Carlos Iribarren

CORRELATES OF URIC ACID AND ITS ASSOCIATION WITH ASYMPTOMATIC CAROTID ATHEROSCLEROSIS : THE ARIC STUDY

The correlates of serum uric acid and the association of uric acid with carotid intimal-medial thickness (an early measure of atherosclerosis) were investigated in participants of the baseline examination of the Atherosclerosis Risk in Communities (ARIC) Study. The study sample included 6522 women (74% white) and 4966 men (79% white) who were aged 45 to 64 years at baseline (1986-1989). Those with prevalent coronary heart disease or previous stroke and those taking uricosuric medication were excluded. The mean (SD) uric acid concentration was 5.9 (1.5) mg/dL. It was highest among black men 45-54 years old (6.9 [1.5] mg/dL), and lowest in white women aged 45-54 years old (5.0 [1.2] mg/dL). The uric acid level was positively correlated in both sexes with a variety of health-related factors, most notably body mass index, creatinine, triglycerides, diuretic use, alcohol intake, hypertension, diabetes, and insulin levels. In a linear regression model adjusting for age and ARIC center, the level of uric acid was directly and significantly associated with B-mode ultrasound carotid intimal-medial thickness in women and white men (but not in black men). However, when known risk factors for atherosclerotic disease and relevant behavioral and biological correlates of uric acid were controlled for in multivariate analysis, the association of uric acid with this early measure of atherosclerosis became negligible in white women and much weaker and not statistically significant in black women and white men. Thus, uric acid itself may not be a risk factor for atherosclerosis. Future analysis of cardiovascular events in the ARIC Study will further elucidate the role of uric acid in atherosclerotic disease.

Association of Weight Loss and Weight Fluctuation with Mortality among Japanese American Men

BACKGROUND Weight loss and fluctuations in weight have been associated with increased risks of death from cardiovascular disease and from all causes. The clinical and public health implications of these associations are unclear. METHODS We examined the long-term relation of weight change and fluctuation in weight with mortality over a 6-year period in 6537 middle-aged Japanese American men enrolled in the Honolulu Heart Program, a prospective study (mean follow-up, 14.5 years). RESULTS Men who had a weight loss of 4.5 kg or more or who had large fluctuations in weight (or both) over a six-year period were, on average, in poorer health than their peers whose weight was more stable. After the exclusion of subjects who died during the first five years of follow-up and after adjustment for confounding factors, a weight loss of more than 4.5 kg was associated with the risk of death from all causes, with the exception of death from cancer. The subjects whose weight fluctuated the most had a significantly higher risk of death from cardiovascular causes (relative risk, 1.41; 95 percent confidence interval, 1.03 to 1.93), death from noncardiovascular and noncancerous causes (relative risk, 1.53; 95 percent confidence interval, 1.12 to 2.10), and death from all causes (relative risk, 1.25; 95 percent confidence interval, 1.05 to 1.48). However, the associations of weight loss and variation in weight with death from cardiovascular causes and from noncardiovascular and noncancerous causes were not found among healthy men who had never smoked. CONCLUSIONS The associations between weight loss or fluctuation and mortality were partially explained by confounding factors and by the presence of preexisting disease. However, weight loss and weight fluctuation were unrelated to death among healthy men who had never smoked. Thus, concern about the health hazards of weight loss and variation may not be applicable to otherwise healthy people.

Low total serum cholesterol and intracerebral hemorrhagic stroke : Is the association confined to elderly men : The kaiser permanente medical care program

BACKGROUND AND PURPOSE Epidemiological studies indicate a higher incidence of intracerebral (but not subarachnoid) hemorrhagic stroke among persons with low total serum cholesterol levels. This report further examines the prospective relationship of total serum cholesterol with subsequent intracerebral hemorrhage in a large, well-defined population. METHODS The cohort included 61756 enrollees in a health plan from the San Francisco-Oakland metropolitan area (46% men, 63% white), aged 40 to 89 years and free of cardiovascular disease at baseline. Sixteen-year incidence of combined nonfatal and fatal intracerebral hemorrhagic stroke (International Classification of Diseases [ICD], 8th revision, code 431, or ICD, 9th revision, codes 431 and 432) was investigated in relation to serum cholesterol measured in multiphasic health checkups made in 1977 through 1985. Intracerebral hemorrhagic events were ascertained using hospital discharge records and as underlying cause of death by the California Mortality Linkage Information System. RESULTS From 1978 through 1993 (average of 10.7 years), there were 386 events (201 in men, 29% fatal; 185 in women, 42% fatal). By multivariate proportional hazards life-table regression analysis, serum cholesterol level below the sex-specific 10th percentile (< 4.62 mmol/L [178 mg/dL] in men), compared with higher cholesterol level, was associated with a significantly increased risk of intracerebral hemorrhage in men aged 65 years or older (relative risk, 2.7; 95% confidence interval, 1.4 to 5.0). An excess risk was also observed among elderly women at the lowest cholesterol range, but a chance finding could not be ruled out. No relationship was seen among men or women aged 40 to 64, and no statistical interaction of low serum cholesterol with hypertension was found in either sex. CONCLUSIONS In these data, the association between low serum cholesterol level and intracerebral hemorrhage was confined to elderly men.

Validation of death certificate diagnosis of out-of-hospital sudden cardiac death

The validity of death certificate diagnosis of out-of-hospital sudden cardiac death (OOH-SCD) was studied among 108,676 30- to 74-year-old residents in 5 Minnesota communities using 6-year mortality data (1985 to 1990). Among 4,244 total deaths, location of death was listed on the certificate as out of hospital in 2,035 cases. Of those, 911 were judged not to have OOH-SCD because they had actually been admitted to the hospital or were noncardiovascular deaths. Among the remaining 1,124, 254 were diagnosed as OOH-SCD using a thorough, physician-based procedure that used clinical records, autopsy reports, and an informant (next-of-kin) interview. We used only death certificate information to define OOH-SCD simply and inexpensively as ICD-9 code 427.5 (cardiac arrest) plus location of death listed as out-of-hospital. Compared with the physician diagnosis, sensitivity was only 24%, whereas specificity was 85%. When the definition of OOH-SCD was expanded to include ICD codes 410-414 (acute myocardial infarction and chronic coronary artery disease), sensitivity improved to 87%, whereas specificity became 66%. However, even with this higher sensitivity and specificity, only 27% of the cases labeled OOH-SCD by death certificate agreed with the physician diagnosis. Death certificate diagnosis of OOH-SCD included many erroneous cases, and may not have been suitable for study of etiologic factors, such as cardiac dysrhythmias. Death certificate diagnosis may be useful to assess population time trends in OOH-SCD, provided that misclassification (false-positive rate) remains constant over time.

Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis. A case-control study. The ARIC Study Investigators. Atherosclerosis Risk in Communities.

Oxidative modification of LDL is believed to be a crucial step in atherosclerosis. Thus, antioxidant vitamins may have a role in the prevention of coronary disease. We examined the cross-sectional association of serum vitamin levels, the susceptibility of LDL to hemin-induced oxidation (lag phase to conjugated diene formation), and the malondialdehyde-LDL (MDA-LDL) to native LDL radioactivity binding ratio with carotid intima-media thickness (IMT), a measure of asymptomatic early atherosclerosis. The participants in this observational study were 231 asymptomatic age-, sex-, race-, and field center-matched case-control pairs selected from the Atherosclerosis Risk in Communities (ARIC) study cohort on the basis of B-mode carotid artery ultrasonograms obtained from 1986 through 1989. Cases exceeded the 90th percentile of IMT, and control subjects were below the 75th percentile of IMT for all arterial segments. Biochemical analyses were performed on fasting frozen (-70 degrees C) serum specimens collected from 1990 through 1992. In conditional logistic regression adjusting for age, blood storage time, total cholesterol, and log-triglyceride concentrations, serum beta-cryptoxanthin and lutein plus zeaxanthin levels were inversely related to the extent of atherosclerosis (odds ratio [OR] per 1-SD increase: 0.75, 95% confidence interval [CI]: 0.59-0.94; and OR per 1-SD increase: 0.76, 95% CI: 0.59-0.95, respectively). Increases in alpha-carotene and lycopene were associated with nonsignificantly lower odds of being a case, whereas beta-carotene, retinol, and alpha-tocopherol were unrelated to IMT. Although not reaching statistical significance, the lag phase and autoantibodies against MDA-LDL were positively associated with asymptomatic atherosclerosis. After adjustment for potential confounders, only the inverse association of lutein plus zeaxanthin with asymptomatic atherosclerosis was maintained. This study supports a modest inverse association between circulating levels of some carotenoids, particularly lutein plus zeaxanthin, and carotid IMT. These findings suggest that these carotenoid compounds (regarded as biomarkers of fruit and vegetable intake) may be important in early stages of atherosclerosis.

Association of Serum Vitamin Levels, LDL Susceptibility to Oxidation, and Autoantibodies Against MDA-LDL With Carotid Atherosclerosis: A Case-Control Study

Oxidative modification of LDL is believed to be a crucial step in atherosclerosis. Thus, antioxidant vitamins may have a role in the prevention of coronary disease. We examined the cross-sectional association of serum vitamin levels, the susceptibility of LDL to hemin-induced oxidation (lag phase to conjugated diene formation), and the malondialdehyde-LDL (MDA-LDL) to native LDL radioactivity binding ratio with carotid intima-media thickness (IMT), a measure of asymptomatic early atherosclerosis. The participants in this observational study were 231 asymptomatic age-, sex-, race-, and field center-matched case-control pairs selected from the Atherosclerosis Risk in Communities (ARIC) study cohort on the basis of B-mode carotid artery ultrasonograms obtained from 1986 through 1989. Cases exceeded the 90th percentile of IMT, and control subjects were below the 75th percentile of IMT for all arterial segments. Biochemical analyses were performed on fasting frozen (-70 degrees C) serum specimens collected from 1990 through 1992. In conditional logistic regression adjusting for age, blood storage time, total cholesterol, and log-triglyceride concentrations, serum beta-cryptoxanthin and lutein plus zeaxanthin levels were inversely related to the extent of atherosclerosis (odds ratio [OR] per 1-SD increase: 0.75, 95% confidence interval [CI]: 0.59-0.94; and OR per 1-SD increase: 0.76, 95% CI: 0.59-0.95, respectively). Increases in alpha-carotene and lycopene were associated with nonsignificantly lower odds of being a case, whereas beta-carotene, retinol, and alpha-tocopherol were unrelated to IMT. Although not reaching statistical significance, the lag phase and autoantibodies against MDA-LDL were positively associated with asymptomatic atherosclerosis. After adjustment for potential confounders, only the inverse association of lutein plus zeaxanthin with asymptomatic atherosclerosis was maintained. This study supports a modest inverse association between circulating levels of some carotenoids, particularly lutein plus zeaxanthin, and carotid IMT. These findings suggest that these carotenoid compounds (regarded as biomarkers of fruit and vegetable intake) may be important in early stages of atherosclerosis.

High uric acid: A metabolic marker of coronary heart disease among alcohol abstainers?

The association between serum uric acid level and risk of coronary heart disease (CHD) over 21 years was investigated among 6411 middle-aged Japanese-American men who were participants in the Honolulu Heart Program. In an age-stratified Cox regression model, high serum uric acid (quartile 4 [>6.7 mg/dl], relative to quartile 1 [<5.0 mg/dl]) was a significant predictor of definite CHD (RR = 1.33; 95% confidence interval = 1.08-1.63; p = 0.006). However, when adjustment for confounders (body mass index, heavy alcohol consumption, triglycerides, diastolic blood pressure, blood glucose, and the ratio of animal to vegetable protein) was made, the association of high uric acid with coronary events was substantially reduced and became nonsignificant (RR = 1.14; 95% confidence interval = 0.92-1.42; p = 0.21). There was a significant interaction between serum uric acid and drinking status (P = 0.03). Thus, the risk of definite CHD associated with high urate levels (quartile 4), relative to low levels (quartile 1), was elevated in the abstainers (RR = 1.40; 95% confidence interval = 1.01-1.93; p = 0.02), but not in light and moderate drinkers (RR = 1.1 1; 95% confidence interval = 0.79-1.55; p = 0.58) or among the heavy drinkers (>40 ml of ethanol/day; RR = 0.57; 95% confidence interval = 0.27-1.21; p = 0.08). It is concluded that elevated uric acid may be associated with higher CHD among alcohol abstainers. Whether raised urate is an etiological factor for CHD or a manifestation of existing arterial disease in nondrinkers deserves further investigation.

Lack of association between ferritin level and measures of LDL oxidation : The ARIC Study

Abstract Body iron status has been implicated in atherosclerotic cardiovascular disease. The main hypothesis was that high iron status was associated with increased oxidation of LDL. The associations of serum ferritin (a marker of iron status) and dietary iron intake with the susceptibility of LDL to in vitro oxidation (lag phase) and autoantibodies against MDA-modified LDL (two markers of oxidation stress) were examined among 281 men and 192 women with a mean age of 59 years (S.D.=5) who participated in the Atherosclerosis Risk in Communities (ARIC) Study visit 2 in 1990 through 1992. Lag phase duration and the autoantibodies against MDA-modified LDL were weakly correlated with each other ( r =0.19, P =0.001 in men; r =0.15, P =0.03 in women). In linear regression analysis adjusting for age, field center, blood storage time, and carotid atherosclerosis case-control status, there was no association between ferritin level and the lag-phase, or between ferritin level and autoantibodies against MDA-modified LDL in either sex. Further adjustment for traditional cardiovascular risk factors (smoking, vitamin supplement use, body mass index, LDL cholesterol, hypertension and diabetes) did not alter these null results. Ferritin was significantly and positively correlated with body mass index in both sexes ( r =0.21 among men and r =0.22 among women) and with the waist-to-hip ratio among women ( r =0.26). In addition, among women, ferritin was positively correlated with orosomucoid ( r =0.24) and with sialic acid ( r =0.19). Dietary iron was not associated with the parameters of LDL oxidation or with ferritin level. These findings do not support a role of body iron stores in promoting oxidation of LDL.

Relationship of Lipoproteins, Apolipoproteins, Triglycerides and Lipid Ratios to Plasma Total Cholesterol in Young Adults: The CARDIA Study

Objective To characterize the association of carrier lipoproteins, apolipoproteins, triglycerides and various lipid ratios with total cholesterol in young adults. Design Cross-sectional data from the baseline examination (1985–1986) of The Coronary Artery Risk Development In Young Adults (CARDIA) Study, a multicenter investigation of a biracial cohort of 4941 men and women aged 18–30 years. Methods Multiple linear regression models to estimate mean levels of lipids and lipoproteins for each category of total cholesterol, stratified by race and sex and adjusted for age and education level. Results As expected, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I) and triglycerides increased linearly with the level of total cholesterol in all race-sex subgroups. The LDL-C/HDL-C, ApoB/ApoA-I and LDL-C/ApoB ratio also increased with total cholesterol in all race–sex subgroups. The HDL-C/ApoA-I ratio, indicative of cholesterol content per HDL particle, did not vary with total cholesterol except in white men, in whom it was slightly lower for those with high total cholesterol than those with low total cholesterol concentrations. White men showed higher triglyceride concentrations and lower HDL-C for any given total cholesterol strata. All these associations of lipoproteins, apolipoproteins and lipid ratios with total cholesterol were independent of body mass index, smoking status, fitness level and Keys score. Conclusions Young adults with low total cholesterol have lipoprotein profiles characterized by low atherogenic potential. White men with high total cholesterol levels, compared with other groups, showed a lipid profile more conducive to atherogenesis.