Design of the Women's Health Initiative clinical trial and observational study

We examined whether the synthesis of interleukin-1 or tumor necrosis factor, two cytokines with potent inflammatory activities, is influenced by dietary supplementation with n-3 fatty acids. Nine healthy volunteers added 18 g of fish-oil concentrate per day to their normal Western diet for six weeks. We used a radioimmunoassay to measure interleukin-1 (IL-1 beta and IL-1 alpha) and tumor necrosis factor produced in vitro by stimulated peripheral-blood mononuclear cells. With endotoxin as a stimulus, the synthesis of IL-1 beta was suppressed from 7.4 +/- 0.9 ng per milliliter at base line to 4.2 +/- 0.5 ng per milliliter after six weeks of supplementation (43 percent decrease; P = 0.048). Ten weeks after the end of n-3 supplementation, we observed a further decrease to 2.9 +/- 0.5 ng per milliliter (61 percent decrease; P = 0.005). The production of IL-1 alpha and tumor necrosis factor responded in a similar manner. Twenty weeks after the end of supplementation, the production of IL-1 beta, IL-1 alpha, and tumor necrosis factor had returned to the presupplement level. The decreased production of interleukin-1 and tumor necrosis factor was accompanied by a decreased ratio of arachidonic acid to eicosapentaenoic acid in the membrane phospholipids of mononuclear cells. We conclude that the synthesis of IL-1 beta, IL-1 alpha, and tumor necrosis factor can be suppressed by dietary supplementation with long-chain n-3 fatty acids. The reported antiinflammatory effect of these n-3 fatty acids may be mediated in part by their inhibitory effect on the production of interleukin-1 and tumor necrosis factor.

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The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells

ContextIt is commonly suggested that more than 50% of patients with coronary
heart disease (CHD) lack any of the conventional risk factors (cigarette smoking,
diabetes, hyperlipidemia, and hypertension). This claim implies that other
factors play a significant role in CHD and has led to considerable interest
in nontraditional risk factors and genetic causes of CHD.ObjectiveTo determine the prevalence of the 4 conventional risk factors among
patients with CHD.Design, Setting, and PatientsIn 2002-2003, we analyzed data for 122 458 patients enrolled in
14 international randomized clinical trials of CHD conducted during the prior
decade. Patients included 76 716 with ST-elevation myocardial infarction,
35 527 with unstable angina/non–ST-elevation myocardial infarction,
and 10 215 undergoing percutaneous coronary intervention.Main Outcome MeasuresPrevalence of each conventional risk factor and number of conventional
risk factors present among patients with CHD, compared between men and women
and by age at trial entry.ResultsAmong patients with CHD, at least 1 of the 4 conventional risk factors
was present in 84.6% of women and 80.6% of men. In younger patients (men ≤55
years and women ≤65 years) and most patients presenting either with unstable
angina or for percutaneous coronary intervention, only 10% to 15% of patients
lacked any of the 4 conventional risk factors. This pattern was largely independent
of sex, geographic region, trial entry criteria, or prior CHD. Premature CHD
was related to cigarette smoking in men and cigarette smoking and diabetes
in women. Smoking decreased the age at the time of CHD event (at trial entry)
by nearly 1 decade in all risk factor combinations.ConclusionsIn direct contrast with conventional thinking, 80% to 90% of patients
with CHD have conventional risk factors. Although research on nontraditional
risk factors and genetic causes of heart disease is important, clinical medicine,
public health policies, and research efforts should place significant emphasis
on the 4 conventional risk factors and the lifestyle behaviors causing them
to reduce the epidemic of CHD.

https://jamanetwork.com/journals/jama/articlepdf/197133/JOC30796.pdf

Prevalence of Conventional Risk Factors in Patients With Coronary Heart Disease

Objective : To estimate by how much and how quickly a given reduction in serum cholesterol concentration will reduce the risk of ischaemic heart disease.

Design : Data on the incidence of ischaemic heart disease and serum cholesterol concentration were analysed from 10 prospective (cohort) studies, three international studies in different communities, and 28 randomised controlled trials (with mortality data analysed according to allocated treatment to ensure the avoidance of bias). Main outcome measure - Decrease in incidence of ischaemic heart disease or mortality for a 0.6 mmol/l (about 10%) decrease in serum cholesterol concentration.

Results : For men results from the cohort studies showed that a decrease of serum cholesterol concentration of 0.6 mmol/l (about 10%) was associated with a decrease in incidence of ischaemic heart disease of 54% at age 40 years, 39% at age 50, 27% at 60, 20% at 70, and 19% at 80. The combined estimate from the three international studies (for ages 55-64 years) was 38% (95% confidence interval 33% to 42%), somewhat greater than the cohort study estimate of 27%. The reductions in incidence of ischaemic heart disease in the randomised trials (for ages 55-64 years) were 7% (0 to 14%) in the first two years, 22% (15% to 28%) from 2.1-5 years, and 25% (15% to 35%) after five years, the last estimate being lose to the estimate of 27% for the long term reduction from the cohort studies. The data for women are limited but indicate a similar effect. Conclusions - The results from the cohort studies, international comparisons, and clinical trials are remarkably consistent. The cohort studies, based on half a million men and 18 000 ischaemic heart disease events, estimate that a long term reduction in serum cholesterol concentration of 0.6 mmol/l (10%), which can be achieved by moderate dietary change,lowers the risk of ischaemic heart disease by 50% at age 40, falling to 20% at age 70. The randomised trials, based on 45 000 men and 4000 ischaemic heart disease events show that the full effect of the reduction in risk is achieved by five years.

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By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease

Type 2 diabetes may be a risk factor for dementia, but the associated pathological mechanisms remains unclear. We evaluated the association of diabetes alone or combined with the apolipoprotein E (APOE) gene with incident dementia and neuropathological outcomes in a population-based cohort of 2,574 Japanese-American men enrolled in the Honolulu-Asia Aging Study, including 216 subjects who underwent autopsy. Type 2 diabetes was ascertained by interview and direct glucose testing. Dementia was assessed in 1991 and 1994 by clinical examination and magnetic resonance imaging and was diagnosed according to international guidelines. Logistic regression was used to assess the RR of developing dementia, and log-linear regression was used to estimate the incident rate ratio (IRR) of neuropathological outcomes. Diabetes was associated with total dementia (RR 1.5 [95% CI 1.01-2.2]), Alzheimer's disease (AD; 1.8 [1.1-2.9]), and vascular dementia (VsD; 2.3 [1.1-5.0]). Individuals with both type 2 diabetes and the APOE epsilon4 allele had an RR of 5.5 (CI 2.2-13.7) for AD compared with those with neither risk factor. Participants with type 2 diabetes and the epsilon4 allele had a higher number of hippocampal neuritic plaques (IRR 3.0 [CI 1.2-7.3]) and neurofibrillary tangles in the cortex (IRR 3.5 [1.6-7.5]) and hippocampus (IRR 2.5 [1.5-3.7]), and they had a higher risk of cerebral amyloid angiopathy (RR 6.6, 1.5-29.6). Type 2 diabetes is a risk factor for AD and VsD. The association between diabetes and AD is particularly strong among carriers of the APOE epsilon4 allele. The neuropathological data are consistent with the clinical results.

https://diabetes.diabetesjournals.org/content/diabetes/51/4/1256.full.pdf

Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study

The incidence of myocardial infarction and death from coronary heart disease was studied in defined samples of 45 to 68 year old Japanese men in Japan, Hawaii and California. The incidence rate was lowest in Japan where it was half that observed in Hawaii (P less than 0.01). The youngest men in the sample in Japan were at particularly low risk. The incidence among Japanese men in California was nearly 50 percent greater than that of Japanese in Hawaii (P less than 0.05). A striking increase in the incidence of myocardial infarction appears to have occurred in the Japanese who migrated to the United States; this increase is more pronounced in California than in Hawaii.

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Incidence of myocardial infarction and death from coronary heart disease

Various risk factors were evaluated to explain a significantly greater incidence of coronary heart disease in men of Japanese ancestry resident in Hawaii compared with men resident in Japan. The independent predictors of incidence of coronary heart disease in both Japan and Hawaii were systolic blood pressure, serum cholesterol, relative weight and age. These factors appeared to influence incidence similarly in both areas because in each case the correlation coefficients for Japan and Hawaii did not differ significantly. The hypothesis that the greater incidence in Hawaii could be attributed to differences in levels of these risk factors was tested with the Walker-Duncan method. The four variable multiple logistic function describing the probability of coronary heart disease in Japan was applied to the cohort characteristics observed in Hawaii. The estimated incidence thus obtained was not significantly different from that actually observed in the men resident in Hawaii. Therefore the increased coronary risk profile in Hawaii compared with Japan can account for the greater incidence of coronary heart disease in the former. Current cigarette smoking was significantly related to the risk of coronary heart disease in Hawaii but not in Japan. This difference requires further investigation.

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Coronary heart disease risk factors in Japan and Hawaii

A high prevalence of chronic bronchitis and expiratory slowing occurred among former employees of a poison gas factory in Japan. Even among nonsmokers, almost one half of the men who had been exposed repeatedly to mustard gas or lewisite before 1945 had a persistent productive cough. Former poison gas workers showed a more bronchitic type of airway obstructive syndrome than ordinary patients with chronic obstructive pulmonary disease in Hiroshima and Chicago, but they did not have less anatomic evidence of emphysema. Using standardized methods of study, few differences between the ordinary clinic patients in Japan and those in the United States were demonstrated when groups were matched for age, sex, and severity of expiratory slowing.

Chronic obstructive lung disease in Japanese poison gas workers.

Publisher Summary This chapter presents a comparative epidemiologic study of diabetes and hyperlipidemia, which was made among Japanese residents on the Island of Hawaii. These residents were the migrants from Hiroshima and the Japanese in Hiroshima Prefecture. The prevalence of diabetes, including those with positive diabetic history, was higher in Japanese men on the Island than in Hiroshima men, but the difference was not statistically significant. However, a significant difference was observed in women. The prevalence was 17.0% of the group aged between 40 and 59 years and 38.7% of the group aged over 60 years in Hawaiian women, whereas it was 6.3% and 25.8% in Hiroshima women. This trend of a higher prevalence of diabetes in Hawaiian subjects was also noted by a comparison in nonobese cases, in cases matched by physical activity levels, and in relatives between these two groups. The prevalence of hypercholesterolemia and hypertriglyceridemia was elevated in Hawaiian Japanese. The diet of Hawaiian Japanese was characterized by a higher intake of saturated fat and simple carbohydrate and low-complex carbohydrate. This dietary habit influences the prevalence of diabetes mellitus, hyperlipemia, and cardiovascular complications. A reduction in atherogenic diet intake in subjects with diabetes mellitus might be a more important approach to the prevention of cardiovascular complications than a control of the blood-sugar level in diabetes mellitus.

Michihiro Miyanishi

Papers

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Incidence of myocardial infarction and death from coronary heart disease

Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: Coronary heart disease risk factors in Japan and Hawaii

Chronic obstructive lung disease in Japanese poison gas workers.

Preliminary studies of the prevalence and mortality of diabetes mellitus in Japanese in Japan and on the island of Hawaii.