Abdominal obesity and carotid artery wall thickness. The Los Angeles Atherosclerosis Study.

OBJECTIVE: To determine whether or not abdominal obesity is associated with the intima-media thickness (IMT) of the carotid artery wall independently of total body obesity and major risk factors for atherosclerosis. DESIGN: : Longitudinal epidemiological study. SUBJECTS: A total of 573 middle-aged employees of a utility company. MEASUREMENTS: Sagittal and transverse abdominal diameters, their ratio and difference were used as measures of abdominal obesity. RESULTS: Abdominal diameters and body mass index (BMI) were significantly associated with blood pressure, serum lipoproteins and fasting insulin. In cross-sectional multiple regression models, the sagittal/transverse ratio and BMI were significantly associated with IMT in the presence of atherosclerosis risk, but the sagittal diameter was not. In longitudinal models, baseline BMI was an independent predictor of IMT progression but the sagittal and transverse diameters were not. CONCLUSION: These findings do not support the hypothesis that abdominal obesity is an independent predictor of carotid artery IMT. The consistent pattern of association of measures of general obesity with carotid artery IMT emphasizes the continuing need for prevention and control of this important risk factor.

Influence of leptin on changes in body fat during growth in African American and white children.

OBJECTIVE: The aim of this study was to determine whether initial levels or temporal changes in fasting leptin were associated with longitudinal changes in body-fat mass in children. RESEARCH METHODS AND PROCEDURES: The study group consisted of 85 children (42 white and 43 African American) with a mean initial age of 8.1 +/- 0.1 years. The children had between three and six annual visits for repeated measurements of body composition by DXA and fasting leptin level. Fat mass and fasting leptin level were not normally distributed and were log-transformed. Data were analyzed using SAS Proc mixed growth models, with log fat as the dependent variable. RESULTS: Initial leptin level was a significant predictor of the change in fat mass over time (p < 0.0001), with high initial leptin levels resulting in increased fat gain, independent of initial fat levels. This relationship remained significant when the data were analyzed separately by race (whites, p < 0.0001; African Americans, p = 0.008). The relationship between the initial level of leptin and the change in fat mass was not modified by race, sex, or Tanner Stage. The rate of change in leptin during the study was significantly related to the rate of change in fat mass in African Americans (p = 0.008) but not in whites (p = 0.490). DISCUSSION: In conclusion, high fasting leptin level at the start of the study was significantly associated with increasing fat mass in this cohort, indicating that the children may be developing resistance to the effects of leptin.

Longitudinal changes in body fat in African American and Caucasian children: influence of fasting insulin and insulin sensitivity.

Obesity is associated with hyperinsulinemia and reduced insulin sensitivity, both risk factors for type 2 diabetes. However, it is not clear whether these risk factors occur as a result of obesity or whether they contribute to the development of obesity. The aims of this study were to determine whether baseline (first visit) or changes in insulin measures over time were associated with longitudinal changes in body fat mass during growth in children. The study group consisted of 137 children (83 Caucasian and 54 African American) with a mean age of 8.1 yr at baseline. The children returned for 3-6 annual visits for measurement of fasting insulin, insulin sensitivity (Si), and acute insulin response (AIR) from the tolbutamide-modified frequent sampling iv glucose tolerance test and for determination of body composition by dual energy x-ray absorptiometry. Data were analyzed using SAS Proc mixed growth models. Total fat mass increased with time by 15.6%/yr (P = 0.013), but the rate of increase was not significantly influenced by race, sex, or Tanner stage. However, fasting insulin (positive effect), Si (negative effect), and AIR (positive effect) were significantly associated with the rate of increase in fat mass. In conclusion, in this cohort of children, growth-related increases in body fat were significantly associated with increases in fasting insulin and AIR and decreases in Si.

Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles atherosclerosis study.

BACKGROUND: Carotenoids are hypothesized to explain some of the protective effects of fruit and vegetable intake on risk of cardiovascular disease. The present study assessed the protective effects of the oxygenated carotenoid lutein against early atherosclerosis. EPIDEMIOLOGY: Progression of intima-media thickness (IMT) of the common carotid arteries over 18 months was determined ultrasonographically and was related to plasma lutein among a randomly sampled cohort of utility employees age 40 to 60 years (n=480). Coculture: The impact of lutein on monocyte response to artery wall cell modification of LDL was assessed in vitro by quantification of monocyte migration in a coculture model of human intima. Mouse models: The impact of lutein supplementation on atherosclerotic lesion formation was assessed in vivo by assigning apoE-null mice to chow or chow plus lutein (0.2% by weight) and LDL receptor-null mice to Western diet or Western diet plus lutein. IMT progression declined with increasing quintile of plasma lutein (P for trend=0.007, age-adjusted; P=0.0007, multivariate). Covariate-adjusted IMT progression (mean+/-SEM) was 0.021+/-0.005 mm in the lowest quintile of plasma lutein, whereas progression was blocked in the highest quintile (0.004+/-0.005 mm; P=0.01). In the coculture, pretreatment of cells with lutein inhibited LDL-induced migration in a dose-dependent manner (P<0.05). Finally, in the mouse models, lutein supplementation reduced lesion size 44% in apoE-null mice (P=0.009) and 43% in LDL receptor-null mice (P=0.02). CONCLUSIONS: These epidemiological, in vitro, and mouse model findings support the hypothesis that increased dietary intake of lutein is protective against the development of early atherosclerosis.

Growth of visceral fat, subcutaneous abdominal fat, and total body fat in children.

OBJECTIVE: To examine the patterns of growth of visceral fat, subcutaneous abdominal fat, and total body fat over a 3- to 5-year period in white and African American children. RESEARCH METHODS AND PROCEDURES: Children (mean age: 8.1 +/- 1.6 years at baseline) were recruited from Birmingham, Alabama, and those with three or more repeated annual measurements were included in the analysis (N = 138 children and 601 observations). Abdominal adipose tissue (visceral and subcutaneous) was measured using computed tomography. Total body fat and lean tissue mass were measured by DXA. Random growth curve modeling was performed to estimate growth rates of the different body fat compartments. RESULTS: Visceral fat and total body fat both exhibited significant growth effects before and after adjusting for subcutaneous abdominal fat and lean tissue mass, respectively, and for gender, race, and baseline age (5.2 +/- 2.2 cm(2)/yr and 1.9 +/- 0.8 kg/yr, respectively). After adjusting for total body fat, the growth of subcutaneous abdominal fat was not significant. Whites showed a higher visceral fat growth than did African Americans (difference: 1.9 +/- 0.8 cm(2)/yr), but there was no ethnic difference for growth of subcutaneous abdominal fat or total body fat. There were no gender differences found for any of the growth rates. DISCUSSION: Growth of visceral fat remained significant after adjusting for growth of subcutaneous abdominal fat, implying that the acquisition of the two abdominal fat compartments may involve different physiologic mechanisms. In contrast, growth of subcutaneous abdominal fat was explained by growth in total body fat, suggesting that subcutaneous fat may not be preferentially deposited in the abdominal area during this phase of growth. Finally, significantly higher growth of visceral fat in white compared with African American children is consistent with cross-sectional findings.

From early to late adolescence: alcohol use and anger relationships.

PURPOSE: To evaluate the longitudinal relationship of alcohol use in early adolescence to anger in late adolescence. METHODS: Data were collected in Indianapolis, Indiana, from 1987 to 1993 as part of a large drug abuse prevention trial. Fifty percent of the 1201 students were female, 75%, white, and 69%, low socioeconomic status, who were surveyed in grades 6/7, 9/10, and 11/12. Subjects were asked four anger-related questions: "When I have a problem, I get mad at people," "When I have a problem, I do bad things or cause trouble," "When I have a problem, I say or do nasty things," and "I am a hotheaded person." Two additional items asked subjects to report the number of alcoholic drinks consumed and frequency of drunkenness in the past 30 days. Odds ratios (OR) were used to assess the predictive relationship of alcohol use in early adolescence to anger in late adolescence. RESULTS: Early use of alcohol increased the odds of later anger. Specifically, alcohol use in the past month in grade 6/7 increased the odds in grade 11/12 of saying or doing nasty things (OR = 8.23, p < .01), self-reported hotheadedness (OR = 9.72, p < .01), and high anger on a composite anger scale (OR = 4.84, p < .05). Drunkenness in the past month in grade 6/7 increased the odds of self-reported hotheadedness (OR = 6.17, p <.05) and high anger on the anger scale (OR = 3.20, p < .05) in grade 9/10 and doing something bad to cause trouble in grade 11/12 (OR = 24.97, p < .01). For subjects in grade 9/10, alcohol use in the past month increased the odds in grade 11/12 of doing something bad to cause trouble (OR = 2.79, p < .05), saying or doing nasty things (OR = 2.02, p < .05), and self-reported hotheadedness (OR = 2.51, p < .05). CONCLUSIONS: The present study showed that alcohol use in early adolescence was associated with increased anger, both in middle and late adolescence, controlling for gender, age, and socioeconomic status. The findings suggest that alcohol and drug prevention programs delivered in early adolescence may have the capacity to prevent risk for later anger and related violent behavior.

Work-related stress and early atherosclerosis.

The purpose of this study was to examine the link between work-related stress and early atherosclerosis as measured by common carotid artery intima-media thickness and focal lesions in the common carotid artery and bifurcation. Four hundred sixty-seven members of an occupational cohort (total N = 573) were examined via questionnaires and B-mode ultrasound. We used multiple linear and logistic models to regress lesion risk and intima-media thickness on work-related stress scores from a questionnaire administered at an 18-month follow-up examination. In an age-adjusted model, the prevalence of carotid lesions among men scoring in the highest stress quintile was 36% compared with 21% among men in the lowest quintile. We also observed an increase in intima-media thickness in the highest quintile relative to the lowest (difference = 0.048 +/- 0.025 mm) among men. Among women, stress was not related to the prevalence of lesions or intima-media thickness. These findings suggest that men with greater work-related stress are at increased risk for atherosclerotic disease. Women in this age group may be protected from such effects, or current work-place questionnaires may not accurately assess stress in women.

Blood pressure, LDL cholesterol, and intima-media thickness: a test of the "response to injury" hypothesis of atherosclerosis.

The "response to injury" hypothesis is a plausible model of the development of atherosclerosis supported by observations from animal models. The present study uses epidemiological data to investigate the hypothesis that wall damage due to hypertension is a precursor of low density lipoprotein cholesterol (LDL-C)-mediated atherosclerosis. The Los Angeles Atherosclerosis Study is following a cohort of 576 participants who were aged 40 to 60 years and were free of symptomatic cardiovascular disease at recruitment. Common carotid artery intima-media thickness (IMT) was assessed by B-mode ultrasonography. After exclusion for nonfasting blood draw and other missing data, 511 subjects were available for analysis. IMT was regressed on LDL-C within tertiles of systolic blood pressure (SBP): low (93 to 122 mm Hg), middle (123 to 132 mm Hg), and high (133 to 175 mm Hg). Covariates were age, sex, body height, body mass index, ethnicity, smoking status, diabetes, and pharmacological treatment for hypertension or hypercholesterolemia. IMT was significantly related to LDL-C in the high SBP group (beta=0.025+/-0.008, where beta values are IMT [mm]/LDL-C [mmol/L]; P=0.002) but not in the middle (beta=-0.006+/-0.008, P=0.39) or low (beta=-0.004+/-0.009, P=0.64) SBP group. The slope in the high SBP group was significantly greater than in the middle (P=0.004) or low (P=0.014) SBP group. Results were similar for women and men, and after the exclusion of diabetics and persons using antihypertensive or lipid-lowering medications. Elevated LDL-C was associated with increased IMT in the upper tertile of SBP but not in the lower tertiles. These findings are consistent with the hypothesis that wall injury due to elevated SBP increases the susceptibility of the artery wall to LDL-C-mediated atherogenesis.

Beneficial antithrombotic effects of the association of pharmacological oral magnesium therapy with aspirin in coronary heart disease patients.

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. The aim of our study was to determine whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in stable patients with coronary artery disease (CAD). In a randomized prospective, double-blind, cross-over and placebo controlled study, 42 patients with stable CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800-1,200 mg/day) or placebo for 3 months (Phase 1) followed by a 4-week washout period, and the cross-over treatment for 3 months (Phase 2). PDT, platelet aggregation, platelet P-selectin flow-cytometry, monocyte tissue factor procoagulant activity (TF-PCA) and adhesion molecules density were assessed before and after each phase. PDT was evaluated by an ex-vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35 percent in patients who received magnesium versus placebo (D change from baseline: -24 vs. 26 microm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA or adhesion molecules. Oral magnesium treatment inhibits PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD.

Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease.

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. This study examines whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in patients with coronary artery disease (CAD). In a randomized prospective, double-blind, crossover, and placebo-controlled study, 42 patients with CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800 to 1,200 mg/day) or placebo for 3 months (phase 1) followed by a 4-week wash-out period, and the crossover treatment for 3 months (phase 2). PDT, platelet aggregation, platelet P-selectin flow cytometry, monocyte tissue factor procoagulant activity (TF-PCA), and adhesion molecule density were assessed before and after each phase. PDT was evaluated by an ex vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35% in patients who received magnesium versus placebo (delta change from baseline -24 vs 26 mm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA, or adhesion molecules. Oral magnesium treatment inhibited PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD.

Automated intima-media thickness: the Los Angeles Atherosclerosis Study.

Common carotid artery (CCA) intima-media thickness (IMT) from B-mode ultrasound is a widely used measure of early atherosclerosis. This study evaluated within- and between-sonographer reproducibility of automated edge-tracking IMT using a low-cost mobile scanner. B-mode images of the left and right CCA were acquired on two occasions (interval of 2-14 days) by two sonographers for 38 subjects, aged 31-75 y. Reproduciblity error was measured as the mean absolute difference (MAD+/-SEM) and the standard deviation of differences (SDdelta) between repeated measurements. Within-sonographer (MAD=0.027+/-0.006 mm; SDdelta=0.044 mm) and between-sonographer errors (MAD=0.041+/-0.008 mm; SDdelta=0.064) in IMT (mean=0.74, SD=0.14) of a single artery were small compared to those of other protocols. Combined averaging across both body positions and arteries reduced intersonographer MAD by 47% (MAD=0.022+/-0.003 mm; SDdelta=0.029 mm). These data demonstrate that the proposed IMT protocol reduces reproducibility error by more than 50% relative to several protocols used in other major studies.

Dietary calcium, calcium supplementation, and blood pressure in African American adolescents.

BACKGROUND: Intake of calcium from the diet is inversely associated with blood pressure in observational studies and animal models but randomized trials in humans have found only small effects of calcium supplementation on blood pressure. A blood pressure-lowering effect of calcium supplementation may thus be restricted to persons with a low intake of calcium from the diet and specific genetic or other characteristics. OBJECTIVE: A randomized trial was conducted to assess the effect of calcium supplementation on blood pressure in African American adolescents. Rapid growth during adolescence may increase calcium requirements, and avoidance of milk and milk products by some African Americans can result in low intake of calcium. DESIGN: One hundred sixteen adolescents (65 girls, 51 boys; mean age: 15.8 y) were given calcium (1.5 g/d) or placebo for 8 wk in a randomized, double-blind, crossover design. Blood pressure was measured after 2, 4, and 8 wk. Dietary calcium was determined with a validated food-frequency questionnaire. RESULTS: The net effect (+/-SE) of calcium supplementation on diastolic blood pressure was a reduction of 1.9 +/- 1.1 mm Hg (P = 0.04, one-tailed t test). Blood pressure reduction was greater in adolescents with lower intake of calcium from the diet (P = 0.003, one-tailed t test for interaction): -4.9 +/- 1.6, -2.3 +/- 1.6, and 1.4 +/- 1.8 mm Hg for change in the lower (0.024-0.067 g Ca/MJ), middle (0.069-0.091 g Ca/MJ), and upper (0.093-0.217 g Ca/MJ) tertiles, respectively. No main effect on systolic blood pressure was detected. CONCLUSION: These findings suggest that calcium supplementation may lower diastolic blood pressure in African American adolescents with low dietary intakes of calcium.

Analysis of data from group-randomized trials with repeat observations on the same groups.

This study used Monte Carlo simulations to evaluate the performance of alternative models for the analysis of group-randomized trials having more than two time intervals for data collection. The major distinction among the models tested was the sampling variance of the intervention effect. In the mixed-model ANOVA, the sampling variance of the intervention effect is based on the variance among group x time-interval means. In the random coefficients model, the sampling variance of the intervention effect is based on the variance among the group-specific slopes. These models are equivalent when the design includes only two time intervals, but not when there are more than two time intervals. The results indicate that the mixed-model ANOVA yields unbiased estimates of sampling variation and nominal type I error rates when the group-specific time trends are homogenous. However, when the group-specific time trends are heterogeneous, the mixed-model ANOVA yields downwardly biased estimates of sampling variance and inflated type I error rates. In contrast, the random coefficients model yields unbiased estimates of sampling variance and the nominal type I error rate regardless of the pattern among the groups. We discuss implications for the analysis of group-randomized trials with more than two time intervals.

Dietary calcium, alcohol, and incidence of treated hypertension in the NHANES I epidemiologic follow-up study.

Evidence concerning the relation between dietary calcium intake and development of hypertension is inconsistent. Some of this inconsistency may be due to interaction of this relation with other factors. The current study was designed to test for an interaction between alcohol consumption and the relation of dietary calcium intake to 10-year incidence of hypertension in a sample of the US adult population: the Epidemiologic Follow-up Study (1982-1984) of the First National Health and Nutrition Examination Survey (NHANES I) (1971-1975). Interactive logistic regression models were estimated with incident hypertension defined as self-reported treatment with antihypertensive medication. After exclusion of participants with evidence of hypertension at baseline (resulting n = 6,634), odds ratios for hypertension were estimated for each 1-g/day increase in calcium intake. The relation between dietary calcium and incident hypertension showed significant interactions with frequency of alcohol use (odds ratio (OR) = 1.33 for daily drinkers, OR = 0.84 for others; p = 0.005 for difference), age (OR = 0.75 for < or = 40 years at baseline, OR = 1.00 for > 40 years; p = 0.004), and body mass index, defined as weight (kg) divided by height (m) squared (OR = 0.82 for < or = 26, OR = 1.01 for > 26; p = 0.018). Interactions with sex and race (black vs. white) were not significant (p > or = 0.4). These findings suggest that a protective effect of foods containing calcium on the risk of developing hypertension may vary across levels of alcohol consumption and other risk factors for hypertension.

Association of serum total cholesterol with coronary disease and all-cause mortality: multivariate correction for bias due to measurement error.

Measurement error in the exposure under investigation is an important but often ignored source of bias in observational studies. The authors examined the impact of measurement error in the association between total serum cholesterol and 16-year coronary heart disease and all-cause mortality in a cohort of 6,137 middle-aged men of Japanese descent in the Honolulu Heart Program (1973-1988). A Cox regression model that enables modeling of survival time with correction for measurement errors in multiple covariates was employed. After controlling for age, body mass index, systolic blood pressure, smoking status, alcohol consumption, dietary cholesterol, and total calorie intake, a difference of one standard deviation (38 mg/dL) in total cholesterol was associated with a significant increase in the risk of coronary disease death (uncorrected hazard ratio = 1.35). After correction for measurement errors in total cholesterol and covariates (except smoking and age), the estimated hazard ratio increased to 1.65 (a 22% increase). A U-shaped relation was observed between total cholesterol levels and the risk of all-cause mortality. This association was then examined with a quadratic model and with a two-slope or V-shaped regression model. In the quadratic fit, the magnitude of the quadratic total cholesterol term increased threefold after the adjustment for measurement error. In the V fit, the hazard ratio of all-cause death corresponding to a change in one standard deviation above 214 mg/dL (the nadir of the V) was 1.15, and increased to 1.49 (by 29%) after the correction. The corresponding hazard ratio of a change in one standard deviation below 214 mg/dL was 1.11, and increased to 1.37 (by 23%) after the correction. The authors conclude that the impact of elevated total cholesterol on the risk of coronary disease and all-cause mortality may be greater than previously estimated with standard methods of analysis. In addition, the correction for measurement error in total cholesterol and covariates did not explain the excess mortality associated with low total cholesterol. More research is needed to elucidate the fundamental issues underlying the U-shaped association, i.e., confounding versus causal implications.

Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany.

The relation between mortality (all cause; cancer; cardiovascular diseases (International Classification of Diseases, Ninth Revision (ICD-9), codes 390-459); ischemic heart diseases (ICD-9 codes 410-414)) and exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F) was investigated in a retrospective cohort study. The cohort consisted of 1,189 male workers in a chemical plant in Hamburg, Federal Republic of Germany, who had produced phenoxy herbicides, chlorophenols, and other herbicides and insecticides known to be contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin and other, higher chlorinated dioxins and furans. The authors reported previously on cancer mortality in this cohort for the follow-up period 1952-1989. The current study covers the years 1952-1992 and investigates the relation of PCDD/F exposure to mortality using a quantitative estimate of PCDD/F exposure for the whole cohort derived from blood and adipose tissue levels measured in a subgroup (n = 190). Quintiles and deciles of these estimates served as dose parameters in the estimation of relative risks (RRs), using year-of-birth stratified Cox regression. An unexposed cohort of gas workers served as an external reference group. The total mortality was elevated in all dose groups. The highest relative risk was observed for the highest 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) decile (RR = 2.43, 95% confidence interval (CI) 1.80 to 3.29). Cancer mortality and mortality due to ischemic heart diseases showed a dose-dependent relation with TCDD and all PCDD/F combined. The highest relative risks for cancer (RR = 3.30, 95% CI 2.05 to 5.31) and ischemic heart diseases (RR = 2.48, 95% CI 1.32 to 4.66) were observed in the highest PCDD/F exposure group. The pattern of effects and tests for trend were similar when the lowest exposure group within the chemical worker cohort served as the reference, but the relative risks were smaller and the confidence intervals were larger. Potential confounding exposures complicate the interpretation of the internal comparison. These findings indicate a strong dose-dependent relation between mortality due to cancer or ischemic heart diseases and exposure to polychlorinated dioxins and furans.

Low serum cholesterol and mortality. Which is the cause and which is the effect?

BACKGROUND: Many studies have reported an association between a low or lowered blood total cholesterol (TC) level and subsequent nonatherosclerotic disease incidence or death. The question of whether low TC is a true risk factor or alternatively a consequence of occult disease at the time of TC measurement remains unsettled. To shed new light onto this problem, we analyzed TC change over a 6- year period (from exam 1 in 1965 through 1968 to exam 3 in 1971 through 1974) in relation to subsequent 16-year mortality in a cohort of Japanese American men. METHODS AND RESULTS: The study was based on 5941 men 45 to 68 years of age without prior history of coronary heart disease, stroke, cancer, or gastrointestinal-liver disease at exam 1 who also participated in exam 3 of the Honolulu Heart Program. The association of TC change with mortality end points was investigated with two different approaches (continuous and categorical TC change) with standard survival analysis techniques. Falling TC level was accompanied by a subsequent increased risk of death caused by some cancers (hemopoietic, esophageal, and prostate), noncardiovascular noncancer causes (particularly liver disease), and all causes. The risk-factor-adjusted rate of all-cause mortality was 30% higher (relative risk, 1.30; 95% CI, 1.06 to 1.59) among persons with a decline from middle (180 to 239 mg/dL) to low (< 180 mg/dL) TC than in persons remaining at a stable middle level. By contrast, there was no significant increase in all-cause mortality risk among cohort men with stable low TC levels. Nonillness mortality (deaths caused by trauma and suicide) was not related to either TC change or the average of TC levels in exams 1 and 3. CONCLUSIONS: These results add strength to the reverse-causality proposition that catabolic diseases cause TC to decrease.