Atsushi Hozawa

Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study.

Objective To examine the relationship between the normal nocturnal decline in blood pressure and the risk of cardiovascular mortality in individuals with and without high 24-h blood pressure values. Methods We obtained 24-h ambulatory blood pressure readings from 1542 residents of Ohasama, Japan, who were aged 40 years or more and were representative of the Japanese general population. We then followed up their survival for a mean of 9.2 years. The relationship was analysed using a Cox proportional hazards model adjusted for possible confounding factors. Results There was a linear relationship between the nocturnal decline in blood pressure and cardiovascular mortality. On average, each 5% decrease in the decline in nocturnal systolic/diastolic blood pressure was associated with an approximately 20% greater risk of cardiovascular mortality. There were no significant interactions for the risk between 24-h systolic/diastolic blood pressure values and continuous values for the nocturnal decline in blood pressure (P for interaction > 0.6). Even when 24-h blood pressure values were within the normal range (< 135/80 mmHg, average 118/69 mmHg), diminished nocturnal decreases in systolic/diastolic blood pressure were associated with an increased risk of cardiovascular mortality. Conclusions This is the first study to demonstrate that a diminished nocturnal decline in blood pressure is a risk factor for cardiovascular mortality, independent of the overall blood pressure load during a 24-h period, in the general population.

Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study

To investigate the association between cardiovascular mortality and short-term variabilities in blood pressure and heart rate, we performed a long-term prospective study of ambulatory blood pressure monitoring in Ohasama, Japan, starting in 1987. We obtained ambulatory blood pressure and heart rate in 1542 subjects ≥40 years of age. Blood pressure and heart rate variabilities were estimated as a standard deviation measured every 30 minutes by ambulatory monitoring. There were 67 cardiovascular deaths during the follow-up period (mean=8.5 years). The Cox proportional hazards model, adjusted for possible confounding factors, demonstrated a significant increase in cardiovascular mortality, with an increase in daytime systolic ambulatory blood pressure variability. A similar trend was observed in daytime diastolic and nighttime ambulatory blood pressures. Cardiovascular mortality rate increased linearly, with a decrease in daytime heart rate variability. Subjects in whom the daytime systolic ambulatory blood pressure variability was larger than third quintile and the daytime heart rate variability was lower than the mean−SD were at extremely high risk of cardiovascular mortality. The blood pressure and heart rate variabilities obtained every 30 minutes by ambulatory blood pressure monitoring were independent predictors for cardiovascular mortality in the general population.

Prediction of stroke by ambulatory blood pressure monitoring versus screening blood pressure measurements in a general population : the Ohasama study

Objective To investigate the association between 24 h, daytime and night-time ambulatory blood pressures and first symptomatic stroke, to compare their predictive powers for stroke with that of casual (screening) blood pressure, and to compare the predictive power for stroke between daytime and night-time blood pressures, in a general population in Ohasama, Japan. Design A prospective cohort study. Subjects and methods We obtained ambulatory blood pressure on 1464 subjects aged ≥ 40 years without history of symptomatic stroke, then followed-up their stroke-free survival. There were 74 first symptomatic stroke during the follow-up period (mean = 6.4 years). The prognostic significance of blood pressure for stroke risk was examined by a Cox proportional hazards regression model adjusted for possible confounding factors. Results The non-parametric and parametric analysis indicated that 24-h, daytime and night-time ambulatory blood pressures were linearly related with stroke risk. The likelihood ratio analysis demonstrated that these ambulatory blood pressures were significantly better related to stroke risk than did screening blood pressure, and that daytime blood pressure better predicted stroke risk than did night-time blood pressure. Conclusions The present study which prospectively investigated the relation between ambulatory blood pressure and first symptomatic stroke risk in a general population demonstrated that (i) ambulatory blood pressure values were linearly related to stroke risk; (ii) ambulatory blood pressures had the stronger predictive power for stroke risk than did screening blood pressure; and (iii) daytime blood pressure better related to stroke risk than did night-time blood pressure.

Obesity and risk of cancer in Japan

We conducted a population‐based prospective cohort study in Japan to examine the relationship between body mass index (BMI) and the risk of incidence of any cancer and of cancer at individual sites. Body mass index was calculated from self‐administered body weight and height at baseline. Relative risks (RR) and 95% confidence intervals (CI) were calculated in multivariate proportional‐hazards models. Among 27,539 persons (15,054 women and 12,485 men) aged 40 years or older who were free of cancer at enrollment in 1984, 1,672 (668 women and 1,004 men) developed cancer during 9 years of follow‐up. In women, after adjustment for potential confounders, the RR of all cancers associated with different BMI, relative to a BMI of 18.5–24.9, were 1.04 (95% CI = 0.85–1.27) for BMI = 25.0–27.4, 1.29 (1.00–1.68) for BMI = 27.5–29.9 and 1.47 (1.06–2.05) for BMI ≥30.0 (p for trend = 0.007). Higher BMI was also significantly associated with higher risk of cancers of the colorectum, breast (postmenopausal), endometrium and gallbladder in women. In men, we observed significantly increased all‐cancer risk among only never‐smokers. Overweight and obesity could account for 4.5% (all subjects) or 6.2% (never‐smokers) of the risk of any cancer in women and −0.2% (all subjects) or 3.7% (never‐smokers) in men. The value for women was within the range among women reported from Western populations (3.2%–8.8%). Our data demonstrate that excess weight is a major cancer risk among Japanese women.

Impact of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese Longitudinal Cohort Study

PURPOSE We evaluated the association of nocturia with fracture and death in a large, community based sample of Japanese individuals 70 years old or older. MATERIALS AND METHODS The baseline in this population based study was determined in 2003 by an extensive health interview with each participant. In this study we followed 784 individuals with a mean ± SD age of 76.0 ± 4.6 years (range 70 to 97). Information on mortality and fracture during the study period was provided by the National Health Insurance system and details on fractures were collected from medical records. We compared the risk of bone fracture and death with or without nocturia in a multivariate Cox proportional hazard model. RESULTS Nocturia (2 or greater voids per night) was present in 359 of the 784 participants (45.7%). Fracture was observed in 41 cases, including 32 fall related cases. For all fractures and fall related fractures with nocturia the HR was 2.01 (95% CI 1.04-3.87) and 2.20 (95% CI 1.04-4.68, each p = 0.04). Death occurred in 53 cases. The mortality rate in individuals with nocturia was significantly higher than in those without nocturia. For mortality in patients with nocturia the age-gender adjusted HR was 1.91 (95% CI 1.07-3.43, p = 0.03). Even when further adjusted for diabetes, smoking status, history of coronary disease, renal disease and stroke, tranquilizers, hypnotics and diuretics, the positive relationship was unchanged (HR 1.98, 95% CI 1.09-3.59, p = 0.03). CONCLUSIONS During a 5-year observation period elderly individuals with nocturia were at greater risk for fracture and death than those without nocturia.

Prognosis of white-coat and masked hypertension: International Database of HOme blood pressure in relation to Cardiovascular Outcome.

Home blood pressure monitoring is useful in detecting white-coat and masked hypertension and is recommended for patients with suspected or treated hypertension. The prognostic significance of white-coat and masked hypertension detected by home measurement was investigated in 6458 participants from 5 populations enrolled in the International Database of HOme blood pressure in relation to Cardiovascular Outcomes. During a median follow-up of 8.3 years, 714 fatal plus nonfatal cardiovascular events occurred. Among untreated subjects (n=5007), cardiovascular risk was higher in those with white-coat hypertension (adjusted hazard ratio 1.42; 95% CI [1.06–1.91]; P=0.02), masked hypertension (1.55; 95% CI [1.12–2.14]; P<0.01) and sustained hypertension (2.13; 95% CI [1.66–2.73]; P<0.0001) compared with normotensive subjects. Among treated patients (n=1451), the cardiovascular risk did not differ between those with high office and low home blood pressure (white-coat) and treated controlled subjects (low office and home blood pressure; 1.16; 95% CI [0.79–1.72]; P=0.45). However, treated subjects with masked hypertension (low office and high home blood pressure; 1.76; 95% CI [1.23–2.53]; P=0.002) and uncontrolled hypertension (high office and home blood pressure; 1.40; 95% CI [1.02–1.94]; P=0.04) had higher cardiovascular risk than treated controlled patients. In conclusion, white-coat hypertension assessed by home measurements is a cardiovascular risk factor in untreated but not in treated subjects probably because the latter receive effective treatment on the basis of their elevated office blood pressure. In contrast, masked uncontrolled hypertension is associated with increased cardiovascular risk in both untreated and treated patients, who are probably undertreated because of their low office blood pressure.Home blood pressure monitoring is useful in detecting white-coat and masked hypertension and is recommended for patients with suspected or treated hypertension. The prognostic significance of white-coat and masked hypertension detected by home measurement was investigated in 6458 participants from 5 populations enrolled in the International Database of HOme blood pressure in relation to Cardiovascular Outcomes. During a median follow-up of 8.3 years, 714 fatal plus nonfatal cardiovascular events occurred. Among untreated subjects (n=5007), cardiovascular risk was higher in those with white-coat hypertension (adjusted hazard ratio 1.42; 95% CI [1.06–1.91]; P =0.02), masked hypertension (1.55; 95% CI [1.12–2.14]; P <0.01) and sustained hypertension (2.13; 95% CI [1.66–2.73]; P <0.0001) compared with normotensive subjects. Among treated patients (n=1451), the cardiovascular risk did not differ between those with high office and low home blood pressure (white-coat) and treated controlled subjects (low office and home blood pressure; 1.16; 95% CI [0.79–1.72]; P =0.45). However, treated subjects with masked hypertension (low office and high home blood pressure; 1.76; 95% CI [1.23–2.53]; P =0.002) and uncontrolled hypertension (high office and home blood pressure; 1.40; 95% CI [1.02–1.94]; P =0.04) had higher cardiovascular risk than treated controlled patients. In conclusion, white-coat hypertension assessed by home measurements is a cardiovascular risk factor in untreated but not in treated subjects probably because the latter receive effective treatment on the basis of their elevated office blood pressure. In contrast, masked uncontrolled hypertension is associated with increased cardiovascular risk in both untreated and treated patients, who are probably undertreated because of their low office blood pressure. # Novelty and Significance {#article-title-34}

Relationship Between Metabolic Risk Factor Clustering and Cardiovascular Mortality Stratified by High Blood Glucose and Obesity NIPPON DATA90, 1990–2000

OBJECTIVE—Metabolic syndrome is diagnosed according to several criteria. Of these, some require glucose intolerance and others require obesity for the diagnosis. We investigated the relationship between metabolic risk factor clustering and cardiovascular disease (CVD) mortality stratified by high blood glucose or obesity. RESEARCH DESIGN AND METHODS—We followed 7,219 Japanese men and women without a history of CVD for 9.6 years. We defined high blood pressure, high blood glucose, high triglycerides, low HDL cholesterol, and obesity as metabolic factors. The multivariate adjusted hazard ratio (HR) for CVD mortality according to the number of clustering metabolic factors was calculated using the Cox proportional hazards model. RESULTS—During follow-up, 173 participants died of CVD. The numbers of metabolic risk factors and CVD mortality were positively correlated (Ptrend = 0.07). The HR was obviously higher among participants with than among those without high blood glucose and clustering of ≥2 other metabolic risk factors (HR 3.67 [95% CI 1.49–9.03]). However, the risk increase was only modest in participants without high blood glucose even if they had ≥2 other metabolic risk factors (1.99 [0.93–4.28]). Conversely, metabolic risk factor clustering was related to CVD mortality irrespective of obesity. CONCLUSIONS—Our findings suggest that glucose tolerance plays an important role in CVD mortality. Because the prevalence of nonobese participants with several metabolic risk factors was quite high and their CVD risk was high, excluding them from the diagnosis of metabolic syndrome because of the absence of obesity might overlook their risk.

Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals

The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ≥0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies.

Relation of Blood Pressure and All-Cause Mortality in 180 000 Japanese Participants. Pooled Analysis of 13 Cohort Studies

Hypertension is a leading cause of death because of cardiovascular disease and predominantly affects total mortality. To reduce avoidable deaths from hypertension, we need to collect blood pressure data and assess their impact on total mortality. To examine this issue, a meta-analysis of 13 cohort studies was conducted in Japan. Poisson regression was used for estimating all-cause mortality rates and ratios. In the model, blood pressure data were treated as continuous (10-mm Hg increase) and categorical (every 10 mm Hg) according to recommendations of the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Hypertension. Potential confounders included body mass index, smoking, drinking, and cohort. The impact of hypertension was measured by the population-attributable fraction. After excluding participants with cardiovascular disease history, 176 389 participants were examined in the analysis. Adjusted mortality rates became larger as the blood pressure increased, and these were more distinct in younger men and women. Hazard ratios also showed the same trends, and these trends were more apparent in younger men (hazard ratio [unit: 10-mm Hg increase] aged 40 to 49 years: systolic blood pressure 1.37 (range: 1.15 to 1.62); diastolic blood pressure 1.46 [range: 1.05 to 2.03]) than older ones (hazard ratio: aged 80 to 89 years: systolic blood pressure 1.09 [range: 1.05 to 1.13]and diastolic blood pressure 1.12 [range: 1.03 to 1.22]). Population-attributable fraction of hypertension was ≈20% when the normal category was used as a reference level and was 10% when we included the prehypertension group in the reference level. In conclusion, high blood pressure raised the risk of total mortality, and this trend was higher in the younger Japanese population.

Characteristics of blood pressure measured at home in the morning and in the evening : the Ohasama study

OBJECTIVE To determine the qualitative and quantitative differences of blood pressure measured at home (home measurement) in the morning versus the evening. METHODS Of 3744 participants, aged 20 years or older in the Ohasama population, more than 14 home measurements in the morning and in the evening, respectively, were obtained in each of 1207 individuals (881 untreated, 56.1 +/- 11.4 years and 326 treated, 66.0 +/- 9.2 years). A casual/screening measurement was also obtained in these individuals. RESULTS The home measurements in the morning were significantly higher than those in the evening. The bivariate linear regression analysis demonstrated that the difference between diastolic home measurement in the morning and that in the evening increased with an increase in diastolic home measurements. The multiple step-wise linear regression analysis, however, demonstrated that male sex, the use of antihypertensive medication, and SD of home measurements in individuals (blood pressure variability), but not level of home measurements, were positively associated with the difference between home measurement in the morning and that in the evening. The SD of home measurement in the evening in individuals was significantly larger than that in the morning, and the SD in treated individuals was significantly larger than that in untreated individuals. The correlations between casual and home measurements were moderate in untreated individuals (r = 0.509-0.567) but poor in treated subjects (r= 0.223-0.384). The correlations between home systolic measurements in the morning and in the evening were very close in both treated and untreated subjects (r = 0.814-0.902). The correlations between the SD of home measurements in the morning and in the evening were moderate in both treated and untreated individuals (r = 0.585-0.657). CONCLUSIONS Qualitative and quantitative differences in home blood pressure measurement, due to the differential time of measurement, should be taken into consideration in clinical use of home blood pressure measurements.