Abstract
Hypertension is a major risk for stroke; a linear or J‐shaped relationship between blood pressure (BP) and stroke have been reported. The authors examined the relationship between systolic and diastolic BP and risk of stroke in the general population in Japan. The study included 11,097 men and women who were divided into quintiles by systolic BP and diastolic BP in each sex. Follow‐up duration was 10.7 years. In men, risks of second to fifth quintiles of systolic BP for all stroke were 1.5 (95% confidence interval [CI], 0.7–3.0), 2.2 (CI, 1.2–4.2), 3.0 (CI, 1.7–5.5), and 4.2 (CI, 2.4–7.6) compared with a reference of the first quintile using Cox's proportional hazard model, respectively. In women, risk of second to fifth quintiles of systolic BP for all stroke were 1.2 (95% CI, 0.6–2.4), 1.5 (CI, 0.8–2.9), 2.2(CI, 1.2–4.1), and 3.1 (CI, 1.7–5.6), respectively. Systolic BP and diastolic BP were related to stroke incidence linearly in the general Japanese population. Systolic BP was slightly more predictive of the risk of stroke than diastolic BP.
The relationship between blood pressure (BP) and stroke is well‐established. In a meta‐analysis, Lawes and colleagues 1 found that the association between BP and risk of stroke was continuous and log linear. 2 , 3 The risk of stroke increases continuously above BP levels of approximately 115/75 mm Hg. Some studies, however, have reported a J‐shaped relationship between BP and mortality 4 , 5 and between BP and stroke in treated hypertensive patients. 6 The purpose of the present study was to attempt to confirm the relationship between BP and stroke and to examine whether the risk of stroke increases linearly, even in the normal range of systolic BP (SBP) and diastolic BP (DBP) in a population‐based cohort study in Japan. We used 2 kinds of categories to classify patients: first, dividing BP into quintiles and second, using conventional BP categories.
MATERIALS AND METHODS
Participants
Data were obtained between April 1992 and July 1995 in 12 districts in rural areas of Japan as part of the Jichi Medical School (JMS) cohort study. Details of the JMS cohort study, which began in 1992 and was a population‐based prospective cohort study aimed at clarifying the risk factors of cardiovascular disease, have been reported elsewhere. 7 Mass screening examinations for cardiovascular diseases have been conducted at these sites since 1983, in accordance with the health and medical service law for the aged. The target patients were residents aged 40 to 69 years in 8 communities, aged 20 to 69 years, and aged 35 years and older (no upper limit) in another. All adults (no age limit) were examined in the remainder. The total number of participants in the JMS cohort study included 12,490 men and women. The overall participation rate was 65.4%. Patients who declined to be followed up or those who had insufficient information about BP and medical history of hypertension were excluded. Six participants were lost to follow‐up. Eligible patients in the present study included 11,097 persons (4315 men and 6782 women).
Patients were divided into specific quintiles by SBP and DBP. They were also divided by conventional BP categories: ≤119, 120–129, 130–139, 140–159, 160–179, and ≥180 mm Hg for SBP and ≤79, 80–84, 85–89, 90–99, 100–109, and ≥110 mm Hg for DBP. Hyperglycemia included impaired glucose tolerance and diabetes mellitus (DM) and was defined as a fasting blood glucose level ≥110 mg/dL or casual blood glucose ≥140 mg/dL <3 hours or without regard to time since mealtime. DM was defined as a fasting blood glucose level ≥126 mg/dL, casual blood glucose ≥200 mg/dL, or treated DM.
The SBP and DBP were measured with a fully automated sphygmomanometer, BP203RV‐II (Nippon Colin, Komaki, Japan), placed on the right arm of a seated patient who had rested in the sitting position for 5 minutes before the measurement. Body mass index was calculated as weight (kg) ÷ height2 (m2). Information about medical history and lifestyle was gathered by questionnaire. Blood glucose, total cholesterol, and triglyceride levels were also measured.
Follow‐Up System
We used the mass screening examination system to obtain baseline data for the cohort study, which was used to check on all participants every year. Those examined were asked whether they had a history of stroke or cardiovascular diseases after enrolling in the present study. Patients with a history were asked where they were hospitalized. Patients who did not come to the screening examination were contacted by mail or phone. Medical records at hospitals in the area were checked to determine results of hospitalization, and public health nurses visited the patients to obtain additional information.
If an incident case was suspected, forms were filled out and duplicate computed tomographic films or magnetic resonance imaging films for strokes were obtained.
Diagnostic Criteria
A diagnosis was determined independently by a committee composed of 1 radiologist, 1 neurologist, and 2 cardiologists. Diagnosis of stroke was determined by the presence of a focal and non‐convulsive neurologic deficit lasting for 24 hours or longer with a clear onset. Stroke subtype was determined by criteria of the National Institute of Neurological Disorders and Stroke. 8
Statistical Analyses
Cutoffs of quintiles for SBP were 114, 124, 135, and 148 mm Hg in men and 110, 120, 132, and 145 mm Hg in women, and for DBP were 69, 76, 82, and 89 mm Hg in men and 66, 73, 79, and 86 mm Hg in women. Sample size for each quintile was calculated for each sex. We needed to assign 757 patients in each group to detect 2.5 times the cumulative rate of stroke in any other group compared with the first quintile, with a power of 80%, in condition of 0.02 of cumulative rate of stroke in the first quintile of men and 1018 patients in condition of 0.15 in women. Hazard ratios (Hrs) were calculated using Cox's proportional hazard model as a reference of lowest category in each analysis. Hrs were first calculated after adjustment for age and then for age, smoking status, drinking status, total cholesterol, and body mass index. These analyses were performed using SAS software version 8.2 edition (SAS Institute, Inc, Cary, NC).
RESULTS
General characteristics of study participants are shown in Table I. Mean ages were 55.1±12.0 years in men and 55.3±11.3 years in women. Mean follow‐up duration was 10.7 years. Crude incidence rates of all strokes were 1.6 (per 1000 person‐years) in the lowest quintile of SBP (≤113 mm Hg) and 10.0 in the highest (SBP ≥148) in men and 0.9 in the lowest quintile ≥109 mm Hg) and 5.7 in the highest (≥145 mm Hg) in women. After adjustment for multiple variables, a linear relationship was found between SBP and stroke incidence. In men, Hrs in the second to fifth quintiles of SBP for all strokes were 1.5 (95% confidence interval [CI], 0.7–3.0), 2.2 (95% CI, 1.2–4.2), 3.0 (95% CI, 1.7–5.5), and 4.2 (95% CI, 2.4–7.6) as a reference of first quintiles with multivariate models, respectively. In women, Hrs in the second to fifth quintiles of SBP for all stroke were 1.2 (95% CI, 0.6–2.4), 1.5 (95% CI, 0.8–2.9), 2.2 (95% CI, 1.2–4.1), and 3.1 (95% CI, 1.7–5.6), respectively. Significant increase of stroke risk started in the third quintile (SBP ≥124 mm Hg) in men and in the fourth (SBP ≥132 mm Hg) in women. A similar linear relationship was seen in the models using conventional SBP categories in men and women (eg, 120–129, 130–139 mm Hg). However, it appeared that quintiles of SBP detected risk of stroke more readily than conventional categories at low levels of SBP. An almost linear relationship between DBP in quintiles and stroke incidence was seen in men and women (Figure 1). In the models using conventional DBP categories, HR was the highest in the highest categories (≥110 mm Hg) compared with the lowest (≤79 mm Hg) in both men and women (men, 6.0; women, 7.9). However, Hrs fluctuated between the lowest and the highest categories in both men and women (Figure 2).
Table I.
General Characteristics of the Jichi Medical School Cohort Study
| Men | Women | |||||
|---|---|---|---|---|---|---|
| No. | Mean | SD | No. | Mean | SD | |
| Age, y | 4315 | 55.1 | 12.0 | 6782 | 55.3 | 11.3 |
| Systolic blood pressure, mm Hg | 4315 | 131.3 | 20.6 | 6782 | 128.0 | 21.2 |
| Diastolic blood pressure, mm Hg | 4315 | 79.1 | 12.4 | 6782 | 76.2 | 12.2 |
| Total cholesterol, mg/dL | 4285 | 185.0 | 34.2 | 6744 | 196.9 | 34.8 |
| HDL cholesterol, mg/dL | 4286 | 48.9 | 13.4 | 6744 | 52.7 | 12.5 |
| Triglycerides, mg/dLa | 4285 | 108.2 | (62.6–186.8) | 6743 | 95.0 | (57.5–157.1) |
| Blood glucose, mg/dL | 4286 | 105.6 | 31.1 | 6733 | 100.6 | 22.6 |
| Body mass index, kg/m2 | 4273 | 23.0 | 2.9 | 6715 | 23.1 | 3.2 |
| Smoking statusb | ||||||
| Curent smoker | 2171 | 50.5% | 372 | 5.6% | ||
| Ex‐smoker | 1216 | 28.3% | 193 | 2.9% | ||
| Nonsmoker | 913 | 21.2% | 6087 | 91.5% | ||
| Drinking statusb | ||||||
| Current drinker | 3157 | 75.4% | 1641 | 25.2% | ||
| Ex‐drinker | 142 | 3.4% | 99 | 1.5% | ||
| Nondrinker | 886 | 21.2% | 4764 | 73.3% | ||
| Hypertensionb | ||||||
| Treated | 422 | 9.8% | 826 | 12.2% | ||
| Nontreated | 1170 | 27.1% | 1382 | 20.4% | ||
| Diabetes mellitusb | 107 | 2.5% | 97 | 1.4% | ||
| Hyperlipidemiab | 54 | 1.3% | 136 | 2.0% | ||
| aGeometric mean (± SD). bPercentage is shown for proportion. Abbreviation: HDL, high‐density lipoprotein. | ||||||
Figure 1.
Hazard ratios (Hrs) for total stroke by quintiles of systolic and diastolic blood pressure in all patients. Hrs and 95% confidence intervals were calculated with adjustment for age, smoking status, drinking status, total cholesterol, body mass index, and diabetes mellitus. Diabetes mellitus was defined as fasting blood glucose ≥140 mg/dL, casual blood glucose ≥200 mg/dL, or treated diabetes mellitus.
Figure 2.
Hazard ratios (Hrs) for total stroke by conventional categories of systolic and diastolic blood pressure in all patients. Hrs and 95% confidence intervals were calculated with adjustment for age, smoking status, drinking status, total cholesterol, body mass index, and diabetes mellitus. Diabetes mellitus was defined as fasting blood glucose ≥140 mg/dL, casual blood glucose ≥200 mg/dL, or treated diabetes mellitus.
Participants taking or not taking antihypertensive treatment were evaluated separately. Although a linear relationship between SBP and stroke started in the third quintile in both men and women, a significant increase was only noted in the fourth and fifth quintile (≥134 mm Hg) in men and was seen only in the fifth quintile (≥141 mm Hg) in women when compared with the first quintile of BP (data not shown). In participants taking antihypertensive treatment, Hrs fluctuated: no significant association was seen in both men and women (Table II). Treated hypertensives were divided into quartiles, which included both men and women because the numbers of participants were small. Risk of stroke increased with DBP, when hyperglycemia or DM was included in the Cox proportional hazard model, but after multiple adjustments only the third quartile of DBP (87–93 mm Hg) was significantly higher than the first quintile (≤78). We did not find an association of SBP with risk of stroke in treated hypertensives in the model including hyperglycemia or DM (Table III).
Table II.
Crude Incidence Rates and Hrs for Total Stroke by Quintiles of SBP and DBP in Patients With Antihypertensive Treatment
| Quintile | SBP, mm Hg | No. | Case | Incidence a | HRb | 95% CI | HRc | 95% CI | |
|---|---|---|---|---|---|---|---|---|---|
| Men | 1st | ≤128 | 82 | 7 | 8.5 | 1.00 | 1.00 | ||
| 2nd | 129–140 | 82 | 10 | 12.7 | 1.83 | 0.69–4.84 | 1.35 | 0.49–3.73 | |
| 3rd | 141–151 | 87 | 9 | 9.9 | 1.48 | 0.55–4.01 | 1.27 | 0.46–3.49 | |
| 4th | 152–161 | 82 | 9 | 10.9 | 1.70 | 0.62–4.62 | 1.42 | 0.51–3.93 | |
| 5th | ≥162 | 89 | 12 | 13.6 | 1.54 | 0.60–3.90 | 1.14 | 0.43–3.03 | |
| Women | 1st | ≤130 | 162 | 9 | 6.3 | 1.00 | 1.00 | ||
| 2nd | 131–140 | 153 | 11 | 7.0 | 1.22 | 0.50–2.95 | 1.21 | 0.48–3.06 | |
| 3rd | 141–149 | 159 | 7 | 4.2 | 0.76 | 0.28–2.05 | 0.70 | 0.25–2.01 | |
| 4th | 150–163 | 182 | 16 | 8.3 | 1.46 | 0.64–3.31 | 1.49 | 0.63–3.50 | |
| 5th | ≥164 | 170 | 18 | 10.3 | 1.91 | 0.86–4.25 | 1.61 | 0.68–3.82 | |
| Quintile | DBP, mm Hg | No. | Case | Incidence a | HRb | 95% CI | HRc | 95% CI | |
| Men | 1st | ≥77 | 84 | 8 | 9.9 | 1.00 | 1.00 | ||
| 2nd | 78–83 | 76 | 9 | 11.7 | 1.78 | 0.67–4.67 | 1.61 | 0.57–4.55 | |
| 3rd | 84–89 | 82 | 10 | 12.0 | 1.71 | 0.67–4.40 | 1.61 | 0.58–4.51 | |
| 4th | 90–97 | 91 | 9 | 9.7 | 1.47 | 0.56–3.87 | 1.32 | 0.46–3.74 | |
| 5th | ≥98 | 89 | 11 | 12.5 | 2.02 | 0.80–5.10 | 1.90 | 0.68–5.32 | |
| Women | 1st | ≤76 | 137 | 9 | 6.4 | 1.00 | 1.00 | ||
| 2nd | 77–83 | 179 | 6 | 3.1 | 0.49 | 0.17–1.37 | 0.66 | 0.22–1.93 | |
| 3rd | 84–88 | 151 | 18 | 11.9 | 2.06 | 0.92–4.59 | 2.74 | 1.14–6.60 | |
| 4th | 89–95 | 184 | 13 | 6.7 | 1.15 | 0.49–2.71 | 1.38 | 0.56–3.39 | |
| 5th | ≥96 | 175 | 15 | 8.2 | 1.60 | 0.69–3.70 | 1.41 | 0.53–3.74 | |
| aCrude incidence rates were calculated per 1000 person‐years. bHazard ratios (Hrs) and 95% confidence intervals (CIs) were calculated after adjustment for age. cHrs and 95% CIs were calculated after adjustment for age, smoking status, drinking status, total cholesterol, body mass index, and diabetes mellitus. Diabetes mellitus was defined as fasting blood glucose ≥140 mg/dL, casual blood glucose ≥200 mg/dL, or treated diabetes mellitus. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. | |||||||||
Table III.
Hrs for Total Stroke by Quartiles of SBP and DBP in All Patients With Antihypertensive Treatment
| mm Hg | HRa | 95%CI | HRb | 95%CI | HRc | 95%CI | HRd | 95%CI | HRe | 95%CI | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SBP | 1st | ≤132 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |||||
| 2nd | 133–145 | 1.09 | 0.61–1.94 | 1.08 | 0.61–1.91 | 1.10 | 0.62–1.94 | 1.04 | 0.57–1.90 | 1.05 | 0.58–1.91 | |
| 3rd | 146–159 | 1.25 | 0.71–2.19 | 1.17 | 0.67–2.06 | 1.23 | 0.70–2.16 | 1.25 | 0.70–2.22 | 1.31 | 0.74–2.33 | |
| 4th | ≥160 | 1.37 | 0.80–2.33 | 1.25 | 0.73–2.15 | 1.35 | 0.79–2.30 | 1.08 | 0.61–1.94 | 1.17 | 0.66–2.08 | |
| Hyperglycemia | (yes vs no) | 2.12 | 1.39–3.23 | 2.11 | 1.35–3.28 | |||||||
| DM | (yes vs no) | 2.80 | 1.50–5.24 | 2.31 | 1.13–4.71 | |||||||
| DBP | 1st | ≤78 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |||||
| 2nd | 79–86 | 1.42 | 0.79–2.56 | 1.47 | 0.81–2.65 | 1.49 | 0.83–2.70 | 1.44 | 0.77–2.68 | 1.46 | 0.78–2.73 | |
| 3rd | 87–93 | 1.92 | 1.07–3.45 | 1.83 | 1.02–3.27 | 1.99 | 1.11–3.57 | 1.91 | 1.03–3.53 | 2.11 | 1.14–3.90 | |
| 4th | ≥94 | 1.81 | 1.01–3.22 | 1.73 | 0.97–3.08 | 1.82 | 1.02–3.23 | 1.53 | 0.81–2.88 | 1.63 | 0.86–3.07 | |
| Hyperglycemia | (yes vs no) | 2.10 | 1.38–3.20 | 2.06 | 1.32–3.21 | |||||||
| DM | (yes vs no) | 2.93 | 1.56–5.48 | 2.48 | 1.22–5.06 | |||||||
| aHazard ratios (Hrs) and 95% confidence intervals (CIs) were calculated with adjustment for age. bAdjustment for age and hyperglycemia. cAdjustment for age and diabetes mellitus (DM). dAdjustment for age, hyperglycemia, smoking status, drinking status, total cholesterol, and body mass index. eAdjustment for age, DM, smoking status, drinking status, total cholesterol, and body mass index. There was no significant relation in variables of smoking status, drinking status, total cholesterol, and body mass index. Hyperglycemia: fasting blood glucose ≥110 mg/dL or casual blood glucose ≥140 mg/dL or treated DM. DM was defined as fasting blood glucose ≥140 mg/dL or casual blood glucose ≥200 mg/dL. Abbreviations: DBP diastolic blood pressure; SBP, systolic blood pressure. | ||||||||||||
DISCUSSION
Consistent with several reviews of cohort studies, we found a linear relationship between BP and stroke in a multicenter cohort study both with quintiles and conventional BP categories. An association of SBP with stroke was not found in patients on antihypertensive therapy: DBP was only associated with stroke in the third quartile after adjustment for age and hyperglycemia.
Lawes and colleagues 1 reported that a log linear relationship was seen between SBP and stroke: 2 large meta‐analyses reported that the log linear association was continuous to levels of at least 115 mm Hg for SBP for all age groups. SBP correlated better than DBP as a risk for stroke or cardiovascular disease mortality. 2 , 3 Cohort studies of stroke incidence are few in Japan: most of them included <5000 people. More than 10,000 patients were followed for >10 years in the present study.
Several cohort studies have confirmed the finding of a positive relationship of SBP with stroke. 9 , 10 , 11 A correlation of DBP with stroke has not been found significant in older adults. 12 In Japan, SBP and DBP have been shown to be strong predictors of stroke. 13 In our data, both SBP and DBP were linearly related to stroke in all subjects and in subjects not receiving antihypertensive treatment.
A linear relationship between BP and mortality has also been seen in many cohort studies using conventional BP categories 14 and quintiles. 15 , 16 Pastor‐Barriuso and colleagues 5 have reported, however, that the association of DBP with all‐cause and cardiovascular mortality was hockey stick‐shaped (flat then increasing) in younger participants and J‐shaped in elderly, although SBP was linearly related to mortality. In the Rotterdam study, 6 a J‐shaped relationship between DBP and the incidence of stroke was found in treated hypertensives and older patients. Boshuizen and colleagues 17 have also reported that an inverse relationship between BP and all‐cause mortality in people older than 85 years was associated with overall health status.
It has been demonstrated that antihypertensive treatment reduces the risk of stroke in many randomized controlled trials 18 , 19 : tight BP control reduces the risk for stroke to the greatest degree. 20 , 21 Lawes and colleagues 1 showed that a 10‐mm Hg greater reduction in SBP is associated with a reduction in the risk of stroke of 31%. In cohort studies, however, the risk of stroke was still higher in treated hypertensives compared with normotensives. 22 , 23 This may be due, in part, to a failure in large numbers of treated patients to achieve goal BP. The same tendency was seen in our results. We found no association of SBP with stroke in treated hypertensives; however, the risk of stroke was increasing with DBP after adjustment for age and hyperglycemia or DM in these patients.
There are some limitations in the present study. The study patients were population‐based, not random samples. The patients were relatively healthy, and the medication rate for hypertension, DM, or hyperlipidemia was low. The present study has several strengths: (1) it was a large‐scale multicenter cohort study, (2) data were obtained in a standardized fashion, and (3) participants were followed for >10 years and the follow‐up rate was high. The diagnosis of stroke was ascertained by an independent committee using internationally accepted diagnostic criteria.
CONCLUSIONS
SBP and DBP linearly relate with stroke incidence in a general population in Japan; increasing risk of stroke started with SBP s <130 mm Hg. SBP was slightly more informative than DBP . In treated hypertensives, we could not find an association between SBP and stroke or DBP and stroke except in the third quartile after adjustment for age and hyperglycemia.
Acknowledgment and disclosures:
The authors thank Dr Yano for comments on the manuscript. This study was supported in part by a scientific research grant from the Ministry of Education, Culture, Sport, Science and Technology, Japan, and by grants from the Foundation for the Development of the Community, Tochigi, Japan.
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