Hirotsugu Ueshima

Cardiovascular Disease and Risk Factors in Asia A Selected Review

Cardiovascular disease (CVD) prevention in Asia is an important issue for world health, because half of the world’s population lives in Asia. Asian countries and regions such as Japan, the Republic of Korea, the People’s Republic of China, Hong Kong, Taiwan, and the Kingdom of Thailand have greater mortality and morbidity from stroke than from coronary heart disease (CHD), whereas the opposite is true in Western countries.1 The reasons why this specific situation is observed in countries with rapid and early-phase westernization, such as Japan and South Korea, are very interesting. The Seven Countries Study conducted by Keys et al2 in 1957 found that Japanese populations had lower fat intake, lower serum total cholesterol, and lower CHD than populations in the United States and Scandinavia, in spite of higher smoking rates. The serum total cholesterol level in Japan has increased rapidly since World War II in accordance with an increase in dietary fat intake from 10% of total energy intake per capita per day to 25%.1,2 Despite this increase, the specific characteristic of lower CHD incidence and mortality than that in Western countries has persisted.3,4 Whether Japanese people and certain other Asian populations have different risk factors for CHD than Western populations has been a subject of discussion for quite some time. In this article, we discuss the existence of higher stroke rates and lower CHD rates in Asian countries than in Western countries and the respective risk factors for this on the basis of extensive reviews of cohort studies. We also discuss whether these risk factors differ from those of Western countries. Along with this, we examine the relationship between serum total cholesterol and total stroke and its subtypes. We also address the emerging problems and important issues for CVD prevention in Asia. An extensive …

Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents.

Summary Background Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up. Methods Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4–14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5–<25·0 kg/m2. Findings All-cause mortality was minimal at 20·0–25·0 kg/m2 (HR 1·00, 95% CI 0·98–1·02 for BMI 20·0–<22·5 kg/m2; 1·00, 0·99–1·01 for BMI 22·5–<25·0 kg/m2), and increased significantly both just below this range (1·13, 1·09–1·17 for BMI 18·5–<20·0 kg/m2; 1·51, 1·43–1·59 for BMI 15·0–<18·5) and throughout the overweight range (1·07, 1·07–1·08 for BMI 25·0–<27·5 kg/m2; 1·20, 1·18–1·22 for BMI 27·5–<30·0 kg/m2). The HR for obesity grade 1 (BMI 30·0–<35·0 kg/m2) was 1·45, 95% CI 1·41–1·48; the HR for obesity grade 2 (35·0–<40·0 kg/m2) was 1·94, 1·87–2·01; and the HR for obesity grade 3 (40·0–<60·0 kg/m2) was 2·76, 2·60–2·92. For BMI over 25·0 kg/m2, mortality increased approximately log-linearly with BMI; the HR per 5 kg/m2 units higher BMI was 1·39 (1·34–1·43) in Europe, 1·29 (1·26–1·32) in North America, 1·39 (1·34–1·44) in east Asia, and 1·31 (1·27–1·35) in Australia and New Zealand. This HR per 5 kg/m2 units higher BMI (for BMI over 25 kg/m2) was greater in younger than older people (1·52, 95% CI 1·47–1·56, for BMI measured at 35–49 years vs 1·21, 1·17–1·25, for BMI measured at 70–89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46–1·56, vs 1·30, 1·26–1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI. Interpretation The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health.

Alcohol and blood pressure: the INTERSALT study.

Abstract Objectives : To assess the relation between alcohol intake and blood pressure in men and women and in men at younger and older ages; to examine the influence of amount and pattern of alcohol consumption, as well as of acute effects, taking into account body mass index, smoking, and urinary sodium and potassium excretion. Design - Subjects reported alcohol consumption20for each of seven days before standardised blood pressure measurement, and whether they had consumed any alcohol in the 24 hours before measurement. Setting : 50 centres worldwide. Subjects : 4844 men and 4837 women aged 20-59. Main outcome measures : Effect of alcohol on blood pressure estimated by taking a weighted average of regression coefficients from centres. Acute effect assessed by examining mean differences in blood pressure of non- drinkers and of heavy drinkers who had and had not consumed alcohol in the 24 hours before measurement. Effect of pattern of consumption assessed by examining mean differences in blood pressure of non-drinkers compared with drinkers (i) whose intake was concentrated in fewer days or who were drinking more frequently, and (ii) whose alcohol intake varied little over the seven days or varied more substantially, as indicated by the standard deviation of daily consumption. Results : Of the 48 centres in which some people reported consuming at least 300 ml/week of alcohol, 35 had positive regression coefficients linking heavy alcohol consumption to blood pressure. Overall, alcohol consumption was associated with blood pressure, significantly at the highest intake. After account was taken of key confounders, men who drank 300-499 ml alcohol/week had systolic/diastolic blood pressure on average 2.7/1.6 mm Hg higher than non-drinkers, and men who drank >=500 ml alcohol/week had pressures of 4.6/3.0 mm Hg higher. For women, heavy drinkers (>=300 ml/week) had blood pressures higher by 3.9/3.1 mm Hg than non-drinkers. Heavy drinking and blood pressure were strongly associated in both sexes, and in men at both younger (20-39 years) and older (40-59 years) ages. In men who were heavy drinkers, episodic drinkers (those with great variation in daily alcohol consumption) had greater differences in blood pressure compared with non-drinkers than did regular drinkers of relatively constant amounts. Conclusion : The significant relation of heavy drinking (3-4 or more drinks/day) to blood pressure, observed in both men and women, and in younger and older men, was independent of and added to the effect on blood pressure of body mass index and urinary excretion of sodium and potassium. The findings indicate the usefulness of targeting those at higher risk as well as the general population to reduce the adverse effects of alcohol on blood pressure.

Dietary sources of sodium in China, Japan, the United Kingdom, and the United States, women and men aged 40 to 59 years: the INTERMAP study.

Public health campaigns in several countries encourage population-wide reduced sodium (salt) intake, but excessive intake remains a major problem. Excessive sodium intake is independently related to adverse blood pressure and is a key factor in the epidemic of prehypertension/hypertension. Identification of food sources of sodium in modern diets is critical to effective reduction of sodium intake worldwide. We used data from the INTERMAP Study to define major food sources of sodium in diverse East Asian and Western population samples. INTERMAP is an international, cross-sectional, epidemiologic study of 4, 680 individuals ages 40 to 59 years from Japan (four samples), Peoples Republic of China (three rural samples), the United Kingdom (two samples), and the United States (eight samples); four in-depth, multipass 24-hour dietary recalls/person were used to identify foods accounting for most dietary sodium intake. In the Peoples Republic of China sample, most (76%) dietary sodium was from salt added in home cooking, about 50% less in southern than northern samples. In Japan, most (63%) dietary sodium came from soy sauce (20%), commercially processed fish/seafood (15%), salted soups (15%), and preserved vegetables (13%). Processed foods, including breads/cereals/grains, contributed heavily to sodium intake in the United Kingdom (95%) and the United States (for methodological reasons, underestimated at 71%). To prevent and control prehypertension/hypertension and improve health, efforts to remove excess sodium from diets in rural China should focus on reducing salt in home cooking. To avoid excess sodium intake in Japan, the United Kingdom, and the United States, salt must be reduced in commercially processed foods.

A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen

In order to estimate the salt and potassium intake in a population and to compare their annual trends, we developed a simple method to estimate population mean levels of 24-h urinary sodium (24HUNaV) and potassium (24HUKV) excretion from spot urine specimens collected at any time. Using 591 Japanese data items from the INTERSALT study as a gold standard, we developed formulas to estimate 24-h urinary creatinine (24HUCrV), 24HUNaV and 24HUKV using both spot and 24-h urine collection samples. To examine the accuracy of the formulas, we applied these equations to 513 external manual workers. The obtained formulas were as follows: (1) PRCr (mg/day) = −2.04 × age + 14.89 × weight (kg) + 16.14 × height (cm) − 2244.45; (2) estimated 24HUNaV (mEq/day) = 21.98 × XNa0.392; (3) estimated 24HUKV (mEq/day) = 7.59 × XK0.431; where PRCr = predicted value of 24HUCr, SUNa = Na concentration in the spot voiding urine, SUK = K concentration in the spot voiding urine, SUCr = creatinine concentration in the spot voiding urine, XNa (or XK) = SUNa (or SUK)/SUCr × PRCr. In the external group, there was a significant but small difference between the estimated and measured values in sodium (24.0 mmol/day) and potassium (3.8 mmol/day) excretion. In every quintile divided by the estimated 24HUNaV or 24HUKV, the measured values were parallel to the estimated values. In conclusion, although this method is not suitable for estimating individual Na and K excretion, these formulas are considered useful for estimating population mean levels of 24-h Na and K excretion, and are available for comparing different populations, as well as indicating annual trends of a particular population.

Serum triglycerides as a risk factor for cardiovascular diseases in the Asia-Pacific region

Background—The importance of serum triglyceride levels as a risk factor for cardiovascular diseases is uncertain. Methods and Results—We performed an individual participant data meta-analysis of prospective studies conducted in the Asia-Pacific region. Cox models were applied to the combined data from 26 studies to estimate the overall and region-, sex-, and age-specific hazard ratios for major cardiovascular diseases by fifths of triglyceride values. During 796 671 person-years of follow-up among 96 224 individuals, 670 and 667 deaths as a result of coronary heart disease (CHD) and stroke, respectively, were recorded. After adjustment for major cardiovascular risk factors, participants grouped in the highest fifth of triglyceride levels had a 70% (95% CI, 47 to 96) greater risk of CHD death, an 80% (95% CI, 49 to 119) higher risk of fatal or nonfatal CHD, and a 50% (95% CI, 29% to 76%) increased risk of fatal or nonfatal stroke compared with those belonging to the lowest fifth. The association between triglycerides and CHD death was similar across subgroups defined by ethnicity, age, and sex. Conclusions—Serum triglycerides are an important and independent predictor of CHD and stroke risk in the Asia-Pacific region. These results may have clinical implications for cardiovascular risk prediction and the use of lipid-lowering therapy.

Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly: Valsartan in Elderly Isolated Systolic Hypertension Study

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (<140 mm Hg) is superior to moderate blood pressure control (≥140 mm Hg to <150 mm Hg) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension. We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension (sitting blood pressure 160 to 199 mm Hg) into 2 groups, according to strict or moderate blood pressure treatment. A composite of cardiovascular events was evaluated for ≥2 years. The strict control (1545 patients) and moderate control (1534 patients) groups were well matched (mean age: 76.1 years; mean blood pressure: 169.5/81.5 mm Hg). Median follow-up was 3.07 years. At 3 years, blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg, respectively. The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg. The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group (hazard ratio: 0.89; [95% CI: 0.60 to 1.34]; P=0.38). In summary, blood pressure targets of <140 mm Hg are safely achievable in relatively healthy patients ≥70 years of age with isolated systolic hypertension, although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets.

INTERMAP : background, aims, design, methods, and descriptive statistics (nondietary)

Blood pressure (BP) above optimal (⩽120/⩽80 mmHg) is established as a major cardiovascular disease (CVD) risk factor. Prevalence of adverse BP is high in most adult populations; until recently research has been sparse on reasons for this. Since the 1980s, epidemiologic studies confirmed that salt, alcohol intake, and body mass relate directly to BP; dietary potassium, inversely. Several other nutrients also probably influence BP. The DASH feeding trials demonstrated that with the multiple modifications in the DASH combination diet, SBP/DBP (SBP: systolic blood pressure, DBP: diastolic blood pressure) was sizably reduced, independent of calorie balance, alcohol intake, and BP reduction with decreased dietary salt. A key challenge for research is to elucidate specific nutrients accounting for this effect. The general aim of the study was to clarify influences of multiple nutrients on SBP/DBP of individuals over and above effects of Na, K, alcohol, and body mass. Specific aims were, in a cross-sectional epidemiologic study of 4680 men and women aged 40–59 years from 17 diverse population samples in China, Japan, UK, and USA, test 10 prior hypotheses on relations of macronutrients to SBP/DBP and on role of dietary factors in inverse associations of education with BP; test four related subgroup hypotheses; explore associations with SBP/DBP of multiple other nutrients, urinary metabolites, and foods. For these purposes, for all 4680 participants, with standardized high-quality methods, assess individual intake of 76 nutrients from four 24-h dietary recalls/person; measure in two timed 24-h urine collections/person 24-h excretion of Na, K, Ca, Mg, creatinine, amino acids; microalbuminuria; multiple nutrients and metabolites by nuclear magnetic resonance and high-pressure liquid chromatography. Based on eight SBP/DBP measurements/person, and data on multiple possible confounders, utilize mainly multiple linear regression and quantile analyses to test prior hypotheses and explore relations of multiple dietary and urinary variables to SBP/DBP of individuals.The 4680 INTERMAP participants are equally divided across four age/gender strata: diverse in ethnicity, education, occupation, physical activity; use of cigarettes, alcohol; diagnosed high BP, CVD, diabetes; CVD family history; women vary in parity, use of contraceptive medication and hormone replacement therapy.

Marine-Derived n-3 Fatty Acids and Atherosclerosis in Japanese, Japanese-American, and White Men : A Cross-Sectional Study

OBJECTIVES We sought to examine whether marine-derived n-3 fatty acids are associated with less atherosclerosis in Japanese versus white populations in the U.S. BACKGROUND Marine-derived n-3 fatty acids at low levels are cardioprotective through their antiarrhythmic effect. METHODS A population-based cross-sectional study in 281 Japanese (defined as born and living in Japan), 306 white (defined as white men born and living in the U.S.), and 281 Japanese-American men (defined as Japanese men born and living in the U.S.) ages 40 to 49 years was conducted to assess intima-media thickness (IMT) of the carotid artery, coronary artery calcification (CAC), and serum fatty acids. RESULTS Japanese men had the lowest levels of atherosclerosis, whereas whites and Japanese Americans had similar levels. Japanese had 2-fold higher levels of marine-derived n-3 fatty acids than whites and Japanese Americans in the U.S. Japanese had significant and nonsignificant inverse associations of marine-derived n-3 fatty acids with IMT and CAC prevalence, respectively. The significant inverse association with IMT remained after adjusting for traditional cardiovascular risk factors. Neither whites nor Japanese Americans had such associations. Significant differences between Japanese and whites in multivariable-adjusted IMT (mean difference 39 mum, 95% confidence interval [CI]: 21 to 57mum, p < 0.001) and CAC prevalence (mean difference 10.7%, 95% CI: 2.9% to 18.4%, p = 0.007) became nonsignificant after we adjusted further for marine-derived n-3 fatty acids (22 mum, 95% CI: -1 to 46 mum, p = 0.065 and 5.0%, 95% CI: -5.3% to 15.4%, p = 0.341, respectively). CONCLUSIONS Very high levels of marine-derived n-3 fatty acids have antiatherogenic properties that are independent of traditional cardiovascular risk factors and may contribute to lower the burden of atherosclerosis in Japanese, a lower burden that is unlikely the result of genetic factors.

Food Omega-3 Fatty Acid Intake of Individuals (Total, Linolenic Acid, Long-Chain) and Their Blood Pressure. INTERMAP Study

Findings from short-term randomized trials indicate that dietary supplements of omega-3 polyunsaturated fatty acids (PFA) lower blood pressure of hypertensive persons, but effect size in nonhypertensive individuals is small and nonsignificant. Data are lacking on food omega-3 PFA and blood pressure in general populations. The International Study of Macro- and Micro-nutrients and Blood Pressure (INTERMAP) is an international cross-sectional epidemiologic study of 4680 men and women ages 40 to 59 from 17 population-based samples in China, Japan, United Kingdom, and United States. We report associations of food omega-3 PFA intake (total, linolenic acid, long-chain) of individuals with blood pressure. Systolic and diastolic blood pressure were measured 8 times at 4 visits. With several models to control for possible confounders (dietary, other), linear regression analyses showed inverse relationship of total omega-3 PFA from food (percent kilocalories, from four 24-hour dietary recalls) to systolic and diastolic blood pressures. With adjustment for 17 variables, estimated systolic blood pressure/diastolic blood pressure differences with 2 standard deviation higher (0.67% kcal) omega-3 PFA were −0.55/−0.57 mm Hg (Z-score −1.33, −2.00); for 2238 persons without medical or dietary intervention, −1.01/−0.98 mm Hg (Z −1.63, −2.25); for 2038 nonhypertensive persons from this sub-cohort, −0.91/−0.92 mm Hg (Z −1.80, −2.38). For linolenic acid (largely from vegetable foods), blood pressure differences were similar, eg, for the 2238 “nonintervened” individuals, −0.97/−0.87 mm Hg (Z −1.52, −1.95); blood pressure differences were −0.32/−0.45 mm Hg for long-chain omega-3 PFA (largely from fish). In summary, food omega-3 PFA intake related inversely to blood pressure, including in nonhypertensive persons, with small estimated effect size. Food omega-3 PFA may contribute to prevention and control of adverse blood pressure levels.