Tomoyuki Kabutoya

An alpha-adrenergic blocker titrated by self-measured blood pressure recordings lowered blood pressure and microalbuminuria in patients with morning hypertension: the Japan Morning Surge-1 Study.

Background The impact on microalbuminuria of strict treatment aimed at lowering of self-measured morning blood pressure using an adrenergic blockade is unclear. Methods We conducted an open-label multicenter trial, the Japan Morning Surge-1 Study, that enrolled 611 hypertensive patients, whose self-measured morning systolic blood pressure levels were more than 135 mmHg while taking antihypertensive drugs. These were randomly allocated to an experimental group, whose members received bedtime administration of 1–4 mg doxazosin (doxazosin group) or a control group whose members continued without any add-on medication (control group). The urinary albumin/creatinine ratio was investigated at the baseline and 6 months after the randomization. Results Both the morning and evening blood pressures and urinary albumin/creatinine ratio (−3.4 vs. 0.0 mg/gCr for urinary albumin/creatinine ratio; P < 0.001) were more markedly reduced in the doxazosin group than in the control group. This difference in the urinary albumin/creatinine ratio between the two groups was more marked in the patients with microalbuminuria (n = 238, −27.9 vs. −8.1 mg/gCr, P < 0.001). The reduction of urinary albumin/creatinine ratio was significantly associated with the use of doxazosin, and the change in all self-measured blood pressures (morning, evening, the average morning–evening), and these associations were independent of each other (P < 0.001). Conclusion Adding a bedtime dose of an α-adrenergic blocker titrated by self-measured morning blood pressure in treated hypertensive patients with uncontrolled morning hypertension significantly reduced blood pressure and urinary albumin excretion rate, particularly in those with microalbuminuria.

Cornell Product Left Ventricular Hypertrophy in Electrocardiogram and the Risk of Stroke in a General Population

Left ventricular hypertrophy (LVH), assessed by ECG, is associated with an increased risk for cardiovascular events among hypertensive subjects. We evaluated the risks of LVH in a Japanese general population including normotensive and prehypertensive subjects. We measured ECG and blood pressure in 10 755 subjects at baseline. The Cornell product (CP) and Sokolow-Lyon (SL) voltage were calculated as markers of LVH (CP ≥2440 mm×ms and SL voltage ≥38 mm). Follow-up was performed for 10 years, and the incidence of stroke and myocardial infarction was evaluated. The prevalence of CP-LVH was 2.7% for normotensives, 5.2% for prehypertensives, and 11.0% for hypertensives, and the prevalence of SL-LVH was 5.0%, 8.2%, and 15.2%, respectively. In all of the subjects, CP-LVH and SL-LVH were both predictors of stroke (CP-LVH: hazard risk: 1.62, 95% CI: 1.19 to 2.20, P=0.002; SL-LVH: hazard risk: 1.29, 95% CI: 0.98 to 1.71, P=0.07) after adjustment for confounding factors but were not predictors of myocardial infarction. The adjusted hazard ratio of CP-LVH predicting stroke was especially high in the normotensives (hazard risk: 7.53; 95% CI: 3.39 to 16.77). In the normotensives, diabetes mellitus and hyperlipidemia were significant determinants of CP-LVH but not of SL-LVH. In all of the hypertensive subgroups (normotensives, prehypertensives, and hypertensives), the c-statistic for the equation predicting stroke increased when CP-LVH was added to the model but not when SL-LVH was added. In conclusion, both CP-LVH and SL-LVH are risk factors for stroke in the Japanese general population. CP-LVH is related to glucose abnormality, and its predictive value for stroke is seen even in normotensives and prehypertensives.

Relationship between morning hypertension identified by home blood pressure monitoring and brain natriuretic peptide and estimated glomerular filtration rate: the Japan Morning Surge 1 (JMS-1) Study.

We evaluated whether morning minus evening systolic blood pressure (SBP) difference (MEdif) in home blood pressure measurements can be a marker for hypertensive target organ damage. The authors analyzed 611 hypertensive patients who had high morning SBP levels (≥135 mm Hg). The patients with morning hypertension (MEdif ≥15 mm Hg, average of morning and evening SBP [MEave] ≥135 mm Hg) were older (P<.001) and had a longer duration of hypertension and antihypertensive medication use, a higher prevalence of left ventricular hypertrophy (LVH) on electrocardiography, a lower glomerular filtration rate by the Cockcroft‐Gault equation (P=.002), and a higher brain natriuretic peptide (BNP) level (P<.001) than those with well‐controlled blood pressure (MEdif <15 mm Hg, MEave <135 mm Hg). The patients with morning hypertension had a higher BNP level than those with well‐controlled blood pressure after adjustment for the confounding factors (28.7 pg/mL vs 20.0 pg/mL; P=.033). In conclusion, morning hypertension is more likely seen among patients with older age and longer duration of hypertension and antihypertensive medication use, and it may be associated with a higher prevalence of LVH and a higher BNP level.

Atrial fibrillation is a major risk factor for stroke, especially in women: the Jichi Medical School cohort study.

Background Only a few population-based cohort studies have investigated the impact of atrial fibrillation (AF) on stroke in Japan. Methods A total of 10 929 participants (4147 men and 6782 women) were included in this population-based prospective cohort study. Baseline data, including electrocardiograms (ECGs) to ascertain AF status, were obtained from April 1992 through July 1995 in 12 areas in Japan. Cox proportional hazards models were used to analyze the association of AF with stroke. Results A total of 54 participants had AF (0.49%). The mean follow-up period was 10.7 years, during which 405 strokes were identified; 12 of these occurred in participants with AF. The crude incidence of stroke in participants with and without AF was 14.9 and 4.5 per 1000 person-years in men, respectively, and 39.3 and 2.7 per 1000 person-years in women. After adjusting for geographical area, sex, age, smoking status, drinking status, obesity, hypertension, dyslipidemia, and diabetes mellitus, the hazard ratios (95% confidence interval) of AF in all participants and in male and female participants were 4.11 (2.28–7.41), 2.12 (0.77–5.84), and 10.6 (5.01–22.4), respectively. The population attributable fraction (PAF) of stroke caused by AF was 2.2%; the PAFs were 1.0% and 3.6% in men and women, respectively. Conclusions The present Japanese population-based prospective cohort study showed that AF is a major risk factor for stroke, especially in women.

Cardiac mortality of premature ventricular complexes in healthy people in Japan.

BACKGROUND AND PURPOSE Premature ventricular complexes (PVCs) are frequently encountered in healthy people. But the association between PVCs and cardiac events is not well established in Japan. We investigated the association of PVCs and cardiac deaths in people without cardiovascular disease in the Jichi Medical School (JMS) Cohort study. METHODS AND SUBJECTS We conducted a prospective cohort study in 12 districts in Japan as part of the JMS cohort study. Baseline data were obtained between April 1992 and July 1995. We excluded subjects who had myocardial infarction and stroke and those who had not received 12-lead electrocardiograms. Coxs proportional hazard model was used to calculate the hazard ratios (HRs) of cardiovascular mortality of subjects with PVCs, using subjects without PVCs as reference. RESULTS A total of 11,158 participants (4333 males and 6825 females) were analyzed. Participants were followed for an average of 11.9 years. PVCs were present in 1.4% of men and 1.1% of women. There were 92 cardiac deaths (47 males and 45 females) during the follow-up period. In crude cardiovascular mortality, HRs (95% confidence interval [CI]) were 5.29 (1.64-17.0) in males and 2.14 (0.29-15.5) in females. Age-adjusted HRs were 3.73 (1.16-12.0) and 0.98 (0.13-7.21), respectively. After further adjustment for body mass index, systolic blood pressure, total cholesterol level, high-density lipoprotein-cholesterol, and blood glucose, HRs were 3.98 (1.21-13.0) and 0.95 (0.13-7.11), respectively. CONCLUSIONS We conclude that PVCs are a predictive factor for cardiac death in men without structural heart disease.

Orthostatic Hypertension Detected by Self-Measured Home Blood Pressure Monitoring: A New Cardiovascular Risk Factor for Elderly Hypertensives

Orthostatic blood pressure (BP) dysregulation is a risk factor for both falls and cardiovascular events. Selfmeasured BP, carried out at home, is both highly reproducible and useful for evaluating antihypertensive treatment. However, there have been a few reports on the clinical implications of orthostatic BP changes in home BP monitoring (HBPM). In the baseline examination for the Japan Morning Surge-1 Study, a multicenter randomized control trial, we evaluated 605 hypertensive outpatients who had a morning systolic BP above 135 mmHg. The plasma brain natriuretic peptide (BNP) level and urinary albumin excretion were measured. When the patients were divided into 10 groups, according to orthostatic BP change evaluated by HBPM, after adjusting for age, gender, body mass index and sitting home BP level, those in the top decile (n=60, orthostatic BP increase >7.8 mmHg) had a higher urinary albumin/creatinine ratio (UAR) than the lowest decile group (geometric mean [SEM range]: 209.1 [134.7–318.7] vs. 34.1 [20.1–56.2] mg/g creatinine [Cr], p=0.003) and the pooled second to ninth decile groups (n=485, 209.1 [134.7–318.7] vs. 39.7 [33.2–47.3] mg/g Cr, p<0.02). Additionally, patients in the top decile had a higher BNP level than the second to ninth decile groups (75.7 [55.0–103.1] vs. 23.6 [20.8–26.6] pg/mL, p=0.003). Evaluation of orthostatic hypertension at home might be a high-risk factor for cardiovascular events in hypertensive subjects with increased levels of BNP and a higher UAR, independent of the home sitting BP level.

The time course of flow-mediated vasodilation and endothelial dysfunction in patients with a cardiovascular risk factor

The relationship between having a cardiovascular risk factor and endothelial dysfunction observed on a time-course analysis of brachial artery flow-mediated vasodilation (FMD) remains unclear. We enrolled 257 patients who had at least one cardiovascular risk factor. We measured FMD magnitude of the percentage change in peak diameter (ΔFMD), maximum FMD rate calculated as the maximum slope of dilation (FMD-MDR), and integrated FMD response calculated as the area under the dilation curve during the 60- and 120-second dilation periods (FMD-AUC60 and FMD-AUC120) using a semiautomatic edge-detection algorithm. FMD-AUC60 and FMD-AUC120 were negatively correlated with the Framingham risk score (FMD-AUC60: r = -0.15, P = .023; FMD-AUC120: r = -0.17, P = .007), whereas this association was not found in the case of either the ΔFMD or the FMR-MDR. The Framingham risk score was significantly higher in patients in the lowest tertile for FMD-AUC120 (FMD-AUC120 <5.0 mm × second) than in those in the highest tertile for FMD-AUC120 (FMD-AUC120 ≥11.0 mm × second) (12.9 ± 8.7 vs. 8.6 ± 7.8%, P = .002). The lowest tertile for FMD-AUC120 was independently associated with the Framingham risk score (β = 0.10, P = .011), after adjustments were made for age, gender, and smoking and drinking status. FMD-AUC120 was associated with cardiovascular risk.

Is very low dose hydrochlorothiazide combined with candesartan effective in uncontrolled hypertensive patients

BackgroundIt is controversial whether the combination of very low dose hydrochlorothiazide (HCTZ) and an angiotensin receptor blocker (ARB) is effective in lowering blood pressure (BP). ObjectivesThe aim of this study was to evaluate the antihypertensive effect and the safety of an ARB and a very low dose of HCTZ in hypertensive patients. MethodsThis is an observational study. We examined 41 hypertensive patients who were treated with candesartan or another ARB at a standard dose but whose home BP was still greater than or equal to 135/85 mmHg. No patients were taking diuretics at baseline. Clinic and ambulatory BP (ABP) measurement and blood/urine analyses were performed at baseline and in the 2nd to 3rd month after treatment. All patients were either maintained at or switched to 8 mg candesartan, and then 6.25 mg HCTZ was added. Other concomitant drugs were not changed throughout the study period. ResultsA total of 41 individuals (age 62.7±12.7 years, 61% male) completed the protocol. The add-on treatment of HCTZ significantly lowered clinic and ABPs for both systolic and diastolic BP. The BP reduction was particularly pronounced in sleep BP. In addition, the rate of nondippers decreased from 48.8 to 36.6%, but the rates of dippers (39.0–43.9%) and extreme-dippers (12.2–19.5%) increased. Serum uric acid increased significantly, but the other metabolic measures were not changed by the combination therapy. ConclusionAdding a very low dose of HCTZ (6.25 mg) to an ARB was very effective in lowering clinic and ABP, particularly for night-time BP.

The Effect of Pulse Rate and Blood Pressure Dipping Status on the Risk of Stroke and Cardiovascular Disease in Japanese Hypertensive Patients

BACKGROUND There have been few reports on the relationship between variation in the diurnal pulse rate (PR) in relation to a nondipper blood pressure (BP) pattern and cardiovascular events in elderly hypertensives. METHODS Ambulatory BP monitoring (ABPM) was conducted at baseline in 811 older Japanese hypertensives (clinical BP >140/90 mm Hg; age >50 years old) enrolled in the Jichi Medical School ABPM study, wave 1. They were followed up for an average of 41 months, and the incidence of subsequent cardiovascular event and death was evaluated. PR nondipping status was defined as (awake PR - sleep PR)/awake PR <0.1. RESULTS The mean age of patients was 72.3 +/- 9.8 years (311 men and 500 women). The nondipper patients had a higher risk of cardiovascular events (11.5% vs. 6.1%, P = 0.006) and stroke (9.9% vs. 5.7%, P = 0.039) than the dippers. Patients were classified into four subgroups: BP dipping plus PR dipping status (n = 471), BP dipping plus PR nondipping (n = 37), BP nondipping plus PR dipping (n = 250), and BP nondipping plus PR nondipping (n = 53). The combination of BP and PR nondipping constituted a higher risk of cardiovascular events and stroke than the other three combinations combined (cardiovascular events: 17.0% vs. 7.5%, P = 0.015; stroke: 17.0% vs. 6.6%, P = 0.005). On Cox proportional hazards modeling, BP nondipping with PR nondipping led to a significant synergistic increase in the risk of stroke (hazard ratio: 8.92; 95% confidence interval: 1.03-77.5, P = 0.048). CONCLUSIONS A blunted PR dip might predict a stroke in elderly hypertensives with a nondipping BP status.

Determinants of Negative White-Coat Effect In Treated Hypertensive Patients: The Jichi Morning Hypertension Research (J-MORE) Study

BACKGROUND The negative white-coat effect (WCE), a phenomenon in which out-of-office blood pressure (BP) is higher than clinic BP, has not been well examined, unlike the WCE. METHODS As part of the Jichi Morning Hypertension Research study, in which clinic and home BP were measured in 969 hypertensive outpatients, 405 patients with normal clinic BP were separately analyzed. Clinic BP was measured on two different occasions, and home BP was measured twice in the morning and twice in the evening for three consecutive days. Clinic and home BP were each averaged from all readings, and negative WCE was defined as clinic systolic BP (SBP) lower than home SBP. RESULTS Negative WCE was observed in 324 (33%) of the patients overall and in 173 (42%) of the patients with controlled BP (clinic BP < 140/90 mm Hg). In multiple logistic regression analysis adjusting for covariates including home SBP and pulse rate, negative WCE was correlated with older age (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.06) and male gender (OR 1.08, 95% CI 1.01-1.14) in overall subjects. Among patients with well-controlled clinic BP, negative WCE was significantly correlated with the presence of ischemic heart disease (OR 1.17, 95% CI 1.04-1.31). The association of negative WCE with age and male gender remained significant under stringent criteria (negative WCE < -10.2 mm Hg (the mean -1 s.d.)). CONCLUSIONS Negative WCE remaining even after clinic BP is controlled may be related to cardiovascular risk factors such as older age, male gender, and a history of ischemic heart disease.