Dan S. Sharp

Orthostatic hypotension predicts mortality in elderly men : the Honolulu Heart Program

BACKGROUND Population-based data are unavailable concerning the predictive value of orthostatic hypotension on mortality in ambulatory elderly patients, particularly minority groups. METHODS AND RESULTS With the use of data from the Honolulu Heart Programs fourth examination (1991 to 1993), orthostatic hypotension was assessed in relation to subsequent 4-year all-cause mortality among a cohort of 3522 Japanese American men 71 to 93 years old. Blood pressure was measured in the supine position and after 3 minutes of standing, with the use of standardized methods. Orthostatic hypotension was defined as a drop in systolic blood pressure (SBP) of >/=20 mm Hg or in diastolic blood pressure of >/=10 mm Hg. Overall prevalence of orthostatic hypotension was 6.9% and increased with age. There was a total of 473 deaths in the cohort over 4 years; of those who died, 52 had orthostatic hypotension. Four-year age-adjusted mortality rates in those with and without orthostatic hypotension were 56.6 and 38.6 per 1000 person-years, respectively. With the use of Cox proportional hazards models, after adjustment for age, smoking, diabetes mellitus, body mass index, physical activity, seated systolic blood pressure, antihypertensive medications, hematocrit, alcohol intake, and prevalent stroke, coronary heart disease and cancer, orthostatic hypotension was a significant independent predictor of 4-year all-cause mortality (relative risk 1.64, 95% CI 1.19 to 2.26). There was a significant linear association between change in systolic blood pressure from supine position to standing and 4-year mortality rates (test for linear trend, P<0.001), suggesting a dose-response relation. CONCLUSIONS Orthostatic hypotension is relatively uncommon, may be a marker for physical frailty, and is a significant independent predictor of 4-year all-cause mortality in this cohort of elderly ambulatory men.

β 2-glycoprotein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: The Honolulu Heart Program

Background— It has been hypothesized that immunoreactivity to &bgr;2-glycoprotein 1 (&bgr;2GP1)-dependent anticardiolipin antibody (aCL), but not &bgr;2GP1-independent aCL, is associated with increased risk of ischemic stroke and myocardial infarction (MI). Methods— We performed a nested case-control study examining aCL as a risk factor for ischemic stroke and MI by using stored frozen sera obtained from subjects enrolled in the Honolulu Heart Program and followed for up for 20 years. We measured &bgr;2GP1-dependent and &bgr;2GP1-independent aCL and anti-&bgr;2GP1 immunoreactivity in 259 men who developed an ischemic stroke, in 374 men who developed an MI, and in a control group of 1360 men who remained free of both conditions. Results— Only &bgr;2GP1-dependent aCL of the IgG class was significantly associated with both incident ischemic stroke and MI. This association was attenuated in the last 5 years of the 20-year follow-up. For stroke, the risk factor–adjusted relative odds for men with a positive versus a negative &bgr;2GP1-dependent aCL of the IgG class were 2.2 (95% CI 1.5 to 3.4) at 15 years and 1.5 (95% CI 1.0 to 2.3) at 20 years. For MI, the adjusted relative odds were 1.8 (95% CI 1.2 to 2.6) at 15 years and 1.5 (95% CI 1.1 to 2.1) at 20 years. Conclusions— These data suggest that aCL IgG, particularly the &bgr;2GP1-dependent variety, is an important predictor of future stroke and MI in men.

Effect of Dietary Calcium and Milk Consumption on Risk of Thromboembolic Stroke in Older Middle-aged Men: The Honolulu Heart Program

BACKGROUND AND PURPOSE Evidence suggests that dietary calcium is protective against hypertension. This report examines whether the effect has an influence on thromboembolic stroke. METHODS Since 1965, the Honolulu Heart Program has followed a cohort of men in a study of cardiovascular disease. This report examines the effect of baseline dietary calcium and milk intake on stroke risk in 22 years of follow-up in 3150 older middle-aged men (55 to 68 years). RESULTS Men who were nondrinkers of milk experienced stroke at twice the rate (P < .05) of men who consumed 16 oz/d or more (7.9 versus 3.7 per 100, respectively). While the rate of stroke decreased with increasing milk intake (P < .05), the decline in stroke risk with increased consumption was modest for those who consumed under 16 oz/d. Intake of dietary calcium was also associated with a reduced risk of stroke (P < .01), although its association was confounded with milk consumption. Calcium intake from nondairy sources was not related to stroke, suggesting that other constituents or covariates related to milk consumption may be important. CONCLUSIONS We conclude that an association between milk consumption and a reduced risk of stroke in older middle-aged men cannot be explained by intake of dietary calcium. Since milk is often part of a diverse pattern of dietary intake, it is difficult to determine whether milk consumption has a direct role in reducing the risk of stroke. Data suggest that consumption of milk in older middle age is not harmful, and when combined with a balanced diet, weight control, and physical activity, reductions in the risk of stroke may occur.

Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men

Decreased low-density lipoprotein (LDL) particle size is associated with coronary heart disease (CHD) risk among middle-aged Caucasian populations, and has been consistently correlated with increased plasma levels of triglyceride and decreased levels of high-density lipoprotein (HDL) cholesterol. This study examines whether these risk factors predict CHD among older Japanese-American men. With use of the Honolulu Heart Program Lipoprotein Exam 3 (1980 to 1982) as baseline, and 12-year follow-up for CHD events, a nested, case-control study was designed. One hundred forty-five incident CHD cases were identified and matched to 2 controls each. LDL particle diameter (size) was determined by gradient gel electrophoresis. A 10-angstrom (A) decrease in LDL size at baseline was associated with increased risk of incident CHD (relative risk 1.28, 95% confidence interval 1.01 to 1.63). After adjustment for baseline risk factors, the LDL size association was no longer statistically significant (relative risk 1.13, 95% confidence interval 0.86 to 1.49). When principal components analysis was used to define a composite variable for LDL size, triglycerides, and HDL cholesterol, this component predicted CHD independent of smoking, alcohol consumption, physical activity, body mass index, hypertension, diabetes, and beta-blocker use (p <0.01). Therefore, this prospective analysis of data from older, Japanese-American men demonstrated that decreased LDL size is a univariate predictor of incident CHD, and that a composite risk factor of LDL size, triglyceride, and HDL cholesterol was a risk factor for CHD independent of other risk factors.

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.

Combined Effects of HDL Cholesterol, Triglyceride, and Total Cholesterol Concentrations on 18-Year Risk of Atherosclerotic Disease

BACKGROUND Whether the combination of a low level of HDL cholesterol (HDL-C) and high level of triglyceride (TG) confers increased risk of cardiovascular disease and whether risk varies across levels of total cholesterol (TC) are not well established. Combined effects of HDL-C, TG, and TC on the incidence of atherosclerotic disease were examined prospectively in Japanese-American men from the Honolulu Heart Program. METHODS AND RESULTS Among 1,646 men aged 51 to 72 years who were free of coronary heart disease (CHD), stroke, and cancer and were not taking lipid-lowering medication, 318 developed atherosclerotic events (angina, coronary insufficiency, aortic aneurysm, definite CHD, or thromboembolic stroke) and 170 developed definite CHD between 1970 and 1988. Subjects were stratified by TC level (desirable, < 200 mg/dL; borderline high, 200 to 239 mg/dL; high, > or = 240 mg/dL), HDL-C level (< 35 and > or = 35 mg/dL), and TG level (< 200 and > or = 200 mg/dL). With Cox regression with high HDL-C and low TG as reference, age-adjusted relative risks (RR) of atherosclerotic events were significantly elevated in men with low HDL-C and high TG at borderline-high (RR, 2.46; 95% CI, 1.48 to 4.09) and high (RR, 2.21; 95% CI, 1.34 to 3.66) TC levels but not in men with desirable TC levels (RR, 0.89; 95% CI, 0.38 to 2.09). Elevated risks were independent of blood pressure, obesity, fat distribution, diabetes, smoking, and alcohol. Results were not materially altered by exclusion of subjects with angina alone and were similar but somewhat weaker for CHD. CONCLUSIONS Risk of atherosclerotic disease appears elevated in subjects with low HDL-C and high TG levels when TC is borderline high or high, independent of other cardiovascular risk factors. These findings support recent cholesterol screening recommendations and suggest that joint effects of HDL-C and TG may be important to consider.

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.

Predictors of myocardial lesions in men with minimal coronary atherosclerosis at autopsy the Honolulu Heart Program

Some cardiovascular risk factors are associated with clinical coronary heart disease but not with autopsy evidence of coronary atherosclerosis. To determine whether these risk factors might operate through mechanisms other than atherosclerosis, we examined associations between cardiovascular risk factors and subsequent intramural myocardial lesions assessed by protocol autopsy between 1965 and 1984 in 120 Japanese-American men from the Honolulu Heart Program who had minimal coronary atherosclerosis (American Heart Association (AHA) panel score < 3 on scale of 1 to 7). Age-adjusted prevalence of myocardial lesions was related to smoking status (P < 0.01), as well as amount, duration, and pack-years of smoking (P < 0.03). In a multiple logistic model, smoking (20 pack-years) was directly associated and fish intake (> or = 2 times/wk) was inversely associated with myocardial lesions independently of age, cholesterol, systolic blood pressure, body mass index, alcohol, diabetes, total calories, and animal protein intake (odds ratio (OR) = 1.5, 95% confidence intervals (CI) = 1.1 to 2.0 and OR = 0.35, 95% CI = 0.2 to 0.9, respectively). The protective effect of fish intake was most evident among men who did not have hypertension at baseline. Indices of obesity, body fat distribution, and physical activity and levels of triglyceride and alcohol intake were not associated with myocardial lesions. Thus, the adverse effects of smoking and the protective effects of fish consumption may extend to individuals relatively free of coronary atherosclerosis, possibly through hemostatic mechanisms or effects on small intramural arteries.

The Synergy of Low Lung Function and Low Body Mass Index Predicting All-Cause Mortality Among Older Japanese-American Men

OBJECTIVE: To assess the joint characteristics of low standardized weight and compromised pulmonary function in predicting all‐cause mortality.

Internal Validity of the Physical Activity Index over 26 Years in Middle‐Aged and Older Men

OBJECTIVE: To determine the internal validity of the physical activity index (PAI).