse, and being unmarried were significant predictors of greater risk of coronary death in the multivariate model. These results indicate that central adiposity, reflected by an increased WHR, is an important risk factor for death from coronary artery disease in women, most of whom were postmenopausal. The association of central adiposity with risk of coronary death is independent, for the most part, of its association with hypertension and diabetes.

The ECG QT interval is associated with risk of sudden cardiac death (SCD). A previous genome-wide association study demonstrated that allelic variants (rs10494366 and rs4657139) in the nitric oxide synthase 1 adaptor protein (NOS1AP), which encodes a carboxy-terminal PDZ ligand of neuronal nitric oxide synthase, are associated with the QT interval in white adults. The present analysis was conducted to validate the association between NOS1AP variants and the QT interval and to examine the association with SCD in a combined population of 19 295 black and white adults from the Atherosclerosis Risk In Communities Study and the Cardiovascular Health Study.We examined 19 tagging single-nucleotide polymorphisms in the genomic blocks containing rs10494366 and rs4657139 in NOS1AP. SCD was defined as a sudden pulseless condition of cardiac origin in a previously stable individual. General linear models and Cox proportional hazards regression models were used. Multiple single-nucleotide polymorphisms in NOS1AP, including rs10494366, rs4657139, and rs16847548, were significantly associated with adjusted QT interval in whites (P<0.0001). In whites, after adjustment for age, sex, and study, the relative hazard of SCD associated with each C allele at rs16847548 was 1.31 (95% confidence interval 1.10 to 1.56, P=0.002), assuming an additive model. In addition, a downstream neighboring single-nucleotide polymorphism, rs12567209, which was not correlated with rs16847548 or QT interval, was also independently associated with SCD in whites (relative hazard 0.57, 95% confidence interval 0.39 to 0.83, P=0.003). Adjustment for QT interval and coronary heart disease risk factors attenuated but did not eliminate the association between rs16847548 and SCD, and such adjustment had no effect on the association between rs12567209 and SCD. No significant associations between tagging single-nucleotide polymorphisms in NOS1AP and either QT interval or SCD were observed in blacks.In a combined analysis of 2 population-based prospective cohort studies, sequence variations in NOS1AP were associated with baseline QT interval and the risk of SCD in white US adults.

The relationship between body fat distribution, measured by the ratio of waist-to-hip circumferences (WHR), and the 2 year incidence of diabetes mellitus was examined in a cohort of 41,837 women aged 55-69 years. The 399 women who reported the new onset of diabetes had a significantly greater mean body mass index (kg/m2) and WHR than non-cases. After adjustment for body mass index (BMI), age and education level using multivariate logistic regression, WHR was a significant independent predictor of diabetes in a dose-response fashion. Cases were 4.6 times (95% CI = 3.8, 5.6) more likely than non-cases to be in the upper tertile of WHR and 2.2 times (95% CI = 1.8, 2.7) more likely to be in the middle tertile. Women in the highest tertiles of both WHR and BMI had a 14.4-fold (95% CI = 9.5, 21.9) higher risk of diabetes than women in the lowest tertiles. These results demonstrate that increased abdominal adiposity is a significant independent risk factor for the development of diabetes mellitus in older women.

Blood pressure (BP) data obtained during a BP screening program were analyzed to determine the prevalence of "significant" hypertension, defined by the Second National Heart, Lung, and Blood Institute Task Force on Blood Pressure Control in Children-1987 as the level of BP above which medical evaluation and intervention are recommended. In 14,686 black and white St. Paul and Minneapolis schoolchildren aged 10 to 15 years, BP was measured twice during an initial screening examination. Children with systolic BP in the upper 30 percentiles of distribution after the initial screening had their BP remeasured two additional times at a rescreening examination. The prevalence of significant hypertension was determined according to BP criteria established by the Task Force report. After the two screening BP measurements were averaged, significant systolic hypertension was found in 1.0%, significant diastolic hypertension in 3.5%, and significant systolic or diastolic hypertension, or both, in 4.2% of the students. After the rescreening examination, the percentage of students remaining with significant hypertension was reduced to 0.3% for systolic, 0.8% for diastolic, and 1.1% for systolic or diastolic hypertension, or both. These results show that significant hypertension is uncommon in pre-high-school students and confirm the need for repeated BP measurements to make an accurate diagnosis of hypertension. However, the results should not detract from current recommendations to monitor BP in children on a yearly basis to detect longitudinal BP tracking patterns that may be consistent with early essential hypertension.

Background:The utility of metabolic syndrome (MetS) for predicting mortality among older adults, the highestrisk population, is not well established.In addition, few studies have compared the predictive utility of MetS to that of its individual risk factors.Methods: We evaluated relationships of MetS (as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III (ATPIII)], International Diabetes Foundation [IDF], and World Health Organization [WHO]) and individual MetS criteria with mortality between 1989 and 2004 among 4258 US adults 65 years or older and free of prevalent cardiovascular disease (CVD) in the Cardiovascular Health Study, a multicenter, population-based, prospective cohort.Total, CVD, and non-CVD mortality were evaluated.Cox proportional hazards models were used to estimate the mortality hazard ratio (relative risk [RR]) predicted by MetS.Results: At baseline (mean age, 73 years), 31% of men and 38% of women had MetS (ATPIII).During 15 years of follow-up, 2116 deaths occurred.After multivariable adjustment, compared with persons without MetS, those

Normotensive adults on low-sodium, weight-loss, and control diets recorded preferences and perceived saltiness for sodium chloride (NaCl) added to cream soup at intervals over 1 yr. Reduction in sodium intake and excretion accompanied a shift in preference toward less salt: preferred concentrations by ad libitum salting declined from 0.72% at the onset to 0.33% NaCl at week 24; hedonic scores for high concentrations of NaCl decreased significantly while scores for low concentrations increased. After 3 mo of sodium restriction, NaCl preferences readjusted to a lower level: ad libitum additions of NaCl were similar after 13, 24, and 52 wk. Less hedonic variation was observed among controls than among Na-restricted groups. The weight-loss group showed increased liking for mid-range NaCl levels. Mechanisms underlying preference changes, including physiological, behavioral, and context effects, may provide insights into maintenance of low-sodium diets for treatment and prevention of hypertension.

Fish and omega-3 fatty acid consumption reduce risk of cardiac death, but mechanisms are not well established. Heart rate variability (HRV) predicts cardiac death and reflects specific electrophysiological pathways and influences. We hypothesized that habitual consumption of fish and marine omega-3 fatty acids would be associated with more favorable HRV, elucidating electrophysiological influences and supporting effects on clinical risk.In a population-based cohort of older US adults, we evaluated cross-sectional associations of usual dietary fish and omega-3 consumption during the prior year and ECG-derived (n=4263) and 24-hour Holter monitor-derived (n=1152) HRV. After multivariable adjustment, consumption of tuna or other broiled/baked fish was associated with specific HRV components, including indices suggesting greater vagal predominance and moderated baroreceptor responses (eg, higher root mean square successive differences of normal-to-normal intervals [P=0.001]; higher normalized high-frequency power [P=0.008]; and lower low-frequency/high-frequency ratio [P=0.03]) and less erratic sinoatrial node firing (eg, lower Poincaré ratio [P=0.02] and higher short-term fractal scaling exponent [P=0.005]) but not measures of circadian fluctuations (eg, 24-hour standard deviation of normal-to-normal intervals). Findings were similar for estimated dietary consumption of marine omega-3 fatty acids. For magnitudes of observed differences in HRV comparing the highest to lowest category of fish intake, differences in relative risk of cardiac death during 10.8 years of follow-up ranged from 1.1% (for difference in standard deviation of normal-to-normal intervals) to 5.9% and 8.4% (for differences in Poincaré ratio and short-term fractal scaling exponent) lower risk.Habitual tuna/other fish and marine omega-3 consumption are associated with specific HRV components in older adults, particularly indices of vagal activity, baroreceptor responses, and sinoatrial node function. Cellular mechanisms and implications for clinical risk deserve further investigation.

Because body fat distribution has been recognized as a disease risk factor, practical methods for the measurement of body girths are needed. In two groups of postmenopausal women aged 55-69 years in the upper midwestern United States, the authors examined the reliability and accuracy of self-measurement by mail questionnaire of waist, hip, upper arm, wrist and calf girths. Intra-class correlations for waist girth were 0.96 when two self-measurements were compared and 0.93 when self-measurement was compared with technician measurement. Other intra-class correlations were at least 0.85 for repeat self-measurements except for wrist, which had an intra-class correlation of 0.66. For comparisons of self-measurement with technician measurement, intra-class correlations ranged from 0.71 for upper arm to 0.96 for hips. There was slight overestimation of waist girths and underestimation of hip girths when self-measurement was compared with technician measurement. Accuracy of self-measurement did not seem to vary according to age or educational status, but for hip, wrist, and calf girths it appeared that self-measurement underestimated technician measurement as girth size increased. For most girths, within-person variation in girth measurement also increased as girth size increased. Overall, girth self-measurement was both repeatable when re-ascertained by mail and accurate when compared with subsequent technician measurement.

Spatial QRS/T angle and spatial T-wave axis were shown to be strong independent predictors of incident coronary heart disease (CHD) and total mortality, but they are not routinely available. We evaluated whether frontal plane QRS/T angle, easily obtained as the difference between frontal plane axes of QRS and T, provides a suitable substitute for spatial QRS/T angle as a risk predictor. Our study consisted of 13,973 participants from the ARIC Study. Outcome variables were incident CHD and total mortality during a median follow-up of 14 years. Electrocardiographic variables were categorized as abnormal (>/=95th percentile), borderline (>/=75th and <95th percentile), and normal (<75th percentile) separately for men and women. Cox regression was used to assess the effect of electrocardiographic variables on risk of each outcome. The normal category was considered the reference cell. With adjustment for demographic and clinical characteristics, both QRS/T angles were approximately equally strong predictors of total mortality with >50% increased risk. Spatial QRS/T angle was a stronger predictor of incident CHD in women, with a 114% increased risk, but it was not significantly associated with risk of incident CHD in men. Similarly, frontal plane QRS/T angle was statistically significant for only women with a 74% increased risk of incident CHD. In conclusion, frontal plane QRS/T angle as an easily derived risk measure is a suitable clinical substitute for spatial QRS/T angle for risk prediction.

Case studies and small trials suggest that acupuncture may effectively treat hypertension, but no large randomized trials have been reported. The Stop Hypertension with the Acupuncture Research Program pilot trial enrolled 192 participants with untreated blood pressure (BP) in the range of 140/90 to 179/109 mm Hg. The design of the trial combined rigorous methodology and adherence to principles of traditional Chinese medicine. Participants were weaned off antihypertensives before enrollment and were then randomly assigned to 3 treatments: individualized traditional Chinese acupuncture, standardized acupuncture at preselected points, or invasive sham acupuncture. Participants received < or = 12 acupuncture treatments over 6 to 8 weeks. During the first 10 weeks after random assignment, BP was monitored every 14 days, and antihypertensives were prescribed if BP exceeded 180/110 mm Hg. The mean BP decrease from baseline to 10 weeks, the primary end point, did not differ significantly between participants randomly assigned to active (individualized and standardized) versus sham acupuncture (systolic BP: -3.56 versus -3.84 mm Hg, respectively; 95% CI for the difference: -4.0 to 4.6 mm Hg; P=0.90; diastolic BP: -4.32 versus -2.81 mm Hg, 95% CI for the difference: -3.6 to 0.6 mm Hg; P=0.16). Categorizing participants by age, race, gender, baseline BP, history of antihypertensive use, obesity, or primary traditional Chinese medicine diagnosis did not reveal any subgroups for which the benefits of active acupuncture differed significantly from sham acupuncture. Active acupuncture provided no greater benefit than invasive sham acupuncture in reducing systolic or diastolic BP.

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

To determine the causes of the nationwide decline in deaths due to coronary heart disease, the Minnesota Heart Survey enumerated coronary deaths among persons 30 to 74 years old in Minneapolis–St. Paul. The survey also ascertained rates of hospitalization and case fatality during hospitalization for acute myocardial infarction. For deaths occurring between 1970 and 1978 that were due to coronary heart disease, the rates outside the hospital declined by 43 per cent in men and 40 per cent in women, and the rates in hospital emergency rooms increased by 311 per cent in men and 200 per cent in women. In both these years about two thirds of all such deaths occurred outside hospital wards. Between 1970 and 1980, hospitalization rates for acute infarction in persons 30 to 74 years old declined 8 per cent among men and 26 per cent among women, and case fatality in the hospital in persons 45 to 74 years old declined 29 per cent in men and 27 per cent in women. These changes are probably due to the combined influence of changes in risk factors in the population and improved care of patients with acute myocardial infarction before and during hospitalization. (N Engl J Med 1983; 309:1353–8.)

The prognostic value of the exercise electrocardiogram was examined in the 6,438 usual care men of the Multiple Risk Factor Intervention Trial in relation to fatal and nonfatal coronary heart disease events, rest electrocardiographic abnormalities and coronary heart disease risk factors. An abnormal response to exercise, denned as an ST depression integral of 16 μV-s or more, was observed in 12.2% of the men. There was a nearly fourfold increase in 7 year coronary mortality among men with an abnormal response to exercise compared with men with a normal ST segment in exercise (risk ratio 3.8, 95% confidence limits 2.5 to 5.5). The risk ratio for coronary death, adjusted for age, diastolic blood pressure, serum cholesterol and smoking status at baseline was 3.5, and the corresponding adjusted risk ratio for death from all causes was 1.6. A similar trend toward excess coronary events was seen for angina pectoris (risk ratio of 1.6). The trend was not significant for nonfatal myocardial infarction. Multivariate analyses indicated that the ST depression integral was a strong independent predictor of future coronary death (p < 0.001). Men with an abnormal electrocardiogram at rest (mainly high amplitude R waves) and with an abnormal ST response to exercise had an over sixfold relative risk for coronary death compared with men with an abnormal electrocardiogram at rest and a normal ST response to exercise. These results suggest that exercise testing may be indicated for improved risk assessment and the assessment of the significance of minor rest electrocardiographic abnormalities in middle-aged men with elevated levels of coronary heart disease risk factors.

Data are sparse regarding the prevalence, incidence, and independent prognostic value of minor and/or major electrocardiographic (ECG) abnormalities in asymptomatic postmenopausal women. There is no information on the effect, if any, of hormonal treatment on the prognostic value of the ECG.To examine association of minor and major baseline and incident ECG abnormalities with long-term cardiovascular morbidity and mortality.Post-hoc analysis of the estrogen plus progestin component of the Women's Health Initiative study, a randomized controlled primary prevention trial of 14 749 postmenopausal asymptomatic women with intact uterus who received 1 daily tablet containing 0.625 mg of oral conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate or a matching placebo. Participants were enrolled from 1993 to 1998, and the estrogen plus progestin trial was stopped on July 7, 2002.The Novacode criteria were used to define minor, major, and incident ECG abnormalities. Cardiovascular end points included incident coronary heart disease (CHD) and cardiovascular disease (CVD) events.Among women with absent (n = 9744), minor (n = 4095), and major (n = 910) ECG abnormalities, there were 118, 91, and 37 incident CHD events, respectively. The incident annual CHD event rates per 10 000 women with absent, minor, or major ECG abnormalities were 21 (95% confidence interval [CI], 18-26), 40 (95% CI, 32-49), and 75 (95% CI, 54-104), respectively. After 3 years of follow-up, 5% of women who had normal ECG at baseline developed new ECG abnormalities with an annual CHD event rate of 85 (95% CI, 44-164) per 10 000 women. The adjusted hazard ratios for CHD events were 1.55 (95% CI, 1.14-2.11) for minor baseline, 3.01 (95% CI, 2.03-4.46) for major baseline, and 2.60 (95% CI, 1.08-6.27) for incident ECG abnormalities. There were no significant interactions between hormone treatment assignment and ECG abnormalities for risk prediction of cardiovascular end points. For prediction of CHD events, the addition of ECG findings to the Framingham risk score increased from 0.69 to 0.74 the area under the receiver operating characteristic curve. Similar findings were found for incident CVD events.Among asymptomatic postmenopausal women, clinically relevant baseline and incident ECG abnormalities are independently associated with increased risk of cardiovascular events and mortality, and the information is incremental to the established method of risk stratification.clinicaltrials.gov Identifier: NCT00000611.

To examine the prevalence of prehypertension and hypertension among children receiving well-child care in community-based practices.Children aged 3 to 17 years with measurements of height, weight, and blood pressure (BP) obtained at an initial (index) well-child visit between July 2007 and December 2009 were included in this retrospective cohort study across 3 large, integrated health care delivery systems. Index BP classification was based on the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents: normal BP, <90th percentile; prehypertension, 90th to 94th percentile; hypertension, 3 BP measurements ≥95th percentile (index and 2 subsequent consecutive visits).The cohort included 199 513 children (24.3% aged 3-5 years, 34.5% aged 6-11 years, and 41.2% aged 12-17 years) with substantial racial/ethnic diversity (35.9% white, 7.8% black, 17.6% Hispanic, 11.7% Asian/Pacific Islander, and 27.0% other/unknown race). At the index visit, 81.9% of participants were normotensive, 12.7% had prehypertension, and 5.4% had a BP in the hypertension range (≥95th percentile). Of the 10 848 children with an index hypertensive BP level, 3.8% of those with a follow-up BP measurement had confirmed hypertension (estimated 0.3% prevalence). Increasing age and BMI were significantly associated with prehypertension and confirmed hypertension (P < .001 for trend). Among racial/ethnic groups, blacks and Asians had the highest prevalence of hypertension.The prevalence of hypertension in this community-based study is lower than previously reported from school-based studies. With the size and diversity of this cohort, these results suggest the prevalence of hypertension in children may actually be lower than previously reported.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

OBJECTIVE—The purpose of this study was to determine whether implementation of a multicomponent organizational intervention can produce significant change in diabetes care and outcomes in community primary care practices. RESEARCH DESIGN AND METHODS—This was a group-randomized, controlled clinical trial evaluating the practical effectiveness of a multicomponent intervention (TRANSLATE) in 24 practices. The intervention included implementation of an electronic diabetes registry, visit reminders, and patient-specific physician alerts. A site coordinator facilitated previsit planning and a monthly review of performance with a local physician champion. The principle outcomes were the percentage of patients achieving target values for the composite of systolic blood pressure (SBP) &amp;lt;130 mmHg, LDL cholesterol &amp;lt;100 mg/dl, and A1C &amp;lt;7.0% at baseline and 12 months. Six process measures were also followed. RESULTS—Over 24 months, 69,965 visits from 8,405 adult patients with type 2 diabetes were recorded from 238 health care providers in 24 practices from 17 health systems. Diabetes process measures increased significantly more in intervention than in control practices, giving net increases as follows: foot examinations 35.0% (P &amp;lt; 0.0.001); annual eye examinations 25.9% (P &amp;lt; 0.001); renal testing 28.5% (P &amp;lt; 0.001); A1C testing 8.1%(P &amp;lt; 0.001); blood pressure monitoring 3.5% (P = 0.05); and LDL testing 8.6% (P &amp;lt; 0.001). Mean A1C adjusted for age, sex, and comorbidity decreased significantly in intervention practices (P &amp;lt; 0.02). At 12 months, intervention practices had significantly greater improvement in achieving recommended clinical values for SBP, A1C, and LDL than control clinics (P = 0.002). CONCLUSIONS—Introduction of a multicomponent organizational intervention in the primary care setting significantly increases the percentage of type 2 diabetic patients achieving recommended clinical outcomes.

Cardiac autonomic dysfunction has been suggested as a possible biologic pathway for the association between fine particulate matter ≤ 2.5 µm in diameter (PM2.5) and cardiovascular disease (CVD). We examined the associations of PM2.5 with heart rate variability, a marker of autonomic function, and whether metabolic syndrome (MetS) modified these associations.We used data from the Multi-Ethnic Study of Atherosclerosis to measure the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences (rMSSD) of 5,465 participants 45-84 years old who were free of CVD at the baseline examination (2000-2002). Data from the U.S. regulatory monitor network were used to estimate ambient PM2.5 concentrations at the participants' residences. MetS was defined as having three or more of the following criteria: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, high blood pressure, and high fasting glucose.After controlling for confounders, we found that an interquartile range (IQR) increase in 2-day average PM2.5 (10.2 µg/m3) was associated with a 2.1% decrease in rMSSD [95% confidence interval (CI), -4.2 to 0.0] and nonsignificantly associated with a 1.8% decrease in SDNN (95% CI, -3.7 to 0.1). Associations were stronger among individuals with MetS than among those without MetS: an IQR elevation in 2-day PM2.5 was associated with a 6.2% decrease in rMSSD (95% CI, -9.4 to -2.9) among participants with MetS, whereas almost no change was found among participants without MetS (p-interaction = 0.005). Similar effect modification was observed in SDNN (p-interaction = 0.011).These findings suggest that autonomic dysfunction may be a mechanism through which PM exposure affects cardiovascular risk, especially among persons with MetS.

Background There is paucity of knowledge concerning the specific age in youth when the associations of metabolic syndrome (MetS) begin to be operative. Thus, we investigated the relation of age to the associations of childhood MetS with adult MetS, type 2 diabetes mellitus and high carotid intima‐media thickness. Methods and Results Five thousand eight‐hundred three participants were analyzed in 4 cohort studies (Cardiovascular Risk in Young Finns, Bogalusa Heart Study, Princeton Lipid Research Study, Insulin Study). International cutoffs and previously used 75th percentile cutoffs were used for children to define MetS and its components. Mean follow‐up period was 22.3 years. Logistic regression was used to calculate risk ratios and 95% confidence intervals. Childhood MetS and overweight were associated with over 2.4‐fold risk for adult MetS from the age of 5 years onward. Risk for type 2 diabetes mellitus was increased from the age of 8 (risk ratio, 2.6–4.1; 95% confidence interval, 1.35–6.76 and 1.12–7.24, respectively) onward for the 2 childhood MetS criteria based on international cut‐off values and for childhood overweight. Risk for high carotid intima‐media thickness was significant at ages 11 to 18 years in relation to childhood MetS or overweight (risk ratio, 2.44–4.22; 95% confidence interval, 1.55–3.55 and 2.55–5.66, respectively). Continuous childhood MetS score was associated with adult MetS from the age of 5, with type 2 diabetes mellitus from the age of 14 and with high carotid intima‐media thickness from the age of 11 years onward. Conclusions Adult MetS was predicted by MetS in childhood beginning at age 5. However, adult type 2 diabetes mellitus and subclinical atherosclerosis were not predicted by childhood data until after age 8. Body mass index measurement alone at the same age points provided similar findings.

Left ventricular mass is a strong predictor of cardiovascular disease (CVD), and magnetic resonance imaging (MRI) of the heart is a standard of reference for left ventricular mass measurement. Ethnicity is believed to affect electrocardiographic (ECG) performance. We evaluated the diagnostic and prognostic performance of ECG for left ventricular hypertrophy (LVH) as defined by MRI in relationship to ethnicity. Data were analyzed from 4,967 participants (48% men, mean age 62 ± 10 years; 39% white, 13% Chinese, 26% African American, 22% Hispanic) enrolled in the Multi-Ethic Study of Atherosclerosis (MESA) who were followed for a median of 4.8 years for incident CVD. Thirteen traditional ECG-LVH criteria were assessed, and showed overall and ethnicity-specific low sensitivity (10%-26%) and high specificity (88%-99%) in diagnosing MRI-defined LVH. Ten of 13 ECG-LVH criteria showed superior sensitivity and diagnostic performance in African Americans as compared with whites (P = .02-.001). The sum of amplitudes of S wave in V1, S wave in V2, and R wave in V5 (a MESA-specific ECG-LVH criterion) offered higher sensitivity (40.4%) compared with prior ECG-LVH criteria while maintaining good specificity (90%) and diagnostic performance (receiver operating characteristic area = 0.65). In fully adjusted models, only the MESA-specific ECG-LVH criterion, Romhilt-Estes score, Framingham score, Cornell voltage, Cornell duration product, and Framingham-adjusted Cornell voltage predicted increased CVD risk (P < .05). Electrocardiography has low sensitivity but high specificity for detecting MRI-defined LVH. The performance of ECG for LVH detection varies by ethnicity, with African Americans showing higher sensitivity and overall performance compared with other ethnic groups.

Electrocardiographic bundle branch block (BBB) has higher cardiac and all-cause death. However, reports on the association between BBBs and mortality in the general populations are conflicting. The aim of this study was to evaluate the risk for coronary heart disease (CHD) and all-cause death associated with left BBB (LBBB) and right BBB (RBBB) during 14 years of follow-up in 66,450 participants from the Women's Health Initiative (WHI) study. Cox proportional-hazards regression was performed for mortality risk in Women with LBBB (n = 714) and those with RBBB (n = 832). In risk models adjusted for demographic and clinical risk factors in women with cardiovascular disease (CVD), hazard ratios for CHD death were 2.92 (95% confidence interval 2.08 to 4.08, p <0.001) for LBBB and 1.62 (95% confidence interval 1.08 to 2.43, p <0.05) for RBBB, and only LBBB was a significant predictor of all-cause death (hazard ratio 1.43, 95% confidence interval 1.11 to 1.83, p <0.01). In CVD-free women, only LBBB was a significant predictor of CHD death (fully adjusted hazard ratio 2.17, 95% confidence interval 1.37 to 3.43, p <0.01), and neither blocks was predictive of all-cause death. From several repolarization variables that were significant mortality predictors in univariate risk models, after adjustment for other electrocardiographic covariates and risk factors, ST J-point depression in lead aVL ≤−30 μV in women with LBBB was an independent predictor of CHD death, with a more than fivefold increase in risk. None of the repolarization variables were independent predictors in women with RBBB. In conclusion, prevalent LBBB in CVD-free women and LBBB and RBBB in women with CVD were significant predictors of CHD death. In women with LBBB, ST J-point depression in lead aVL was a strong independent predictor of CHD death. Electrocardiographic bundle branch block (BBB) has higher cardiac and all-cause death. However, reports on the association between BBBs and mortality in the general populations are conflicting. The aim of this study was to evaluate the risk for coronary heart disease (CHD) and all-cause death associated with left BBB (LBBB) and right BBB (RBBB) during 14 years of follow-up in 66,450 participants from the Women's Health Initiative (WHI) study. Cox proportional-hazards regression was performed for mortality risk in Women with LBBB (n = 714) and those with RBBB (n = 832). In risk models adjusted for demographic and clinical risk factors in women with cardiovascular disease (CVD), hazard ratios for CHD death were 2.92 (95% confidence interval 2.08 to 4.08, p <0.001) for LBBB and 1.62 (95% confidence interval 1.08 to 2.43, p <0.05) for RBBB, and only LBBB was a significant predictor of all-cause death (hazard ratio 1.43, 95% confidence interval 1.11 to 1.83, p <0.01). In CVD-free women, only LBBB was a significant predictor of CHD death (fully adjusted hazard ratio 2.17, 95% confidence interval 1.37 to 3.43, p <0.01), and neither blocks was predictive of all-cause death. From several repolarization variables that were significant mortality predictors in univariate risk models, after adjustment for other electrocardiographic covariates and risk factors, ST J-point depression in lead aVL ≤−30 μV in women with LBBB was an independent predictor of CHD death, with a more than fivefold increase in risk. None of the repolarization variables were independent predictors in women with RBBB. In conclusion, prevalent LBBB in CVD-free women and LBBB and RBBB in women with CVD were significant predictors of CHD death. In women with LBBB, ST J-point depression in lead aVL was a strong independent predictor of CHD death.

Atrial fibrillation (AF) is one of the most common arrhythmias seen in clinical practice. Current evidence suggests that serum uric acid (SUA) could be a marker of oxidative damage, a factor reported as a part of the mechanisms of AF. The purpose of the present study was to evaluate whether SUA predicted AF in the Atherosclerosis Risk In Communities (ARIC) study. The present analysis included 15,382 AF-free black and white men and women, aged 45 to 64 years, from the ARIC study, a population-based prospective cohort in the United States. SUA was determined using the uricase-peroxidase method at baseline. The primary outcome was the incidence of AF, defined as the occurrence of AF detected using hospital discharge codes, scheduled study electrocardiograms, and/or death certificates during the follow-up period (1987 to 2004). We identified 1,085 cases of incident AF. In Cox proportional hazards models adjusted for age, gender, race, center, education, body mass index, serum glucose, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, alcohol use, prevalent coronary heart disease and heart failure, serum creatinine, diuretics, and P-wave duration on the electrocardiogram (as a measure of left atrial size) at baseline, the hazard ratio of AF associated with a SD increment in SUA was 1.16 (95% confidence interval 1.06 to 1.26). The association of SUA with AF risk differed by race and gender (p for interaction <0.01). In conclusion, elevated SUA is associated with a greater risk of AF, particularly among blacks and women. Additional studies should replicate this association and explore potential mechanisms. Atrial fibrillation (AF) is one of the most common arrhythmias seen in clinical practice. Current evidence suggests that serum uric acid (SUA) could be a marker of oxidative damage, a factor reported as a part of the mechanisms of AF. The purpose of the present study was to evaluate whether SUA predicted AF in the Atherosclerosis Risk In Communities (ARIC) study. The present analysis included 15,382 AF-free black and white men and women, aged 45 to 64 years, from the ARIC study, a population-based prospective cohort in the United States. SUA was determined using the uricase-peroxidase method at baseline. The primary outcome was the incidence of AF, defined as the occurrence of AF detected using hospital discharge codes, scheduled study electrocardiograms, and/or death certificates during the follow-up period (1987 to 2004). We identified 1,085 cases of incident AF. In Cox proportional hazards models adjusted for age, gender, race, center, education, body mass index, serum glucose, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, alcohol use, prevalent coronary heart disease and heart failure, serum creatinine, diuretics, and P-wave duration on the electrocardiogram (as a measure of left atrial size) at baseline, the hazard ratio of AF associated with a SD increment in SUA was 1.16 (95% confidence interval 1.06 to 1.26). The association of SUA with AF risk differed by race and gender (p for interaction <0.01). In conclusion, elevated SUA is associated with a greater risk of AF, particularly among blacks and women. Additional studies should replicate this association and explore potential mechanisms.

This is a consortium of large children's cohorts that contain measurements of major cardiovascular disease (CVD) risk factors in childhood and had the ability to follow those cohorts into adulthood. The purpose of this consortium is to enable the pooling of data to increase power, most importantly for the follow-up of CVD events in adulthood. Within the consortium, we hope to be able to obtain data on the independent effects of childhood and early adult levels of CVD risk factors on subsequent CVD occurrence.

Blood pressure (BP) tracking (maintaining a BP percentile) across life is not well defined but is important in predicting which children will become hypertensive adults. We computed BP tracking in subjects with BP measured in childhood and adulthood and performed logistic regression to determine the ability of childhood BP to predict adult hypertension (N=5035, 46.7 years, 74.2% white, 17.7% black; 39.6% male). Prevalence of hypertension was 29%. Correlations between systolic BP for child and adolescent were r =0.48; for adolescent and young adult were r =0.40, and for child and young adult were r =0.24 (all P &lt;0.0001). Participants self-reporting adult hypertension were less likely to be white (38.7% black, 27.6% white, 20.9% other; P &lt;0.0001) and female (26.4% females, 32.9% male, P &lt;0.0001). Participants with adult hypertension were more likely to have higher BP and adiposity by age 10 years and abnormal lipids and glucose by age 16 years. There was a graded increase in the frequency of self-reported adult hypertension across the BP change groups, even within the persistently normotensive group (X 2 &lt;0.0001) from 19% in children with a systolic BP% persistently below the median to 80% for individuals with elevated BP in both childhood and adolescence. Although our precision to predict which individual child is at risk of adult BP-related cardiovascular disease is weak, an increase in systolic BP and body mass index percentile from childhood to adolescence should signal a need for lifestyle intervention to prevent future sustained hypertension-related cardiovascular disease.

OBJECTIVE To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. RESEARCH DESIGN AND METHODS From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively. RESULTS Over a median of 21 years (interquartile range 20–21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52]), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28]), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81]) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality. CONCLUSIONS Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.

Due to the sparse data on the repeatability of short and ultra-short term heart rate variability (HRV) measures, we measured the repeatability of common HRV measures derived from 10-second, 2-minute, and 6-minute recordings in 63 healthy men and women, aged 45-64, in Chapel Hill, North Carolina. Three 10-second and 2 six-minute heart rate recordings were obtained during each of 2 visits, separated by 1 to 2 weeks. We partitioned the measurement error into components and computed intraclass correlation coefficients using nested, random effects models. Repeatability improved with the length of recording: intraclass correlation coefficients were greater than 0.7 for 6-minute measures and 2-minute time domain measures and greater than 0.5 for 2-minute frequency domain measures. Repeatability of measures from 10-second records was lower, but improved considerably when the mean from 2 or 3 records was used. Correlations between the same measures from different length recordings were quite high. Our findings support the use of records of at least 5 minutes in length in epidemiological studies, in accordance with previous guidelines. Researchers using 10-second records should consider taking the mean of several recordings, when possible, or using statistical methods to correct for measurement error.

Objectives: To determine the levels and time trends of blood pressure and body size in a healthy population of youth. Study design: Minneapolis, Minnesota, fifth through eighth grade public school children (aged 10 to 14 years) were surveyed in 1986 and 1996. Blood pressure, height, and weight were measured by technicians trained to the same rigorous protocol at each time period, and comparisons were made between the 2 groups (1986 and 1996). Results: In 1986 and 1996, 8222 and 10,241 children, respectively, were measured with participation rates of over 93%. African American, Hispanic, Native American, Asian, and non-Hispanic white groups were all represented. Systolic blood pressure was significantly higher and diastolic blood pressure lower in 1996 than in 1986 in all ethnic and gender groups. Weight and body mass index (wt/ht2) were significantly higher in all groups in 1996. Adjustment for body size largely eliminated the systolic blood pressure differences but had no effect on measured diastolic blood pressure. Conclusions: Body size and systolic blood pressure are rising among school children. Weight and body mass index show substantial increases over 10 years (1986-1996). Diastolic blood pressure fell for unclear reasons. These changes may have future health implications for cardiovascular disease, as these youth move into adulthood. (J Pediatr 1999;134:668-74)

OBJECTIVE— To report long-term risks for total, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality associated with incident diabetes (using current diagnostic criteria) and with incident nonfatal CVD (NF-CVD). RESEARCH DESIGN AND METHODS— A total of 11,645 participants without diabetes or CVD at baseline from the Multiple Risk Factor Intervention Trial who survived to the end of the trial were grouped by during-trial incident diabetes and/or NF-CVD events: neither diabetes nor NF-CVD, diabetes only, NF-CVD only, or both diabetes and NF-CVD. Incident diabetes was defined by use of hypoglycemic agents or fasting glucose ≥126 mg/dl at any time over the 6 trial years. Proportional hazards models tested group differences in mortality over 18 post-trial years. RESULTS— Among 3,859 total deaths were 1,846 from CVD and 1,277 from CHD, with death rates per 10,000 person-years of 203, 97, and 67, respectively. Multivariate-adjusted hazard ratios (HRs) for total mortality were 2.75 (P &amp;lt; 0.0001) for those with NF-CVD and diabetes both, 1.92 (P &amp;lt; 0.0001) for those with NF-CVD only, and 1.49 (P &amp;lt; 0.0001) for those with diabetes only, relative to neither diabetes nor NF-CVD. NF-CVD was associated with a higher hazard of death than diabetes for total (HR 1.29, P = 0.0004), CVD (HR 1.76, P &amp;lt; 0.0001), and CHD (HR 1.88, P &amp;lt; 0.0001) mortality. Only the subgroup of participants on hypoglycemic agents showed an equivalent risk of total mortality relative to participants with NF-CVD (HR 0.93, P = 0.54). CONCLUSIONS— Current diabetes diagnostic criteria conferred significantly increased total, CVD, and CHD mortality risks independent of the impact of NF-CVD. NF-CVD was more strongly predictive of mortality.

There are scant data on the effect of body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters) on cardiovascular events and death in older patients with hypertension.To determine if low body mass in older patients with hypertension confers an increased risk of death or stroke.Participants were 3975 men and women (mean age, 71 years) enrolled in 17 US centers in the Systolic Hypertension in the Elderly Program trial, a randomized, double-blind, placebo-controlled clinical trial of lowdose antihypertensive therapy, with follow-up for 5 years.Five-year adjusted mortality and stroke rates from Cox proportional hazards analyses.There was no statistically significant relation of death or stroke with BMI in the placebo group (P = .47), and there was a U- or J-shaped relation in the treatment group. The J-shaped relation of death with BMI in the treated group (P = .03) showed that the lowest probability of death for men was associated with a BMI of 26.0 and for women with a BMI of 29.6; the curve was quite flat for women across a wide range of BMIs. For stroke, men and women did not differ, and the BMI nadir for both sexes combined was 29, with risk increasing steeply at BMIs below 24. Those in active treatment, however, had lower death and stroke rates compared with those taking placebo.Among older patients with hypertension, a wide range of BMIs was associated with a similar risk of death and stroke; a low BMI was associated with increased risk. Lean, older patients with hypertension in treatment should be monitored carefully for additional risk factors.

We examined the blood pressure of children with and without a family history of hypertension in a longitudinal study. Supine blood pressures were first measured in schoolchildren (mean age 8 years) in 1978 and then on nine more occasions until 1986. Blood pressures of parents were measured in the seated position and their medical histories were obtained in home interviews carried out between 1978 and 1979. Children with a family history of hypertension had a higher mean systolic blood pressure (SBP) at the first screening compared to children without such a family history. This difference persisted at each of the succeeding nine school visits. The parents in hypertensive families had a lower income, greater body weight, were less well-educated and were more likely to be black than parents in families without a history of hypertension. Mothers in hypertensive families were more likely to have a history of heart disease and elevated blood pressure during pregnancy than mothers in normotensive families. The correlations between blood pressure of mothers and their children tended to be higher than those between fathers and their children. Elevated blood pressure emerges well before adolescence among children with a family history of hypertension and the family environment appears to play an important role in its development.

Clinical and epidemiologic studies suggest that the intake of potassium chloride lowers blood pressure. To investigate whether supplemental potassium chloride (96 mmol of microcrystalline potassium chloride a day) reduced the need for antihypertensive medication in hypertensive men on a restricted-sodium diet, we conducted a randomized, placebo-controlled, double-blind clinical trial. A total of 287 men 45 to 68 years of age, 142 given potassium chloride and 145 given placebo, were followed for an average of 2.2 years after the withdrawal of their antihypertensive medication. Men in both groups received instructions on following a low-sodium diet. Overnight urinary sodium excretion fell from 63 mmol per eight hours at base line to an average of 45 mmol per eight hours during follow-up. Participants given supplemental potassium chloride had significantly higher (P less than 0.001) serum potassium levels and urinary potassium excretion (averaging 4.5 mmol per liter and 42.5 mmol per eight hours, respectively) during follow-up than participants given placebo (4.2 mmol per liter and 20.0 mmol per eight hours). Seventy-nine participants in each group required reinstitution of antihypertensive medication according to strict indications defined by the protocol. No significant differences in systolic or diastolic blood pressure were observed between the two groups. During follow-up, systolic and diastolic blood pressure averaged 130.6 and 82.5 mm Hg, respectively, for participants given supplemental potassium, and 132.5 and 83.1 mm Hg for participants given placebo. We conclude that supplemental potassium chloride does not reduce the need for antihypertensive medication in hypertensive men on a restricted-sodium diet.

We evaluated the association between dietary fish intake and several cardiac electrocardiographic parameters in humans relevant to arrhythmic risk. Fish consumption may reduce the incidence of sudden death and atrial fibrillation, possibly related to anti-arrhythmic effects. In a population-based study of 5,096 men and women, we evaluated cross-sectional associations between usual dietary fish intake and electrocardiographic measures of heart rate, atrioventricular conduction (PR interval), ventricular repolarization (QT interval), and ventricular conduction (QRS interval). Multivariate models were adjusted for age, gender, race, education, smoking, body mass index, diabetes, coronary heart disease, physical activity, and intakes of beef or pork, fried fish, fruits, vegetables, alcohol, and total calories. Consumption of tuna or other broiled or baked fish (comparing the highest to the lowest category of intake) was associated with lower heart rate (−3.2 beats/min, 95% confidence interval [CI] = 1.3 to 5.1; p trend <0.001), slower atrioventricular conduction (PR interval +7.2 ms, 95% CI = 1.4 to 12.9; p trend = 0.03), and substantially lower likelihood of prolonged QT (relative risk = 0.50, 95% CI = 0.27 to 0.95; p trend = 0.03). Tuna/other fish intake was not associated with ventricular conduction (p = 0.60). Findings were similar for estimated intake of marine n-3 fatty acids: a 1 g/day higher intake was associated with 2.3 beats/min lower heart rate (95% CI = 0.9 to 3.7), 7.6 ms longer PR interval (95% CI = 3.3 to 11.9), and 46% lower likelihood of prolonged QT (relative risk = 0.54, 95% CI = 0.33 to 0.88). These findings in this large, population-based study suggest that dietary fish intake is associated with cardiac electrophysiology in humans, including heart rate, atrioventricular conduction, and ventricular repolarization, with potential implications for arrhythmic risk.

The association between ventricular premature complexes (VPCs) detected on a rest 2-minute lead I electrocardiographic rhythm strip and sudden cardiac death (SCD), occurring within 1 hour of onset of symptoms, was evaluated in a prospective study of 15,637 apparently healthy white men, aged 35 to 57 years, at the first screening examination (1973 to 1975) to determine eligibility for the Multiple Risk Factor Intervention Trial in Minneapolis/St. Paul, Minnesota. The prevalence of any VPC was 4.4% (681 of 15,637). Over an average follow-up period of 7.5 years, a total of 381 deaths occurred. Of these, 34% (131 of 381) were ascribed to coronary artery disease (CAD) and 31% of the CAD deaths (41 of 131) occurred suddenly. The presence of any VPC was associated with a significantly higher risk for SCD (adjusted relative risk = 3.0; p less than 0.025). On the other hand, the presence of any VPC was not associated with any significant increase in the risk of non-SCD or of total deaths from CAD (adjusted relative risk = 1.0 and 1.6, respectively). When VPC characteristics such as frequency (2 or more uniform VPCs every 2 minutes) and complexity (multiforms, pairs, runs, R-on-T) were examined, those with frequent or complex VPCs were at a significantly increased risk of SCD (adjusted relative risk = 4.2; p less than 0.005), whereas for non-SCD no significant increase in risk was found (adjusted relative risk = 1.6; p = 0.28).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE—To examine the long-term association of metabolic syndrome with mortality among those at high risk for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS—A total of 10,950 Multiple Risk Factor Intervention Trial (MRFIT) survivors were followed for mortality an additional median 18.4 years (1980–1999). Proportional hazards models examined multivariate-adjusted risks associated with Adult Treatment Panel III–defined metabolic syndrome conditions, with BMI substituted for waist circumference. RESULTS—At MRFIT annual visit 6, 4,588 (41.9%) men, mean age (±SD) 53.0 ± 5.9 years, had metabolic syndrome and 6,362 did not. Comparing men with metabolic syndrome to men without, adjusted hazard ratios (HRs) were 1.21 (95% CI 1.13–1.29), 1.49 (1.35–1.64), and 1.51 (1.34–1.70) for 18-year total, CVD, and coronary heart disease mortality, respectively. Among men with metabolic syndrome, elevated glucose (1.54 [1.34–1.78]) and low HDL cholesterol (1.45 [1.17–1.54]) were most predictive of CVD mortality, followed by elevated BMI (1.34 [1.17–1.54]), elevated blood pressure (1.25 [0.98–1.58]), and elevated triglycerides (1.06 [0.86–1.30]). In contrast, for men without metabolic syndrome, the HR for low HDL cholesterol was 1.02 (0.86–1.22). Among metabolic syndrome men with no nonfatal CVD event, smokers with elevated LDL cholesterol showed higher CVD mortality (1.79 [1.22–2.63]) compared with nonsmokers without elevated LDL cholesterol; this additional risk was even greater for metabolic syndrome men with a nonfatal CVD event (2.11 [1.32–3.38]). CONCLUSIONS—Metabolic syndrome is associated with an increased risk of mortality. Among those with metabolic syndrome, risk is further increased by having more metabolic syndrome conditions, by cigarette smoking, and by elevated LDL cholesterol. Primary prevention of each metabolic syndrome condition should be emphasized, and presence of each condition should be treated in accordance with current guidelines.

Black individuals younger than 75 years have more than twice the risk for stroke death than whites in the United States. Regardless of race, stroke death is approximately 50% greater in the "stroke belt" and "stroke buckle" states of the Southeastern United States. We assessed geographic and racial differences in estimated 10-year stroke risk.The Reasons for Geographic and Racial Differences in Stroke study is a population-based cohort of men and women 45 years or older, recruited February 2003 to September 2007 at this report, with oversampling of stroke belt/buckle residents and blacks. Racial and regional differences in the Framingham Stroke Risk Score were studied in 23,940 participants without previous stroke or transient ischemic attack.The mean age-, race-, and sex-adjusted 10-year predicted stroke probability differed slightly across regions: 10.7% in the belt, 10.4% in the buckle, and 10.1% elsewhere (p <0.001). Geographic differences were largest for the score components of diabetes and use of antihypertensive therapy. Blacks had a greater age- and sex-adjusted mean 10-year predicted stroke probability than whites: 12.0 versus 9.2%, respectively (p <0.001). Race differences were largest for the score components of hypertension, systolic blood pressure, diabetes, smoking, and left ventricular hypertrophy.Although blacks had a greater predicted stroke probability than whites, regional differences were small. Results suggest that interventions to reduce racial disparities in stroke risk factors hold promise to reduce the racial disparity in stroke mortality. The same may not be true regarding geographic disparities in stroke mortality.

Data are reported on electrocardiographic left ventricular hypertrophy (ECG LVH) among 8,012 men classified as hypertensive at baseline in the Multiple Risk Factor Intervention Trial. Compared with those allocated to the usual care (UC) control group, men allocated to the special intervention (SI) group experienced a mean reduction of 4 mm Hg in diastolic blood pressure and 7 mm Hg in systolic blood pressure, over 6 years of follow-up. There were 378 new cases of ECG LVH during follow-up; the incidence in the SI group was about 23% less than that in the UC group (4.2 vs 5.4% 2P < 0.01). Among the 189 men with ECG LVH at baseline, those in the SI group experienced about 24% more annual follow-up visits at which they were free of ECG LVH (4.6 vs 3.7 visits; 2P < 0.01). This reduced incidence and increased reversal of ECG LVH in the SI group compared with that in the UC group was consistent with significant overall reductions (2P < 0.001) among SI men in mean wave amplitude in those leads in which voltage is correlated with left ventricular mass (T wave in V1, R wave in aVL and S wave in V3). In SI and UC groups combined, the presence of ECG LVH either at baseline or at follow-up was associated with several-fold increases in death from cardiovascular diseases in general, and death from coronary artery disease in particular. While mortality from cardiovascular disease, including coronary artery disease, was not significantly different in SI and UC groups during follow-up, moderate though still potentially worthwhile benefits that might accompany the observed ECG changes cannot be excluded.

Anecdotes have long suggested that caffeine-containing beverages and other personal habits and excesses trigger palpitations and cardiac extrasystoles. We took the opportunity of a systematic population survey of 7311 men, aged 37–57 yr and free of any history of heart disease or diabetes, to examine the association of ventricular premature beats (VPB) with food and drink, cigarette smoking and sleep habits. Blood pressure and serum cholesterol were also measured and a 2-min rest electrocardiogram recorded at a screening station. In multiple regression analysis a significant relationship with prevalence of VPB was found for age and for the average daily number of cups of tea or coffee consumed, adjusting simultaneously for the influence of other factors. Heavy coffee consumption (≥9 cups/day) was associated with more than twice the likelihood of VPB being present at any age, compared to light consumption (≤2 cups/day) or abstinence.

The associations of abdominal adiposity, fasting serum levels of insulin, and sex hormones with blood lipids, lipoproteins, and apolipoproteins A-I and B were studied cross-sectionally in 75 healthy, postmenopausal white women. In univariate analyses, abdominal adiposity (increased waist-to-hip girth ratio) and fasting insulin concentrations were negatively and significantly associated (P less than 0.05) with plasma high density lipoprotein cholesterol (r = -0.47 and -0.38, respectively) and apolipoprotein A-I (r = -0.37 and -0.36), and positively associated with log triglycerides (r = 0.54 and 0.33) and apolipoprotein B (r = 0.43 and 0.22). Sex hormone binding globulin was positively and significantly associated with high density lipoprotein cholesterol (r = 0.32) and negatively associated with log triglyceride (r = -0.45) and apolipoprotein B (r = -0.36). Estrone was positively and significantly associated with high density lipoprotein cholesterol (r = 0.27), apolipoprotein A-I (r = 0.23) and negatively associated with low density lipoprotein cholesterol (r = -0.24) and apolipoprotein B (r = -0.25). Total estradiol, free estradiol, free testosterone, and total testosterone were more weakly associated with the lipid measures. In multivariate analyses, abdominal adiposity remained significantly associated with high density lipoprotein cholesterol, log triglycerides, apolipoproteins A-I and B after adjustment for sex hormone binding globulin, estrone, and insulin concentrations. Insulin remained associated only with apolipoprotein A-I after adjustment for abdominal adiposity, estrone, and sex hormone binding globulin. Sex hormone binding globulin remained marginally associated with log triglyceride (P = 0.07) after adjustment for the remaining three factors. Estrone remained significantly associated with high density lipoprotein cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the relation between diuretic use and ventricular premature complexes (VPCs) in the Multiple Risk Factor Intervention Trial, data derived from the baseline and annual rest electrocardiograms were analyzed for men in the special-intervention (SI) and usual-care (UC) groups. At baseline, age, diuretic use and presence of other rest electrocardiographic abnormalities were significantly associated with the prevalence of VPCs. Among diuretic users at baseline, those with lower serum potassium levels were most likely to have VPCs. Over the follow-up period among nonhypertensive persons the relative risk (SI/UC) for the occurrence of VPCs during follow-up was 0.83, and for hypertensives this relative risk increased linearly from 1.08 to 1.42, with higher levels of diastolic blood pressure at entry (p < 0.01 for linear trend of relative risk estimates). This was due to an increasing risk among the SI group, and the risk was independent of the presence or absence of rest electrocardiographic abnormalities at baseline. The relative risk estimate, diuretic vs no diuretic, for development of VPCs was approximately 1.2 (p = 0.04) for SI men and 1.1 (p = 0.35) for UC men. The reduction in serum potassium level was greater for those with VPCs, and regression analysis showed that low serum potassium levels were significantly associated with the incidence of VPCs in both study groups. These data confirm and quantify the relation between diuretic drugs and VPCs and suggest that at least 1 mechanism of diuretic-induced VPCs is potassium depletion.

The association of insulin resistance and body mass index (BMI) at age 13 years and change in insulin resistance and BMI from ages 13 to 19 years with systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol at age 19 years was studied in black and non-Hispanic white children. Insulin clamps were conducted at mean ages 13 (N=357), 15 (N=309), and 19 (N=224) years with insulin resistance adjusted for lean body mass. A repeated-measures multiple regression model was used to predict the 3 risk factors and the clustering of the factors with fasting insulin (the insulin resistance [metabolic] syndrome score) at age 19 years from levels of insulin resistance and BMI at age 13 and their changes from ages 13 to 19 years. The tracking correlation between ages 13 and 19 was 0.85 for BMI and 0.42 for insulin resistance. It was 0.18 for fasting insulin (P=0.01) and P=0.11 after adjustment for BMI. In a multiple regression analysis, BMI at 13 years did not predict any of the risk factors at age 19; change in BMI predicted all 3 of the factors and score; insulin resistance at 13 years predicted systolic blood pressure, triglycerides, and score; change in insulin resistance predicted triglycerides and score. These results show an effect for insulin resistance that is independent of BMI, consistent with the hypothesis that reducing insulin resistance, in addition to weight, may be needed to reduce the prevalence of cardiovascular risk.

Introduction Adult obesity and hypertension are leading causes of cardiovascular morbidity/mortality. Although childhood BMI and blood pressure (BP) track into adulthood, how they influence adult cardiovascular risk independent of each other is not well defined. Methods Participants were from two longitudinal studies with a baseline evaluation at mean age of 13 years and a follow-up at mean age of 24 years. Regression models using childhood BP and BMI to predict young adult cardiovascular risk factors were performed. Results In univariate analysis, childhood BMI predicted young adult BP, lipids, glucose, insulin and insulin resistance, whereas childhood BP predicted young adult BP, lipids and glucose. In a multivariable regression model (adjusted for age, sex and race), which included change in BMI and BP from age 13 to 24 years, BMI predicted all young adult risk factors except BP and glucose. Baseline SBP predicted young adult BP, cholesterol, triglycerides and glucose whereas baseline DBP predicted young adult BP, BMI and glucose. Conclusion The results from this study show that BP and BMI act independently in children to influence future cardiovascular risk factors and the combination of high BP and BMI in childhood has an additive effect in predicting the highest levels of young adult cardiovascular risk. Thus, there should be a focus on treating hypertension in overweight and obese children, in addition to attempting to reduce weight.

Atrial fibrillation (AF) is the most common arrhythmia in women. Large studies evaluating key AF risk factors in older women are lacking. We aimed to identify risk factors for AF in postmenopausal women and measure population burden of modifiable risk factors.Prospective observational study.The Women's Health Initiative (WHI) Observational Study.93 676 postmenopausal women were followed for an average of 9.8 years for cardiovascular outcomes. After exclusion of women with prevalent AF or incomplete data, 8252 of the remaining 81 892 women developed incident AF.Incident AF was identified by WHI-ascertained hospitalisation records and diagnosis codes from Medicare claims. Multivariate Cox hazard regression analysis identified independent risk factors for incident AF.Age, hypertension, obesity, diabetes, myocardial infarction and heart failure were independently associated with incident AF. Hypertension and overweight status accounted for 28.3% and 12.1%, respectively, of the population attributable risk. Hispanic and African-American participants had lower rates of incident AF (HR 0.58, 95% CI 0.47 to 0.70 and HR 0.59, 95% CI 0.53 to 0.65, respectively) than Caucasians.Caucasian ethnicity, traditional cardiovascular risk factors and peripheral arterial disease were independently associated with higher rates of incident AF in postmenopausal women. Hypertension and overweight status accounted for a large proportion of population attributable risk. Measuring burden of modifiable AF risk factors in older women may help target interventions.

Newer approaches for classifying gradations of pediatric obesity by level of body mass index (BMI) percentage above the 95th percentile have recently been recommended in the management and tracking of obese children. Examining the prevalence and persistence of severe obesity using such methods along with the associations with other cardiovascular risk factors such as hypertension is important for characterizing the clinical significance of severe obesity classification methods. This retrospective study was conducted in an integrated healthcare delivery system to characterize obesity and obesity severity in children and adolescents by level of body mass index (BMI) percentage above the 95th BMI percentile, to examine tracking of obesity status over 2–3 years, and to examine associations with blood pressure. Moderate obesity was defined by BMI 100-119% of the 95th percentile and severe obesity by BMI ≥120% × 95th percentile. Hypertension was defined by 3 consecutive blood pressures ≥95th percentile (for age, sex and height) on separate days and was examined in association with obesity severity. Among 117,618 children aged 6–17 years with measured blood pressure and BMI at a well-child visit during 2007–2010, the prevalence of obesity was 17.9% overall and was highest among Hispanics (28.9%) and blacks (20.5%) for boys, and blacks (23.3%) and Hispanics (21.5%) for girls. Severe obesity prevalence was 5.6% overall and was highest in 12–17 year old Hispanic boys (10.6%) and black girls (9.5%). Subsequent BMI obtained 2–3 years later also demonstrated strong tracking of severe obesity. Stratification of BMI by percentage above the 95th BMI percentile was associated with a graded increase in the risk of hypertension, with severe obesity contributing to a 2.7-fold greater odds of hypertension compared to moderate obesity. Severe obesity was found in 5.6% of this community-based pediatric population, varied by gender and race/ethnicity (highest among Hispanics and blacks) and showed strong evidence for persistence over several years. Increasing gradation of obesity was associated with higher risk for hypertension, with a nearly three-fold increased risk when comparing severe to moderate obesity, underscoring the heightened health risk associated with severe obesity in children and adolescents.

Electrocardiography has been considered an important tool in the management of Chagas disease (ChD) patients, although its value in elderly infected patients is unknown. This study was designed to investigate the prevalence and prognostic value of electrocardiographic abnormalities in Trypanosoma cruzi infected and noninfected older adults.We studied 1462 participants in Bambuí City, Brazil, with electrocardiogram (ECG) records classified by the Minnesota Code. Follow-up time was 10 years; the endpoint was mortality. Adjustment for potential confounding variables included age, gender, conventional risk factors, and B-type natriuretic peptide (BNP). The mean age was 69 years (60.9% women). The prevalence of ChD was 38.1% (n=557). ECG abnormalities were more frequent in ChD patients (87.6% versus 77.7%, P<0.001). Right bundle branch block (RBBB) with left anterior hemiblock (LAH) was strongly related to ChD (OR: 11.99 [5.60 to 25.69]). During the mean follow-up time of 8.7 years, 556 participants died (253 with ChD), and only 89 were lost to follow-up. ECG variables of independent prognostic value for death in ChD included absence of sinus rhythm, frequent ventricular and supraventricular premature beats, atrial fibrillation, RBBB, old and possible old myocardial infarction, and left ventricular hypertrophy. The presence of any major ECG abnormalities doubled the risk of death in ChD patients (HR: 2.18 [1.35 to 3.53]), but it also increased the risk in non-ChD subjects (HR: 1.50 [1.07 to 2.10]); the risk of death increased with the number of major abnormalities in the same patient.ECG abnormalities are more common among elderly Chagas disease patients and strongly predict adverse outcomes.

Death certificates may lack accuracy and misclassify the cause of death. The validity of proxy-reported cause of death is not well established. The authors examined death records on 336 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a national cohort study of 30,239 community-dwelling US adults (2003-2010). Trained experts used study data, medical records, death certificates, and proxy reports to adjudicate causes of death. The authors computed agreement on cause of death from the death certificate, proxy, and adjudication, as well as sensitivity and specificity for certain diseases. Adjudicated cause of death had a higher rate of agreement with proxy reports (73%; Cohen's kappa (κ) statistic = 0.69) than with death certificates (61%; κ = 0.54). The agreement between proxy reports and adjudicators was better than agreement with death certificates for all disease-specific causes of death. Using the adjudicator assessments as the "gold standard," for disease-specific causes of death, proxy reports had similar or higher specificity and higher sensitivity (sensitivity = 50%-89%) than death certificates (sensitivity = 31%-81%). Proxy reports may be more concordant with adjudicated causes of death than with the causes of death listed on death certificates. In many settings, proxy reports may represent a better strategy for determining cause of death than reliance on death certificates.

Goals for cardiovascular (CV) disease prevention were set by the American Heart Association in 2010 for the concept of CV health. Ideal CV health is defined by 7 CV health metrics: blood pressure, glucose, cholesterol, body mass index, and physical activity on recommended levels; nonsmoking; and a healthy diet. We studied the prevalence of ideal CV health and its associations with ultrasonographically measured carotid intima-media thickness (cIMT) cross-sectionally in 5 international populations.Prevalence of ideal CV health was assessed among 5785 young adults (age, 36.6 ± 3.2 years) comprising 335 participants from the Minneapolis Childhood Cohort Studies (Minnesota), 723 from the Princeton Follow-up Study, 981 from the Bogalusa Heart Study (BHS), 1898 from the Cardiovascular Risk in Young Finns Study (YFS), and 1848 from the Childhood Determinants of Adult Health Study (CDAH). Only 1% of the participants had all 7 ideal CV health metrics. The number of ideal CV health metrics associated inversely with cIMT in the 4 cohorts in which cIMT was available: for each additional ideal CV health metric, cIMT was 12.7 μm thinner in Minnesota (P=0.0002), 9.1 μm thinner in BHS (P=0.05), 10.4 μm thinner in YFS (P<0.0001), and 3.4 μm thinner in CDAH (P=0.03).The number of ideal CV health metrics was inversely associated with cIMT in the cohorts in which cIMT was available, indicating that ideal CV health metrics are associated with vascular health at the population level. Ideal CV health was rare in this large international sample of young adults, emphasizing the need for effective strategies for health promotion.

The objective of this analysis was to determine the natural history and prospective association of cardiovascular risk factors with early repolarization (ER). ER is common and has been suggested to increase risk for cardiovascular mortality in middle-aged adults. Data are sparse regarding the natural history of ER from young adulthood to middle age. We examined 5,069 participants (mean age 25 years at baseline; 40% black) from the CARDIA (Coronary Artery Risk Development in Young Adults) cohort over 20 years. Electrocardiograms were recorded at years 0 (Y0), 7 (Y7), and 20 (Y20) and coded as either definite, probable, possible, or no ER. Logistic regression was used to determine the association of cardiovascular risk factors with the presence of ER cross-sectionally and prospectively. A total of 941 of the 5,069 participants (18.6%) had definite ER at baseline, and only 119 of 2,505 participants (4.8%) at the Y20 examination still demonstrated the presence of ER. Younger age, black race, male sex, longer exercise duration and QRS duration, and lower body mass index (BMI), heart rate, QT index, and Cornell voltage were associated cross-sectionally with the presence of ER. Predictors of maintenance of ER from Y0 to Y20 were black race (odds ratio [OR]: 2.62; 95% CI; 1.61 to 4.25), BMI (OR: 0.62 per 1 SD; 95% CI: 0.40 to 0.94), serum triglyceride levels (OR: 0.66 per 1 SD; 95% CI: 0.45 to 0.98), and QRS duration (OR: 1.68 per 1 SD; 95% CI: 1.37 to 2.06) at baseline. The prevalence of ER was significantly higher than previous estimates among asymptomatic young adults, and the majority of ER regressed by middle age. Black race, lower BMI, lower serum triglyceride levels, and longer QRS duration were independently associated with maintenance of ER over time.

Background Prior studies have demonstrated a link between the metabolic syndrome and increased risk of cardiovascular mortality. Whether the metabolic syndrome is associated with sudden cardiac death is uncertain. Methods and Results We characterized the relationship between sudden cardiac death and metabolic syndrome status among participants of the ARIC (Atherosclerosis Risk in Communities) Study (1987–2012) free of prevalent coronary heart disease or heart failure. Among 13 168 participants, 357 (2.7%) sudden cardiac deaths occurred during a median follow‐up of 23.6 years. Participants with the metabolic syndrome (n=4444) had a higher cumulative incidence of sudden cardiac death than those without it (n=8724) (4.1% versus 2.3%, P &lt;0.001). After adjustment for participant demographics and clinical factors other than components of the metabolic syndrome, the metabolic syndrome was independently associated with sudden cardiac death (hazard ratio, 1.70, 95% confidence interval, 1.37–2.12, P &lt;0.001). This relationship was not modified by sex (interaction P =0.10) or race (interaction P =0.62) and was mediated by the metabolic syndrome criteria components. The risk of sudden cardiac death varied according to the number of metabolic syndrome components (hazard ratio 1.31 per additional component of the metabolic syndrome, 95% confidence interval, 1.19–1.44, P &lt;0.001). Of the 5 components, elevated blood pressure, impaired fasting glucose, and low high‐density lipoprotein were independently associated with sudden cardiac death. Conclusions We observed that the metabolic syndrome was associated with a significantly increased risk of sudden cardiac death irrespective of sex or race. The risk of sudden cardiac death was proportional to the number of metabolic syndrome components.

Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.

Data suggest that the prediction of adult cardiovascular disease using a model comprised entirely of adult nonlaboratory-based risk factors is equivalent to an approach that additionally incorporates adult lipid measures. We assessed and compared the utility of a risk model based solely on nonlaboratory risk factors in adolescence versus a lipid model based on nonlaboratory risk factors plus lipids for predicting high-risk carotid intima-media thickness (cIMT) in adulthood.The study comprised 2893 participants 12 to 18 years of age from 4 longitudinal cohort studies from the United States (Bogalusa Heart Study and the Insulin Study), Australia (Childhood Determinants of Adult Health Study), and Finland (The Cardiovascular Risk in Young Finns Study) and followed into adulthood when cIMT was measured (mean follow-up, 23.4 years). Overweight status was defined according to the Cole classification. Hypertension was defined according to the Fourth Report on High Blood Pressure in Children and Adolescents from the National High Blood Pressure Education Program. High-risk plasma lipid levels were defined according to the National Cholesterol Education Program Expert Panel on Cholesterol Levels in Children. High cIMT was defined as a study-specific value ≥90th percentile. Age and sex were included in each model.In univariate models, all risk factors except for borderline high and high triglycerides in adolescence were associated with high cIMT in adulthood. In multivariable models (relative risk [95% confidence interval]), male sex (2.7 [2.0-2.6]), prehypertension (1.4 [1.0-1.9]), hypertension (1.9 [1.3-2.9]), overweight (2.0 [1.4-2.9]), obesity (3.7 [2.0-7.0]), borderline high low-density lipoprotein cholesterol (1.6 [1.2-2.2]), high low-density lipoprotein cholesterol (1.6 [1.1-2.1]), and borderline low high-density lipoprotein cholesterol (1.4 [1.0-1.8]) remained significant predictors of high cIMT (P<0.05). The addition of lipids into the nonlaboratory risk model slightly but significantly improved discrimination in predicting high cIMT compared with nonlaboratory-based risk factors only (C statistics for laboratory-based model 0.717 [95% confidence interval, 0.685-0.748] and for nonlaboratory 0.698 [95% confidence interval, 0.667-0.731]; P=0.02).Nonlaboratory-based risk factors and lipids measured in adolescence independently predicted preclinical atherosclerosis in young adulthood. The addition of lipid measurements to traditional clinic-based risk factor assessment provided a statistically significant but clinically modest improvement on adolescent prediction of high cIMT in adulthood.

Silent myocardial infarction (SMI) accounts for about half of the total number of MIs, and is associated with poor prognosis as is clinically documented MI (CMI). The electrocardiographic (ECG) spatial QRS/T angle has been a strong predictor of cardiovascular outcomes. Whether spatial QRS/T angle also is predictive of SMI, and the easy-to-obtain frontal QRS/T angle will show similar association are currently unknown. We examined the association between the spatial and frontal QRS/T angles, separately, with incident SMI among 9498 participants (mean age 54 years, 57% women, and 20% African-American), who were free of cardiovascular disease at baseline (visit 1, 1987–1989) from the Atherosclerosis Risk in Communities (ARIC) study. Incident SMI was defined as MI occurring after the baseline until visit 4 (1996–1998) without CMI. The frontal plane QRS/T angle was defined as the absolute difference between QRS axis and T axis. Values greater than the sex-specific 95th percentiles of the QRS/T angles were considered wide (abnormal). A total of 317 (3.3%) incident SMIs occurred during a 9-year median follow-up. In a model adjusted for demographics, cardiovascular risk factors and potential confounders, both abnormal frontal (HR 2.28, 95% CI 1.58–3.29) and spatial (HR 2.10, 95% CI 1.44–3.06) QRS/T angles were associated with an over 2-fold increased risk of incident SMI. Similar patterns of associations were observed when the results were stratified by sex. Both frontal and spatial QRS/T angles are predicative of SMI suggesting a potential use for these markers in identifying individuals at risk.

Adult class II/III obesity (BMI ≥ 35 kg/m2) has significant adverse health outcomes. Early prevention and treatment are critical, but prospective childhood risk estimates are lacking. This study aimed to define the prospective risk of adult class II/III obesity, using childhood BMI.Children ages 3-19 years enrolled in cohorts of the International Childhood Cardiovascular Cohort (i3C) consortium with measured BMI assessments in childhood and adulthood were included. Prospective risk of adult class II/III obesity was modeled based on childhood age, sex, race, and BMI.A total of 12,142 individuals (44% male, 85% white) were assessed at median age 14 [Interquartile range, IQR: 11, 16] and 33 [28, 39] years. Class II/III adult obesity developed in 6% of children with normal weight; 29% of children with overweight; 56% of children with obesity; and 80% of children with severe obesity. However, 38% of the 1440 adults with class II/III obesity (553/1440) were normal weight as children. Prospective risk of adult class II/III obesity varied by age, sex, and race within childhood weight status classifications, and is notably higher for girls, black participants, and those in the United States. The risk of class II/III obesity increased with older adult age.Children with obesity or severe obesity have a substantial risk of adult class II/III obesity, and observed prospective risk estimates are now presented by age, sex, race, and childhood BMI. Clinical monitoring of children's BMI for adult class II/III obesity risk may be especially important for females and black Americans.

Across the Diabetes Prevention Program (DPP) follow-up, cumulative diabetes incidence remained lower in the lifestyle compared with the placebo and metformin randomized groups and could not be explained by weight. Collection of self-reported physical activity (PA) (yearly) with cross-sectional objective PA (in follow-up) allowed for examination of PA and its long-term impact on diabetes prevention.Yearly self-reported PA and diabetes assessment and oral glucose tolerance test results (fasting glucose semiannually) were collected for 3,232 participants with one accelerometry assessment 11-13 years after randomization (n = 1,793). Mixed models determined PA differences across treatment groups. The association between PA and diabetes incidence was examined using Cox proportional hazards models.There was a 6% decrease (Cox proportional hazard ratio 0.94 [95% CI 0.92, 0.96]; P < 0.001) in diabetes incidence per 6 MET-h/week increase in time-dependent PA for the entire cohort over an average of 12 years (controlled for age, sex, baseline PA, and weight). The effect of PA was greater (12% decrease) among participants less active at baseline (<7.5 MET-h/week) (n = 1,338) (0.88 [0.83, 0.93]; P < 0.0001), with stronger findings for lifestyle participants. Lifestyle had higher cumulative PA compared with metformin or placebo (P < 0.0001) and higher accelerometry total minutes per day measured during follow-up (P = 0.001 and 0.047). All associations remained significant with the addition of weight in the models.PA was inversely related to incident diabetes in the entire cohort across the study, with cross-sectional accelerometry results supporting these findings. This highlights the importance of PA within lifestyle intervention efforts designed to prevent diabetes and urges health care providers to consider both PA and weight when counseling high-risk patients.