Physical activity, inflammation, and volume of the aging brain.

Physical activity influences inflammation, and both affect brain structure and Alzheimer's disease (AD) risk. We hypothesized that older adults with greater reported physical activity intensity and lower serum levels of the inflammatory marker tumor necrosis factor α (TNFα) would have larger regional brain volumes on subsequent magnetic resonance imaging (MRI) scans. In 43 cognitively intact older adults (79.3±4.8 years) and 39 patients with AD (81.9±5.1 years at the time of MRI) participating in the Cardiovascular Health Study, we examined year-1 reported physical activity intensity, year-5 blood serum TNFα measures, and year-9 volumetric brain MRI scans. We examined how prior physical activity intensity and TNFα related to subsequent total and regional brain volumes. Physical activity intensity was measured using the modified Minnesota Leisure Time Physical Activities questionnaire at year 1 of the study, when all subjects included here were cognitively intact. Stability of measures was established for exercise intensity over 9 years and TNFα over 3 years in a subset of subjects who had these measurements at multiple time points. When considered together, more intense physical activity intensity and lower serum TNFα were both associated with greater total brain volume on follow-up MRI scans. TNFα, but not physical activity, was associated with regional volumes of the inferior parietal lobule, a region previously associated with inflammation in AD patients. Physical activity and TNFα may independently influence brain structure in older adults.

Generalization of adiposity genetic loci to US Hispanic women.

BACKGROUND: Obesity is a public health concern. Yet the identification of adiposity-related genetic variants among United States (US) Hispanics, which is the largest US minority group, remains largely unknown. OBJECTIVE: To interrogate an a priori list of 47 (32 overall body mass and 15 central adiposity) index single-nucleotide polymorphisms (SNPs) previously studied in individuals of European descent among 3494 US Hispanic women in the Women's Health Initiative SNP Health Association Resource (WHI SHARe). DESIGN: Cross-sectional analysis of measured body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were inverse normally transformed after adjusting for age, smoking, center and global ancestry. WC and WHR models were also adjusted for BMI. Genotyping was performed using the Affymetrix 6.0 array. In the absence of an a priori selected SNP, a proxy was selected (r(2)0.8 in CEU). RESULTS: Six BMI loci (TMEM18, NUDT3/HMGA1, FAIM2, FTO, MC4R and KCTD15) and two WC/WHR loci (VEGFA and ITPR2-SSPN) were nominally significant (P<0.05) at the index or proxy SNP in the corresponding BMI and WC/WHR models. To account for distinct linkage disequilibrium patterns in Hispanics and further assess generalization of genetic effects at each locus, we interrogated the evidence for association at the 47 surrounding loci within 1 Mb region of the index or proxy SNP. Three additional BMI loci (FANCL, TFAP2B and ETV5) and five WC/WHR loci (DNM3-PIGC, GRB14, ADAMTS9, LY86 and MSRA) displayed Bonferroni-corrected significant associations with BMI and WC/WHR. Conditional analyses of each index SNP (or its proxy) and the most significant SNP within the 1 Mb region supported the possible presence of index-independent signals at each of these eight loci as well as at KCTD15. CONCLUSION: This study provides evidence for the generalization of nine BMI and seven central adiposity loci in Hispanic women. This study expands the current knowledge of common adiposity-related genetic loci to Hispanic women.

Significant inverse association of marine n-3 fatty acids with plasma fibrinogen levels in Japanese in Japan but not in whites or Japanese Americans.

BACKGROUND/OBJECTIVES: Numerous studies reported beneficial effects of marine n-3 fatty acids (n-3 FAs) on cardiovascular disease (CVD) and its risk factors. However, the association of marine n-3 FAs with plasma fibrinogen, a risk factor for CVD, remains uncertain. SUBJECTS/METHODS: In a population-based, cross-sectional study of 795 men aged 40-49 without CVD (262 whites in Allegheny County, Pennsylvania, USA, 302 Japanese in Kusatsu, Japan and 229 Japanese Americans in Honolulu, Hawaii, USA), we examined the association of marine n-3 FAs with plasma fibrinogen. Serum FAs were measured by capillary gas-liquid chromatography. Marine n-3 FAs were defined as the sum of docosahexaenoic, eicosapentaenoic and docosapentaenoic acids. Plasma fibrinogen was measured by an automated clot-rate assay. Multiple linear regression analyses were performed to assess the association. RESULTS: White, Japanese and Japanese-American men had mean marine n-3 FAs levels of 3.47%, 8.78% and 4.46%, respectively. Japanese men had a significant inverse association of marine n-3 FAs with fibrinogen (standardized regression coefficient of -0.11, P=0.049), after adjusting for age, body-mass index and current smoking. The significant inverse association remained after further adjusting for diabetes, C-reactive protein, triglycerides and other variables. White or Japanese-American men did not show a significant association. CONCLUSIONS: We observed the significant inverse association of marine n-3 FAs with fibrinogen in Japanese, but not in whites or Japanese Americans. The observation suggests that marine n-3 FAs at very high levels, as seen in the Japanese, may decrease plasma fibrinogen levels.

Predicting risk of dementia in older adults: The late-life dementia risk index.

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years. METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients. RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores. CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

Postmenopausal hormone therapy and subclinical cerebrovascular disease: the WHIMS-MRI Study.

OBJECTIVE: The Women's Health Initiative Memory Study (WHIMS) hormone therapy (HT) trials reported that conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) increases risk for all-cause dementia and global cognitive decline. WHIMS MRI measured subclinical cerebrovascular disease as a possible mechanism to explain cognitive decline reported in WHIMS. METHODS: We contacted 2,345 women at 14 WHIMS sites; scans were completed on 1,424 (61%) and 1,403 were accepted for analysis. The primary outcome measure was total ischemic lesion volume on brain MRI. Mean duration of on-trial HT or placebo was 4 (CEE+MPA) or 5.6 years (CEE-Alone) and scans were conducted an average of 3 (CEE+MPA) or 1.4 years (CEE-Alone) post-trial termination. Cross-sectional analysis of MRI lesions was conducted; general linear models were fitted to assess treatment group differences using analysis of covariance. A (two-tailed) critical value of alpha = 0.05 was used. RESULTS: In women evenly matched within trials at baseline, increased lesion volumes were significantly related to age, smoking, history of cardiovascular disease, hypertension, lower post-trial global cognition scores, and increased incident cases of on- or post-trial mild cognitive impairment or probable dementia. Mean ischemic lesion volumes were slightly larger for the CEE+MPA group vs placebo, except for the basal ganglia, but the differences were not significant. Women assigned to CEE-Alone had similar mean ischemic lesion volumes compared to placebo. CONCLUSIONS: Conjugated equine estrogen-based hormone therapy was not associated with a significant increase in ischemic brain lesion volume relative to placebo. This finding was consistent within each trial and in pooled analyses across trials.

Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study.

OBJECTIVES: To examine the association between incident Alzheimer disease (AD), and plasma A beta 1-40 and A beta 1-42 levels in normal and mild cognitive impairment (MCI) subjects in a subgroup of participants of the Cardiovascular Health Study Cognition Study. METHODS: We determined the plasma A beta 1-40 and A beta 1-42 levels of 274 nondemented subjects (232 normals and 42 with MCI) in 1998-1999 and repeated the measurements in 2002-2003. The mean age of the subjects at baseline was 79.3 +/- 3.6 years. We examined the association between A beta levels and incident AD over the ensuing 4.5 years, controlling for age, cystatin C level (marker of glomerular function), apolipoprotein E-4 allele, Modified-Mini-Mental State Examination scores, and MRI-identified infarcts. RESULTS: In an unadjusted prospective model in normal subjects, both A beta 1-40 and A beta 1-42 levels in 1998-1999 were associated with incident AD (n = 55) in 2002-2003 (longitudinal analysis). In the fully adjusted multivariate model, neither A beta 1-42 nor A beta 1-40 nor their ratio was associated with incident AD. However, adjustment had a very small effect on point estimates for A beta 1-42, from an odds ratio (OR) of 1.61 (p = 0.007) in the unadjusted model to an OR of 1.46 (p = 0.08) in the fully adjusted model. In 2002-2003 (cross-sectional analysis), only the unadjusted models showed that both peptides were associated with AD. CONCLUSIONS: Plasma A beta levels are affected by age and by systemic and CNS vascular risk factors. After controlling for these conditions, A beta-40 and A beta 1-42 are weak predictors of conversion to Alzheimer disease (AD) in normal subjects and are only weakly associated with AD in cross-sectional analysis. Consequently, plasma levels of A beta do not seem to be useful biomarkers for AD.

Serum ghrelin levels are higher in Caucasian men than Japanese men aged 40-49 years.

BACKGROUND: Ghrelin, a 28-amino-acid gastric peptide hormone, has an appetite-stimulating effect and controls the energy balance. Serum ghrelin levels inversely correlate with body mass index. Recently, several papers reported the ethnic difference in the ghrelin levels. To our knowledge, however, no studies have compared the serum ghrelin levels between Caucasians in the USA and the Japanese in Japan. METHODS: We conducted a cross-sectional study of 189 men 40-49 years of age (91 US Caucasians in the U.S. and 98 Japanese in Japan) to examine serum ghrelin levels and metabolic and other factors. RESULTS: Serum ghrelin levels correlated with waist circumferences and lipid profiles among Caucasian Americans and the Japanese. Serum ghrelin levels were significantly higher among Caucasian Americans than among the Japanese (904.5 (632.0, 1132.0) pg/mL, 508.0 (399.0, 1378.3) pg/mL (median and 95% confidence interval), respectively, P < 0.01), although Caucasian Americans were much more obese (BMI: 26.9 +/- 3.3 kg/m(2) versus 23.3 +/- 3.1 kg/m(2) respectively, P < 0.01). The ethnic difference remained after adjusting for metabolic factors, smoking status, and other factors (P < 0.01). CONCLUSIONS: We have shown in our population-based study that serum ghrelin levels among men aged 40-49 are significantly higher in Caucasian Americans than in the Japanese in Japan. Reasons for the ethnic difference in the ghrelin levels are largely unknown and warrant further investigation.

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Coronary artery calcification in older adults to age 99: prevalence and risk factors.

BACKGROUND: Coronary artery calcification has been proposed as a noninvasive method to assess cardiovascular disease (CVD) risk. However, the prevalence and risk factors for coronary artery calcification in populations >65 years have not been well studied. METHODS AND RESULTS: Electron beam tomography was performed to assess coronary artery calcium (CAC) in 614 older adults aged, on average, 80 years (range, 67 to 99 years); 367 (60%) were women, and 143 (23%) were black. Calcium scores ranged from 0 to 5459. Median scores were 622 for men and 205 for women. Scores increased by age and were lower in blacks than in whites. Nine percent of subjects (n=57) had no CAC, and 31% (n=190) had a score lower than 100. A history of CVD was associated with calcium score. Age, male sex, white race, CVD, triglyceride level, pack-years of smoking, and asthma, emphysema, or bronchitis (chronic obstructive pulmonary disease) were independently associated with CAC score in the fourth quartile. CONCLUSIONS: A wide range of CAC scores was observed, suggesting adaptation with aging. CAC may have potential to predict CVD in older adults, but this remains to be determined.

Educational attainment and coronary and aortic calcification in postmenopausal women.

OBJECTIVE: Low socioeconomic status is a risk factor for clinical coronary heart disease, a relatively crude outcome associated with important biases. By avoiding these biases, subclinical assessments could facilitate efforts to understand the association between socioeconomic status and coronary disease. The current study 1) evaluated the nature of the associations between educational attainment and subclinical atherosclerosis and 2) examined if biologic, behavioral, and psychosocial factors mediated these associations. METHODS: Participants were 308 women from the Healthy Women Study who underwent a clinic examination of risk factors either 5 (N = 32) or 8 (N = 276) years after the menopausal transition. Aortic and coronary calcification were measured using electron beam tomography. RESULTS: Logistic regression analysis with orthogonal polynomials revealed a marginally significant linear trend for coronary calcification, with the more educated groups showing lower calcification than the less educated groups. A significant linear trend was also observed for aortic calcification. In addition, a marginally significant quadratic trend was observed for aortic calcification so that the effect began to reverse at the highest level of education. Measured risk factors were associated with education and with the calcification outcomes, but they explained little of the associations between educational attainment and coronary or aortic calcification. None of the factors tested met the minimum criterion for mediation. CONCLUSIONS: The findings show that lower education is associated with greater early stage atherosclerosis. Subclinical assessments, such as electron beam tomography, represent useful alternatives for studies of socioeconomic status and coronary artery disease.

Trajectory of psychological risk and incident hypertension in middle-aged women.

The aim of the study was to test the hypotheses that the trajectory of psychological risk (ie, persistent or increasing measures of depression and anxiety symptoms, anger, and low social support over time) increases the risk for the development of hypertension and that blood pressure levels fluctuate with psychological changes in women. Initially, healthy normotensive middle-aged women (n=541; 90.6% white, 8.9% African American) were followed across an average of 9.2 years of follow-up. Psychological characteristics were assessed repeatedly via standardized questionnaires, and Cox proportional hazards and random regression models were used to analyze their impact, adjusting for hypertension risk factors (age, race, years of education, parental history of hypertension, baseline blood pressure, body mass index, physical activity, alcohol use, and cigarette smoking). Seventy-five women became hypertensive during the follow-up period. Baseline levels of depression, anxiety, anger, and social support did not predict subsequent hypertension. A high level of anxiety throughout the follow-up, an increase in the level of feelings of anger, and a decrease in the level of social support over the follow-up were significant predictors of hypertension incidence (all P<0.05), although covariate adjustment reduced some of the significance levels to nonsignificance. In women, increases in depressive symptoms were significantly associated (P=0.003) with concurrent increases in the level of systolic blood pressure, especially among hypertensive patients (P=0.0001). Increasing levels of anger, decreasing levels of social support, and high anxiety increase the likelihood of women's development of hypertension in midlife. These results emphasize the importance of evaluating the trajectory of psychological risk during the period of evolving hypertension.

Coronary heart disease mortality among men aged 35-44 years by prefecture in Japan in 1995-1999 compared with that among white men aged 35-44 by state in the United States in 1995-1998: vital statistics data in recent birth cohort.

The levels of risk factors for coronary heart disease (CHD) in men in the post World War II (WWII) birth cohort are almost similar between Japan and the USA, except for the considerably higher prevalence of cigarette smoking in Japan and the much higher prevalence of obesity in the USA. The present study evaluated the CHD mortality among men in the post WWII birth cohort by prefecture in Japan in 1995-1999 and then compared the data with those for white men in different states in the USA. There was a greater than 2-fold difference in CHD mortality among men aged 35-44 by prefecture in Japan: 5.3/100,000 in Kumamoto vs 12.6/100,000 in Tochigi. CHD mortality among men aged 35-44 in the top 3 prefectures in Japan is about half that of white men in the USA and is similar to that of white men in the lowest 3 states. The much lower CHD mortality in Japan does not appear to be caused by differences in the classification of causes of death and the results suggest that there may be strong and important protective factors that reduce the risk of CHD in Japan.

Menopause in type 1 diabetic women: is it premature?

Women with type 1 diabetes have a delayed menarche and a greater prevalence of menstrual disorders than women without diabetes. However, little is known about the menopause transition among type 1 diabetic women. The Familial Autoimmune and Diabetes (FAD) Study recruited both adult individuals who were identified from the Children's Hospital of Pittsburgh Type 1 Diabetes Registry for the years 1950-1964 and their family members. Unrelated nondiabetic control probands and their relatives were also evaluated. Women with type 1 diabetes (n = 143) compared with nondiabetic sisters (n = 186) or unrelated control subjects (n = 160) were more likely to have an older age at menarche (13.5, 12.5, and 12.6 years, respectively, P < 0.001), more menstrual irregularities before 30 years of age (45.7, 33.3, and 33.1%, respectively, P = 0.04), and a younger age at menopause (41.6, 49.9, and 48.0 years, respectively, P = 0.05). This resulted in a 6-year reduction in the number of reproductive years (30.0, 37.0, and 35.2 years, respectively, P = 0.05) for women with type 1 diabetes. Risk factors univariately associated with earlier menopause included type 1 diabetes (hazard ratio [HR] 1.99, P = 0.04), menstrual irregularities before 30 years of age (HR 1.87, P = 0.04), nulliparity (HR 2.14, P = 0.01), and unilateral oophorectomy (HR 6.51, P < 0.0001). Multivariate analysis confirmed that type 1 diabetes (HR 1.98, P = 0.056), menstrual irregularities by 30 years of age (HR 2.36, P = 0.01), and unilateral oophorectomy (HR 9.76, P < 0.0001) were independent determinants of earlier menopause in our cohort. We hypothesize that an earlier menopause, which resulted in a 17% decrease in reproductive years, is a major unstudied complication of type 1 diabetes.

Bone mass and breast cancer risk in older women: differences by stage at diagnosis.

BACKGROUND: Older women with low bone mineral density (BMD) have a decreased incidence of breast cancer. It is not known whether this association is confined to early-stage, slow-growing tumors. METHODS: We prospectively studied 8905 women who were 65 years of age or older during the period from 1986 through 1988 and had no history of breast cancer. At study entry, we used single-photon absorptiometry to measure each woman's BMD at three skeletal sites: the wrist, forearm, and heel. The women were followed for a mean of 6.5 years for the occurrence of breast cancer. All statistical tests were two-sided. RESULTS: During 57 516 person-years of follow-up, 315 women developed primary invasive or in situ breast cancer. Multivariate analyses that adjusted for age, obesity, and other covariates revealed that the risk of breast cancer for women in the highest quartile of BMD for all three skeletal sites was 2.7 (95% confidence interval [CI] = 1.4 to 5.3) times greater than that for women in the lowest quartile at all three skeletal sites. The magnitude of increased risk associated with high BMD differed by the stage of disease at diagnosis and was greater for more advanced tumors (relative risk [RR] for TNM [i.e., tumor-lymph node-metastasis] stage II or higher tumors = 5.6; 95% CI = 1.2 to 27.4) than for early-stage disease (RR for in situ/TNM stage I tumors = 2.2; 95% CI = 1.0 to 4.8). CONCLUSIONS: Elderly women with high BMD have an increased risk of breast cancer, especially advanced cancer, compared with women with low BMD. These findings suggest an association between osteoporosis and invasive breast cancer, two of the most prevalent conditions affecting an older woman's health.

Serum levels of C-reactive protein are associated with obesity, weight gain, and hormone replacement therapy in healthy postmenopausal women.

The authors evaluated the cross-sectional and prospective associations between the serum concentration of C-reactive protein and measures of obesity and fat distribution, hormone replacement therapy (HRT) use, and serum sex hormones in postmenopausal women from the Healthy Women Study (Allegheny County, Pennsylvania, 1998). The authors tested the hypothesis that C-reactive protein levels would be higher among HRT users and among women with greater body mass index, waist circumference, or visceral fat. There were 207 women in the study who were > or =8 years postmenopausal (101 HRT users and 106 HRT nonusers). The median levels of C-reactive protein were 3.01 mg/liter in HRT users compared with 1.74 mg/liter in nonusers (p = 0.002). C-reactive protein levels were strongly positively correlated with measures of body size, fatness, fat distribution, and weight gain among HRT users and nonusers. C-reactive protein was also positively correlated with serum estrone levels (r(s) = 0.38) among HRT nonusers. The highest level of C-reactive protein was found among HRT users in the highest quartile of visceral fat (4.29 mg/liter) compared with women not on HRT and in the lowest quartile of visceral fat (0.96 mg/liter). The use of HRT and measures of overall body fatness are important correlates of C-reactive protein among postmenopausal women.

A common promotor variant in the cytochrome P450c17alpha (CYP17) gene is associated with bioavailability testosterone levels and bone size in men.

Cytochrome P450c17alpha (CYP17) encodes an enzyme with 17a-hydroxylase and 17,20-lyase activities, which is essential for the normal production of adrenal and gonadal androgens. Because androgens have powerful effects on bone growth and metabolism, we determined whether a single base pair (bp) substitution (T-->C) in the promoter region (-34 bp) of CYP17 is associated with sex hormone levels, stature, and femoral mass and size in 333 white men aged 51-84 years (mean +/- SD; 66+/-7 years). Femoral neck bone mineral content (BMC), cross-sectional area (CSA), and bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry (DXA). Genotype frequencies did not deviate from Hardy-Weinberg expectations. Serum bioavailable testosterone levels were 20% or 0.5 SDs higher in men with the C/C compared with the T/T genotype, whereas heterozygous men had intermediate hormone levels (p = 0.019). Men with the C/C genotype also were nearly 3 cm taller and had 0.6 SD greater femoral neck CSA than men with the T/T genotype (p < or = 0.01 for both). The association with CSA persisted after adjusting for age, height, and body weight. In contrast, CYP17 genotype was not associated with femoral neck BMC, areal BMD (g/cm2), or estimated volumetric BMD (g/cm3). These results suggest that allelic variation at the CYP17 locus may contribute to the genetic influence on stature and femoral size in men.

Sudden cardiac death, genes, and arrhythmogenesis : consideration of new population and mechanistic approaches from a national heart, lung, and blood institute workshop, part I.

Malignant ventricular arrhythmias are the leading mechanism of death in patients with acute and chronic cardiac pathologies. The extent to which inherited mutations and polymorphic variation in genes determining arrhythmogenic mechanisms affect these patients remains unknown, but based on recent population studies, this risk appears significant, deserving much greater investigation. This report summarizes a National Heart, Lung, and Blood Institute workshop that considered sources of genetic variation that may contribute to sudden cardiac death in common cardiac diseases. Evidence on arrhythmogenic mechanisms in recent population studies suggests a significant portion of the risk of sudden cardiac death in such broad populations may be unrelated to traditional risk factors for predisposing conditions such as atherosclerosis, hypertension, and diabetes and instead may involve unrecognized genetic and environmental interactions that influence arrhythmic susceptibility more directly. Additional population and genetic studies directed at discovering the sources of inherited molecular risk that are most directly linked to arrhythmia initiation and propagation, in addition to studies on previously well-described risk factors, would appear to have considerable potential for reducing premature cardiovascular mortality.

Sudden cardiac death, genes, and arrhythmogenesis: consideration of new population and mechanistic approaches from a National Heart, Lung, and Blood Institute workshop, Part II.

This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.

Usefulness of electron beam tomography to detect progression of coronary and aortic calcium in middle-aged women.

Electron beam tomography (EBT) permits the noninvasive quantification of coronary and aortic calcium as a marker of atherosclerosis. Coronary and aortic calcium are strongly related to premenopausal cardiovascular risk factors in middle-aged women. This report evaluates changes in coronary and aortic calcium over an average of 18 months in 80 women. Measurement variation over time and between readings is also evaluated in these women who were followed through the menopausal transition. Eight years after menopause, 80 women (average age 63 years) underwent serial EBT of the coronary arteries and aorta separated by 18 months. Calcium scores were based on the number and density of calcific deposits. Duplicate readings were obtained to evaluate the effect of reading variation on calcium scores. At baseline, the median calcium score was 0 in the coronary arteries and 58 in the aorta. Average change in coronary (+11) and aortic (+112) calcium were significantly different from zero (p < 0.001). Reading variability did not contribute significantly to the variation in calcium scores. Extent of calcium in the coronary arteries was associated with progression of calcium in the aorta (p = 0.013). Both coronary and aortic calcium were significantly associated with premenopausal cardiovascular risk factors. Thus, progression of coronary and aortic calcium using EBT can be observed over a short time in healthy middle- aged women.