苅尾 七臣

It remains uncertain whether abnormal dipping patterns of nocturnal blood pressure influence the prognosis for stroke. We studied stroke events in 575 older Japanese patients with sustained hypertension determined by ambulatory blood pressure monitoring (without medication). They were subclassified by their nocturnal systolic blood pressure fall (97 extreme-dippers, with greater than or equal to 20% nocturnal systolic blood pressure fall; 230 dippers, with greater than or equal to 10% but <20% fall; 185 nondippers, with <greater than or equal to>0% but <10% fall, and 63 reverse-dippers, with <0% fall) and were followed prospectively for an average duration of 41 months. Baseline brain magnetic resonance imaging (MRI) disclosed that the percentages with multiple silent cerebral infarct were 53% in extreme-dippers, 29% in dippers, 41% in nondippers, and 49% in reverse-dippers. There was a J-shaped relationship between dipping status and stroke incidence (extreme-dippers, 12%; dippers, 6.1%; nondippers, 7.6%, and reverse-dippers, 22%), and this remained significant in a Cox regression analysis after controlling for age, gender, body mass index, 24-hour systolic blood pressure, and antihypertensive medication. Intracranial hemorrhage was more common in reverse-dippers (29% of strokes) than in other subgroups (7.7% of strokes, P=0.04). In the extreme-dipper group, 27% of strokes were ischemic strokes that Occurred during sleep (versus 8.6% of strokes in the other 3 subgroups, P=0.11). In conclusion, in older Japanese hypertensive patients, extreme dipping of nocturnal blood pressure may be related to silent and clinical cerebral ischemia through hypoperfusion during sleep or an exaggerated morning rise of blood pressure, whereas reverse dipping may pose a risk for intracranial hemorrhage.

Objectives We investigated whether white-coat hypertension is a risk factor for stroke in relation to silent cerebral infarct (SCI) in an older Japanese population. Background It remains uncertain whether white-coat hypertension in older subjects is a benign condition or is associated with an increased risk of stroke. Methods We studied the prognosis for stroke in 958 older Japanese subjects (147 normotensives [NT], 236 white-coat hypertensives [WCHT] and 575 sustained hypertensives [SHT]) in whom ambulatory blood pressure monitoring was performed in the absence of antihypertensive treatment. In 585 subjects (61%), we also assessed SCI using brain magnetic resonance imaging. Results Silent cerebral infarcts were found in 36% of NT (n = 70), 42% of WCHT (n = 154), and 53% of SHT (n = 361); multiple SCIs (the presence of greater than or equal to2 SCIs) were found in 24% of NT, 25% of WCHT and 39% of SHT. During a mean 42-month follow-up period, clinically overt strokes occurred in 62 subjects (NT: three [2.0%]; WCHT: five [2.1%]; SHT: 54 [9.4%]), with 14 fatal cases (NT: one [0.7%]; WCHT: 0 [0%]; SHT: 13 [2.3%]). A Cox regression analysis showed that age (p = 0.0001) and SHT (relative risk, [RR] [95% confidence interval, CI]: 4.3 [1.3-14.2], p = 0.018) were independent stroke predictors, whereas WCHT was not significant. When we added presence/absence of SCI at baseline into this model, the RR (95% CI) for SCI was 4.6 (2.0-10.5) (p = 0.003) and that of SI-IT was 5.5 (1.8-18.9) versus WCHT (p = 0.004) and 3.8 (0.88-16.7) versus NT (p = 0.07). Conclusions In older subjects the incidence of stroke in WCHT is similar to that of NT and one-fourth the risk in SHT. Although SCI is a strong predictor of stroke, the difference in stroke prognosis between ST-IT and WCHT was independent of SCI. It is clinically important to distinguish WCHT from SHT even after assessment of target organ damage in the elderly. (J Am Coll Cardiol 2001;38:238-45) (C) 2001 by the American College of Cardiology.

OBJECTIVES We sought to study the association of the silent cerebral infarct (SCI), a predisposing condition of stroke, with hyperinsulinemia and hemostatic abnormalities in older hypertensive subjects. BACKGROUND Hypertension is a powerful risk factor for stroke. However, the role of other risk factors for stroke in hypertensive subjects remains incompletely understood. METHODS We performed brain magnetic resonance imaging and measured cardiovascular risk factors, by administering the 75-g oral glucose tolerance test and measuring plasma insulin and hemostatic variables, in 123 asymptomatic hypertensive subjects (mean age 69 years). RESULTS At least one SCI was detected in 80 subjects (65%), and multiple SCIs were found in 48 subjects (39%). The presence of SCIs was associated with older age, higher levels of 24-h systolic blood pressure, 2-h insulin, thrombin-generation markers (prothrombin fragment 1+2 and thrombin-antithrombin complexes), plasminogen activator inhibitor-1 (PAI-1), D-dimer and von Willebrand factor (vWF), but not with plasmin-alpha(2)-plasmin complex (PIC) levels. The 2-h insulin area under the curve (AUC) was positively correlated with PAI-1 and VWF levels (p < 0.01), and the PAI-1 level was negatively correlated with the PIC level (p < 0.02). Multiple logistic regression analysis revealed that age and the 2-h insulin AUC were significantly associated with SCIs, particularly those located in the subcortical white matter, and hemostatic abnormalities were significantly associated with the presence of multiple SCIs, particularly those located in the basal ganglia. CONCLUSIONS In older asymptomatic hypertensive subjects, hyperinsulinemia appears to be associated with lacunar-type SCIs, particularly those located in the subcortical white matter, and hemostatic abnormalities show an association with the presence of multiple SCIs, particularly those located in the basal ganglia. a Am Coil Cardiol 2001;37:871-7) (C) 2001 by the American College of Cardiology.

Abnormal nocturnal blood pressure (BP) dipping status may be partly determined by nocturnal sympathetic activity. We studied the effect of nighttime dosing of an alpha(1)-adrenergic blocker, doxazosin, on the BP dipping status of 118 hypertensives, all of whom underwent 24-hour ambulatory BP monitoring before and after treatment. The mean nighttime/daytime ratio of systolic BP was increased (0.91 after therapy versus 0.89 at baseline, P<0.05). The patients were initially divided into 4 groups on the basis of their dipping status at the baseline assessment: 18 (15%) were extreme dippers, with a nighttime systolic BP fall of at least 20% of daytime BP; 46 (39%) were dippers (fall between 10% and 20%); 48 (41%) were nondippers (fall between 0% and 10%); and 6 (5%) were risers (nocturnal increase of systolic BP). A shift in dipping status toward less nocturnal BP dipping was observed after doxazosin therapy (P<0.05). Dipping status was determined by nighttime more than by daytime BP, and this was not explained by differences in the number of daytime and nighttime readings. The effects of doxazosin on the mean nocturnal systolic BP changes were an increase of 4.3 mm Hg in extreme dippers and decreases of 0.7 mm Hg in dippers, 12 mm Hg in nondippers, and 18 mm Hg in risers; the reduction was only significant in the latter 2 groups (both P<0.01). To estimate the effects of regression to the mean on the changes in dipping status, we also defined dipping status with the average of the BPs before and after doxazosin and found no difference in the degree of nighttime BP reduction among each group. The reduction of daytime BP was now significantly greater in the subgroups with less dipping: 6.4 mm Hg for extreme dippers and 16 mm Hg for risers (P<0.05). In conclusion nighttime dosing with doxazosin markedly affects the nocturnal BP dipping status of hypertensives, but the apparently greater reduction in nighttime pressure in nondippers and risers may be, at least partly, due to the effect of regression to the mean. The most important determinants of the effect of doxazosin were the absolute BP levels, both day and night, rather than dipping status per se.

There are reports that indicate that diurnal blood pressure (BP) variation, in addition to high BP per se, is related to target organ damage and the incidence of cardiovascular events. However, the determinants of diurnal BP variation are not adequately understood. We used actigraphy and ambulatory BP monitoring td study the diurnal variation of BP and physical activity in 160 adults. Within individuals, activity was more strongly related to pulse rate than to BP. The correlation between BP and activity was stronger during sleep than when awake, but the correlation between activity and pulse rate was higher during the awake period than during sleep. Between individuals, the sleep/awake ratio of systolic BP (SBP) was correlated with mean sleep activity (r=.17, P<0.05), mean awake activity (r= -0.16, P<0.05), and, especially, the ratio of sleep/awake activity (r=.24, P<0.01). Awake BP variability (SD of awake SEP) was positively: correlated with awake activity (r=.16, P<0.05), In regard to the effect of position, the standing-supine SBP difference was negatively correlated with the sleep/awake SBP ratio:(r= -0.39, P<0.01) and positively correlated with awake SBP variability (r=.33, P<0.01). When we divided the subjects into 3 groups, 19 extreme dippers (with a sleep SBP decrease of greater than or equal to 20% of awake SBP), 102 dippers (with decreases of greater than or equal to 10% to <20%), and 39 nondippers (with decreases of <10%), no significant differences existed in awake activity. among the groups. However, the nondippers exhibited greater sleep activity than extreme dippers (P<0.05) and an increased sleep/awake activity ratio compared with extreme dippers and dippers (P<0.01). Extreme dipping may also be associated with increased BP variability (P=0.08). Individual SBP responses to activity (the within-persen slope of awake SBP regressed on activity) did not differ significantly among the 3 subgroups. In conclusion, physical activity is one of the determinants of ambulatory BP and its diurnal variation. We hypothesize that the association of sleep activity to sleep BP and dipping reflects differences in sleep quality.

Background The ACE insertion/deletion (I/D) polymorphism is reported to be associated with myocardial infarction in both whites and Japanese. However, there have been no reports on the association of this polymorphism with stroke in each race. Furthermore, there are some racial differences in the demographics of cardiovascular diseases. In Japanese, stroke (especially that which occurs in preexisting hypertension) is more common and coronary artery disease much less common than in whites. We propose that the ACE I/D polymorphism might be associated with hypertensive cerebrovascular disease in Japanese. Methods and Results To study the association between the ACE IID polymorphism and hypertensive cerebrovascular disease, we identified the ACE I/D genotype in 228 hypertensive and 104 normotensive Japanese subjects. Compared with its detected by magnetic resonance imaging, the ACE*D allele frequency was significantly higher (0.47; P<.001) in the 138 hypertensives with silent or clinically overt ischemic stroke, whereas there was no significant difference between its frequency in hypertensives without lacunae and in 104 normotensive control subjects (0.34). The positive association between the ACE I/D genotype and ischemic stroke in hypertensive patients was independent of other risk factors. Conclusions We found a positive association between the ACE*D allele and ischemic stroke in Japanese hypertensives in our study. The ACE*D allele may be an independent risk factor for the development of cerebrovascular disease in hypertensive patients.

We investigated the relationships between hyperinsulinemia (a major indicator of the insulin resistance syndrome), blood pressure, dyslipidemia, and coagulation factors in 2606 community-dwelling Japanese individuals as part of the Jichi Medical School Cohort Study. An age-related decrease of the fasting insulin level was found in men but not in women. Body mass index, systolic and diastolic blood pressure, triglyceride and fasting glucose levels, and factor VII activity all increased in both sexes as the insulin level became higher, while the HDL cholesterol level decreased. In addition, total cholesterol and LDL cholesterol levels increased as the insulin level became higher and lipoprotein(a) levels decreased in the men. Fibrinogen levels were not related to the insulin level in either sex. Multiple logistic regression analysis revealed that fasting insulin levels were positively correlated with body mass index and fasting glucose and factor VII activity levels, whereas they were negatively correlated with HDL cholesterol in both sexes. In addition, fasting insulin levels were positively correlated with LDL cholesterol levels in men and with triglyceride levels in women. Our results indicate that hyperinsulinemia is associated with high factor VII activity in a general Japanese population as well as with high blood pressure and dyslipidemia. The accumulation of these cardiovascular risk factors in hyperinsulinemic subjects appears to contribute to cardiovascular events in the Japanese as well as in westerners.

To study the relation between diurnal blood pressure variations and silent cerebrovascular damage, we performed both 24-hour ambulatory blood pressure monitoring and brain magnetic resonance imaging in 131 elderly asymptomatic hypertensive patients. Silent cerebrovascular damage was identified by the magnetic resonance imaging findings of lacunae (low intensity in T-1-weighted images and high intensity in T-2-weighted images) and advanced periventricular hyperintense lesions (on T-2-weighted images). The frequency of silent cerebrovascular damage in the 100 patients with sustained hypertension was greater than that in the 31 patients with white coat hypertension. We further classified the former group into nondippers (nocturnal reduction of systolic pressure by <10% of awake systolic pressure; n=46), dippers (reduction by greater than or equal to 10% to <20%; n=38), and extreme dippers (reduction by greater than or equal to 20%; n=16). The extent of silent cerebrovascular damage was least severe in the dipper group (P<.05). This J-shaped relation was not found either with the cardiac hypertrophy detected by electrocardiography or with the renal damage assessed by urinary albumin excretion. More than half of the extreme dippers were patients with isolated systolic hypertension, and this prevalence was significantly greater than that in dippers or in nondippers (21% and 30%, respectively). Extreme dippers also had greater variability of pressure (standard deviation of awake systolic pressure) than dippers. Our results indicate that in addition to nondipping, extreme dipping (marked nocturnal fall of blood pressure should be considered a type of abnormal diurnal blood pressure variation in elderly patients with hypertension who are likely to have advanced silent cerebrovascular damage.

Factor VII (FVII) plays an important role in initiation of the tissue factor-induced coagulation pathway. An increase in FVII coagulant activity (FVIIc) has been proposed as an independent risk factor for coronary artery disease. However, it remains uncertain whether high FVIIc levels are due to an increase in the activation of FVII or an increase in the concentration of FVII mass. We developed a new fluorogenic assay for plasma activated FVII (FVIIa) that used soluble tissue factor. The sensitivity of this assay ranged from 0.2 to 1000 ng FVIIa per milliliter of plasma. Plasma FVIIa levels were measured in 110 healthy subjects and 93 patients with hypertension, diabetes mellitus, and/or cardiovascular disease. The mean plasma FVIIa level in healthy Japanese individuals was 2.5 ng/mL, which was lower than that in Western subjects. Gel filtration analysis showed that most of the circulating FVIIa was in a free form, and binding of FVIIa to tissue factor in plasma was not detected. Aging increased both the FVIIa level and FVII mass, whereas menopause increased mainly the FVII mass. Elderly patients with arterial cardiovascular diseases showed increases in plasma FVIIa levels and FVIIa to FVII antigen (FVII:Ag) ratios. Among the elderly, arterial cardiovascular disease was more common in a high-FVIIa than a low-FVIIa group. Plasma FVIIa levels were not correlated with serum levels of total cholesterol or triglycerides. The FVIIa level and the FVIIa-to-FVII:Ag ratio were positively correlated with fibrinogen level and negatively correlated with body mass index and serum albumin level in the elderly. In conclusion, aging, cardiovascular disease, and malnutrition increased plasma FVIIa levels. FVIIa levels were not correlated with lipid levels or hepatic synthesis, suggesting that FVIIa may be an independent risk factor for cardiovascular disease.