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Sarcopenia, defined as progressive loss of muscle mass, function, and strength is an aging-related disease that share common pathophysiology with frailty. Sarcopenia is one of the risk factors of hypertension. Insulin resistance, oxidative stress, imbalance of catabolism and anabolism, and chronic inflammation are the underlying mechanisms that explain the association between hypertension and sarcopenia. Exercise is beneficial for older hypertensive patients in prevention of sarcopenia and improvement to normal state. It also attributes to cardiovascular risk reduction and prevention of falls. In this review article, we summarize latest issues about sarcopenia and exercise., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Both aging and high blood pressure (BP) are associated with a risk of left ventricular concentricity and hypertrophy. We hypothesized that optimal BP management improves left ventricular remodeling beyond aging. Among 558 hypertensive patients on continuous antihypertensive treatment and without concurrent heart disease who were referred to a cardiology clinic with echocardiography and ambulatory BP monitoring data, 142 patients' echocardiographic data was available after 10 years. Baseline BP and changes in left ventricular geometry were evaluated. Mean age at baseline was 71.0 years old. Baseline daytime BP was 129.9/72.4 ± 17.1/10.2 mmHg and nighttime BP was 122.5/67.1 ± 16.9/9.1 mmHg. After 10 years, left ventricular mass index (LVMI) and relative wall thickness (RWT) significantly decreased from 104.5 ± 26.3 to 97.9 ± 26.4 g/m 2 , p = 0.003 and 0.51 ± 0.09 to 0.47 ± 0.09, p < 0.001, consecutively. Among patients with hypertrophic geometry at baseline, 17.2% reverted to normal geometry at follow-up. Daytime systolic BP (136.9 ± 18.5 mmHg vs 126.2 ± 16.5 mmHg, p = 0.03), nighttime systolic BP (126.2 ± 17.7 mmHg vs 116.3 ± 16.0 mmHg, p = 0.038) and daytime pulse pressure (63.5 ± 17.3 mmHg vs 53.1 ± 14.9 mmHg, p = 0.022) at baseline were higher in patients who remained hypertrophic than those without hypertrophy at follow-up. On logistic regression analysis, daytime, nighttime systolic BP, and daytime pulse pressure were significantly related to the regression of hypertrophy adjusted for age, sex, eGFR, BMI, LVMI, and RWT at baseline. For conclusion, antihypertensive treatment for 10 years improved LV geometry despite aging. Ambulatory BP and pulse pressure at baseline predicted the change of LV geometry after 10 years., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

This study aimed to evaluate the relationship between pulse pressure (PP) and sarcopenia, frailty, and cognitive function in elderly patients with hypertension. We evaluated 435 elderly patients with a history of hypertension who visited the frail outpatient clinic between July 2015 and October 2021. Data at the 1-, 2-, and 3-year follow-ups were available for 222, 177, and 164 patients, respectively. Sarcopenia, frailty, and cognitive function, including Mini-Mental State Examination (MMSE) scores, were evaluated. The patients' mean age was 79.2 ± 6.3 years (male, 34.9%). PP and mean blood pressure (BP) were 60.1 ± 13.6 mmHg and 94.1 ± 13.0 mmHg, respectively. At baseline, lower PP was associated with probable dementia (MMSE score ≤23 points) (OR = 0.960 per 1 mmHg increase; 95% CI, 0.933-0.989; P = 0.006) in the model adjusted for conventional confounding factors and comorbidities, whereas higher PP was associated with low handgrip strength (OR = 1.018 per 1 mmHg increase; 95% CI, 1.001-1.036; P = 0.041). In multivariate-adjusted logistic regression analysis of patients with preserved handgrip strength at baseline, reductions in PP (OR = 0.844; 95% CI, 0.731-0.974; P = 0.020) and mean BP (OR = 0.861; 95% CI, 0.758-0.979; P = 0.022) were significantly associated with the incidence of low handgrip strength at 3 years. In conclusion, a higher PP induced by increased arterial stiffness was associated with lower handgrip strength, whereas a lower PP was associated with probable dementia. Reduced PP was associated with decreased handgrip strength after three years., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Frailty is a state of increased vulnerability to stress resulting from physiological decline associated with aging. Topics of hypertension management and its association with frailty and cognitive function, recent studies of coronavirus disease 2019 infection (COVID-19) in elderly is discussed in this narrative review. While various guidelines for hypertension recommend that frailty is taken into account in treatment decisions, specific assessment tools and clinical decision criteria have not been explicitly established. Hypertension is prevalent in frail individuals, although a direct association has not been reported. Therefore, optimal blood pressure (BP) control is critical for managing cardiovascular risk reduction and preserving quality of life in frail hypertensive patients. BP typically decreases in later life or situations in which patients are dependent on nursing care. Mortality is reported to be high among frail patients with lower BP, raising questions about appropriate BP targets for frail patients. Cognitive decline is one of the domains of frailty, and is associated with a loss of autonomy, lack of self-management, and compromised quality of life. It remains to be clarified whether antihypertensive treatment is beneficial for cognitive function especially in older individuals. Increased severity and mortality of COVID-19 infection has been reported in older people. Clinical manifestations and biomarkers particular to older patients, and lifestyle changes including social isolation during the COVID-19 pandemic is reported. From the knowledge from recent literatures, future perspectives for holistic approach and management of frail older people is addressed., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Minor ST-T changes on electrocardiograms are observed in patients with hypertensive heart disease with a preserved left ventricular ejection fraction (LVEF); however, the relationship between minor ST-T changes and global myocardial work on echocardiograms remains unclear. We evaluated the global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) in 186 hypertensive patients with preserved LVEF (>50%) using an offline analysis system (View Pal, GE). Minor ST-T changes as well as major ST-T changes (depression in ST in lead V5 > 1 mV) were also evaluated by electrocardiography. The mean age was 79.4 ± 8.2 years (men 37.6%). Patients with minor and major ST-changes had a smaller absolute GLS (-20.3 ± 3.1, -18.2 ± 3.7, and -15.2 ± 5.0%, P < 0.001) and a smaller constructive workload [GWI (2148 ± 486, 1938 ± 462, and 1685 ± 701 mmHg%, P = 0.002) and GCW (2419 ± 510, 2185 ± 466, and 1865 ± 702 mmHg%, P < 0.001)] than those with no ST-T changes. Additionally, patients with minor and major ST-T changes had increased wasted myocardial work [GWW (87 ± 61, 105 ± 56, and 127 ± 75 mmHg%, P = 0.045)], which resulted in reductions in the myocardial work efficiency [GWE (95 ± 4, 94 ± 3, and 89 ± 12%, P < 0.001)]. Even after adjustments for confounding factors, including EF, diastolic function parameters, LV hypertrophy, history of heart failure and atrial fibrillation, patients with minor ST-T changes had significantly smaller LV global constructive work in comparison to those without [GWI (2260 ± 33 vs. 2025 ± 76 mmHg%, P = 0.007) and GCW (2501 ± 45 vs. 2210 ± 105 mmHg%, P = 0.003)]. In conclusion, in hypertensive patients with preserved LVEF, minor ST-T changes on electrocardiograms were associated with reduced constructive work in the LV., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Electrocardiographic left ventricular hypertrophy (LVH) diagnosed by Cornell product and the Sokolow-Lyon voltage are associated with anatomical LVH; therefore, we investigated whether Cornell product and the Sokolow-Lyon voltage were associated with echocardiographic regional wall motion (measured by 2D-strain imaging). We reviewed data on 288 consecutive hypertensive patients who underwent both echocardiography and electrocardiography. Electrocardiographic LVH was calculated as follows: Cornell voltage, S in lead V3 + R in lead aVL; Cornell product, Cornell voltage (+0.6 mV for females) × QRS duration; and Sokolow-Lyon voltage, S in lead V1 + R in lead V5. The mean age of the subjects was 64.3 ± 13.2 years; 47.9% were men, and 65.2% were taking antihypertensive medications. Both Cornell product (r = 0.392, P < 0.001) and the Sokolow-Lyon voltage (r = 0.315, P < 0.001) were significantly related to left ventricular mass index (LVMI), and the relationship between Cornell product and LVMI (beta = 0.24, P = 0.001) was independent of the Sokolow-Lyon voltage (beta = 0.25, P < 0.001). In multivariate linear regression analysis in which the two ECG-LVH were included together, Cornell product was related to global longitudinal strain (beta = 0.24, P = 0.002), even after adjusting for the Sokolow-Lyon voltage (P = 0.835). Additionally, the Cornell voltage was related to the inner/outer ratio of circumferential strain (beta = 0.17, P = 0.033) after adjusting for the Sokolow-Lyon voltage (P = 0.318). By contrast, the Sokolow-Lyon voltage was related to the relative wall thickness and E/e' on tissue Doppler imaging, even after adjusting for Cornell product. In conclusion, Cornell product and voltage were associated with longitudinal regional wall motion and with the transmurality of regional wall motion in the short axis direction.

It is unknown whether home blood pressure (BP) variability reduction is associated with target organ damage (TOD) protection independently of home mean BP reduction. We enrolled 310 hypertensive patients whose systolic BP (SBP) at home was over 135 mm Hg. The subjects measured their BP in the morning and evening for 7 days. In addition, we measured urinary albumin excretion (UAE) as a marker of TOD before and after 6 months of candesartan treatment (+thiazidediuretics). At baseline, UAE was associated with average home SBP (r=0.24, P<0.001), the s.d. of home SBP (r=0.15, P=0.011), and the maximum home SBP (r=0.27, P<0.001). During the intervention, significant reductions were found in average home SBP (146±13 vs. 132±12 mm Hg, P<0.001), s.d. of home SBP (12.9±4.8 vs. 11.8±4.4 mm Hg, P<0.001), and maximum home SBP (172.5±18.0 vs. 155.9±17.5 mm Hg, P<0.001). UAE levels were significantly reduced after 6 months of therapy compared with baseline (18.9 vs. 12.1 mg g(-1) Cre, P<0.001). In multiple regression analysis, the treatment-induced reduction in UAE was significantly associated with that of average home BP (P=0.003) but was not associated with that of s.d. of home SBP or that of maximum home SBP. Home BP variability is not itself an interventional target beyond lowering mean home BP during anti-hypertensive treatment.

We aimed this study to test the hypotheses that heart rate (HR) variability, evaluated by ambulatory blood pressure monitoring (ABPM), predicts risk of incident cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM). ABPM was performed in 200 normotensive or hypertensive subjects with T2DM and 257 hypertensive subjects without diabetes (the mean age: 66.9+/-9.2 years; 38% were male). All subjects were untreated at the time of ABPM, and were followed for 67+/-27 months. Various measures of HR variability-standard deviation (s.d.) of HR, the root-mean-square of successive differences (RMSSD) of HR, systolic blood pressure (SBP)-HR relationships evaluated by slope and coefficients of correlation between SBP and HR-were used for the analyses. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals, after controlling for age, sex, body mass index, serum creatinine and 24-h SBP. During follow-up, there were 34 cardiovascular events. Awake HR variability in diabetics was smaller than non-diabetics, but sleep HR variability was similar between the groups. In multivariable analyses, increased sleep HR variability evaluated by s.d. and RMSSD of sleep HR, and slope and correlation coefficient of SBP-HR each was independently associated with the increased risk of CVD in T2DM. For non-diabetics, decreased slope of 24 h SBP-HR, and decreased correlation of 24 h SBP-HR were associated with increased risk of CVD. In conclusion, increased HR variability during sleep was a predictor for incident CVD in T2DM, but not in non-diabetics. Increased HR variability at night would reflect pathophysiological mechanism of T2DM.

Non-dipping (nocturnal blood pressure [BP] decrease<10%) is related to accelerated urinary salt excretion (u-NaCl), and increased risk of left ventricular hypertrophy (LVH) and cardiovascular events. We evaluated whether non-dippers exhibit an advanced extracellular matrix fibrosis, in relation to increased u-NaCl, among normotensive subjects. We measured plasma tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), a marker of collagen fibrosis in extracellular matrix, to evaluate the relationship between non-dipping and u-NaCl in 73 normotensive subjects (no antihypertensive medications, clinic BP<140/90 mmHg and/or 24-h ambulatory BP<125/80 mmHg). Non-dippers had a significantly higher percentage of subjects with impaired fasting glucose (IFG) or diabetes mellitus (DM), and had a greater left ventricular mass index (LVMI), plasma TIMP-1 level and u-NaCl than dippers (IFG or DM: 24.0 vs. 6.3%, p=0.029; LVMI: 118+/-31 vs. 103+/-26 g/m(2), p=0.039; TIMP-1: 168+/-35 vs. 151+/-30 pg/mL, p=0.035; u-NaCl: 5.1+/-1.7 vs. 3.9+/-1.7 g/12 h, p=0.005). In logistic regression analysis, non-dipping was independently associated with u-NaCl and TIMP-1. u-NaCl was correlated with non-dipping (r=0.35, p=0.003) and serum glucose level (r=0.26, p=0.027). On the other hand, TIMP-1 level was significantly correlated with the presence of IFG or DM (r=0.23, p=0.046), but not with u-NaCl. In conclusion, plasma TIMP-1 level, a measure of cardiovascular fibrosis in extracellular matrix, is greater in normotensive non-dippers than in dippers; however, the increased TIMP-1 level may be related to impaired glucose metabolism, and non-dipping may be related to increased u-NaCl associated with high serum glucose levels in normotensive subjects. (Hypertens Res 2008; 31: 2045-2051).

Orthostatic blood pressure (BP) dysregulation is a risk factor for both falls and cardiovascular events. Self-measured 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.

A few reports have demonstrated that cognitive or physical dysfunction is associated with increased mortality in very elderly patients, those over 80 years of age. Using simple clinical tests, we evaluated the impact of cognitive or physical dysfunction on future total and cardiovascular deaths. We conducted a multicenter prospective study of 523 extremely elderly outpatients, aged > or = 80 years (mean +/- SD age: 84 +/- 5.3 years). These patients had normal activities of daily living at baseline. They were followed for an average of 34 months (range: 3-70 months), after which the total and cardiovascular deaths were evaluated. Cognitive and physical functions were evaluated by a short-term memory test using visual working memory and the get-up-and-go test, respectively. Seventy-five deaths, including 36 cardiovascular deaths, occurred during the follow-up period. In a Cox regression analysis model controlling for age, sex, body mass index (BMI), diastolic blood pressure (BP), cholesterol level, and history of cardiovascular diseases, cognitive dysfunction was found to be an independent risk factor for total death (p < 0.001), and cognitive dysfunction (p < 0.001) and physical dysfunction (p = 0.05) were independent risk factors for cardiovascular death. The determinants of cognitive dysfunction were associated with a lower diastolic BP (p = 0.04) adjusted for age, BMI, and a history of cardiovascular disease. Cognitive function, which was associated with lower BP levels, and physical function were the independent predictors of total and cardiovascular mortality among all cardiovascular risk factors in the very elderly, those at least 80 years of age.

It has been reported that subjects with prehypertension (pre-HT) (systolic blood pressure [SBP] 120-139 mmHg and/or diastolic blood pressure [DBP] 80-89 mmHg) have an increased risk of cardiovascular disease (CVD). We evaluated the prevalence and determinants of pre-HT in a Japanese general population. We enrolled 4,706 males and 7,342 females aged 18 to 90 years whose BPs were measured at baseline. The subjects' BPs were classified as follows: normotension (NT: SPB/DBP < 120/80 mmHg), pre-HT (120/80-139/89 mmHg), and hypertension (HT: > or = 140/90 mmHg or treated hypertension). The prevalence of pre-HT was 34.8% (males), and 31.8% (females). Body mass index (BMI) of more than 23.0 kg/m2 was the strongest determinant of pre-HT (Males--BMI: 23.0-24.9 kg/m2, odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.21-1.79; BMI: 25.0-26.9 kg/m2, OR = 2.20, 95% CI =1.68-2.87; BMI: 27.0-29.9 kg/m2, OR = 2.75, 95% CI = 1.80-4.19; BMI: > or = 30.0 kg/m2, OR = 3.39, 95% CI = 1.21-9.46. Females--BMI: 23.0-24.9 kg/m2, OR = 1.67, 95% CI = 1.42-1.95; BMI: 25.0-26.9 kg/m2, OR = 1.79, 95% CI = 1.46-2.19; BMI: 27.0-29.9 kg/m2, OR = 3.65, 95% CI = 2.73-4.89; BMI: > or = 30.0 kg/m2, OR = 4.23, 95% CI = 2.33-7.70). The other determinants of pre-HT were hyperlipidemia (Males: OR = 1.25; Females: OR = 1.43), and aging (by 10 years; Males: OR = 1.12; Females: OR = 1.48). Determinants of pre-HT in females were impaired glucose tolerance (OR = 1.41, 95% CI = 1.03-1.94), diabetes (OR = 2.01, 95% CI = 1.16-3.47) and a family history of HT in both parents (OR = 1.90, 95% CI = 1.38-2.62), whereas in males the only other predictor was alcohol drinking (OR = 1.45, 95% CI = 1.23-1.70). In conclusion, even subjects with a mild increase of BMI (23.0-24.9 kg/m2) had an increased risk of pre-HT in a Japanese population, and the level of BMI associated with pre-HT was lower than that in Western countries. Additionally, there were gender differences in the determinants of pre-HT.

Strong adherence to antihypertensive therapy has been shown to reduce the frequency of cardiovascular events by strictly controlling blood pressure. Although calcium channel blockers (CCBs) are among the most popular antihypertensive drugs in Japan, few trials have been conducted using high CCB doses in Japanese patients. In this study, we administered amlodipine 5 mg or 10 mg to patients with hypertension in order to compare the efficacy and tolerability of low and high doses, and measured two surrogate markers of hypertensive target organ damage, i.e., brain natriuretic peptide (BNP) as a risk marker of cardiac overload and microalbuminuria as a measure of renal damage. Seventy-two patients were randomly assigned to either amlodipine 5 mg (n = 35) or 10 mg (n = 37) dose groups. The latter group achieved greater reductions in clinic as well as both morning and evening home BP levels without an increase in pulse rate (the differences between the two groups in clinic/morning/evening systolic BP were 4.7/4.7/5.4 mmHg, and for diastolic BP they were 4.2/3.6/3.8 mmHg). Reductions in BNP and urinary albumin/creatinine ratio (UAR) levels were significantly correlated with the reductions in systolic BP levels (BNP, clinic/morning BP: r = 0.256, p = 0.030/r = 0.330, p = 0.005; UAR, clinic BP: r = 0.316, p = 0.007). In conclusion, the higher dose (10 mg) of amlodipine induced greater reductions in all BP levels than did the lower dose, without increasing the pulse rate. These additional reductions were significantly correlated with reductions in hypertensive cardiac overload, as evaluated by BNP levels, and a reduction in renal damage, as evaluated by microalbuminuria levels. Moreover, a reduction in the microalbuminuria may have occurred concomitant with a reduction in clinic systolic BP level.

It has been established that a positive association exists between the augmentation index (AIx) and left ventricular mass (LVM) in hypertensives, but it remains unclear whether this association is affected by age or gender. The aim of the study was to assess the effect of age and gender on the association between carotid AIx and LVM in hypertensive patients. We performed arterial tonometry and echocardiography in 512 treated hypertensive patients who were divided into 4 groups by gender and age (older or younger than 65 years). Correlations between carotid AIx and echocardiographic indices were evaluated by univariable and multivariable models. In females, carotid AIx increased with age up to 60 years, but decreased thereafter. In univariable analyses, carotid AIx was positively correlated with the LVM index in younger females (r=0.25, p=0.04) and males (r=0.48, p<0.001), but not in the older age groups. Multivariable analyses showed that this positive correlation in younger males remained significant (beta=0.39, p<0.001) after adjusting for age, body mass index, and mean arterial pressure. In contrast, in the older subjects, carotid AIx was negatively correlated with relative wall thickness in females (beta= -0.14, p=0.034) and males (beta= -0.17, p=0.037) independent of age and mean arterial pressure. A significant association between carotid AIx and LVM index was seen only in younger males. The lack of any such association in older hypertensives can be explained by both the plateau in the values of carotid AIx, and the fact that LVM increased with age.

Stroke is sometimes seen in patients with congestive heart failure (CHF). The factors that best predict incident stroke in hospitalized CHF patients are not well known. We performed this pilot study to explore the clinical markers of incident stroke in CHF patients. We studied 111 hospitalized patients with CHF (mean age, 67+/-11 years). Ambulatory blood pressure (BP) monitoring, blood tests, and echocardiography were performed in these patients just before they left the hospital, and all cardiovascular events during the study period were followed for an average of 18+/-9 months. Cox regression analysis was performed to explore the predictors of incident stroke using age, sex, body mass index (BMI), casual and ambulatory systolic BP (SBP), and brain-type natriuretic peptide (BNP). There were 10 stroke events (9%) during the follow-up period. The stroke group had higher nocturnal SBP and plasma BNP levels than the non-stroke group. With Cox regression analysis, both nocturnal SBP and BNP were significant predictors of incident stroke independent of other covariates. When nocturnal BP of 120 mmHg and BNP of 600 pg/mL (75th percentile) were used as cutoffs, nocturnal SBP > or =120 mmHg was associated with a 7-fold increase in the risk of incident stroke, while BNP > or =600 pg/mL was associated with a 46.6-fold increase. However, abnormal circadian BP patterns were not associated with incident stroke. In this pilot study, elevated nocturnal BP and high plasma BNP just before patients left the hospital were significant predictors of stroke events in CHF patients. Further study is needed to confirm this hypothesis.

Baroreflex sensitivity (BRS) is a primary mechanism for acute and chronic control of blood pressure (BP). However, there are few data showing the relationship between BRS and ambulatory BP (ABP). We assessed the hypothesis that BRS specifically contributes to some specific parameters of ABP in never-treated hypertensive/normotensive subjects. We studied 128 subjects (mean age: 54.5+/-13 years, 60% male) consisting of 92 untreated hypertensive and 36 normotensive subjects. Radial tonometric BP and simultaneous RR interval were recorded for 10 min, and the Valsalva maneuver was performed 3 times for each subject. BRS was calculated in two ways: the spontaneous-BRS by the spectral method, and the Valsalva-BRS by the slope method, using commercial software. ABP monitoring was performed on the same day as the BRS test. Of 128 subjects, we obtained BRS from 111 subjects with the Valsalva method and 123 subjects with the spontaneous method. Univariate analyses showed that the Valsalva-BRS was negatively correlated only with morning systolic BP (r=-0.21, p=0.03). Multivariable analyses showed that the Valsalva-BRS (ms/mmHg) was independently associated with the morning systolic BP (beta=-0.26, p=0.022), even after adjusting for age, sex, body mass index, presence of diabetes, duration of hypertension, clinic systolic BP and pulse rates. The spontaneous-BRS estimates were inversely correlated with clinic pulse rates in the same model. In conclusion, impaired BRS evaluated by the Valsalva method was associated with high morning BP level, independent of other confounders. Morning hypertension might be partly mediated by impaired BRS.

It has been reported that masked hypertension, a state in which patients show normal clinic blood pressure (BP) but elevated out-of-clinic BP by self-measured home BP, is a predictor of cardiovascular morbidity much like sustained hypertension. In addition, nocturnal BP is closely associated with cardiovascular disease. This might mean that ambulatory and self-measured home BP monitoring each provide independent information. We performed ambulatory BP monitoring, self-measured home BP monitoring, echocardiography and carotid ultrasonography in 165 community-dwelling subjects. We subclassified the patients according to the ambulatory and self-measured home BP levels as follows: in the masked nocturnal hypertension group, the self-measured home BP level was <135/85 mmHg and the ambulatory nocturnal BP level was >or=120/75 mmHg; in the normotensive group, the self-measured home BP level was <135/85 mmHg and the ambulatory nocturnal BP level was <120/75 mmHg. The intima-media thickness (IMT) and relative wall thickness (RWT) were greater in the masked nocturnal hypertension group than in the normotensive group (IMT: 0.76+/-0.20 vs. 0.64+/-0.14 mm, p<0.05; RWT: 0.50+/-0.14 vs. 0.41+/-0.10, p<0.05). Even in hypertensives with well-controlled self-measured home BP, elevated ambulatory nocturnal BP might promote target organ damage. We must rule out masked hypertension using self-measured home BP monitoring, and we might also need to rule out nocturnal masked hypertension using ambulatory BP monitoring.

Impaired glucose tolerance (IGT) is associated with cardiovascular risk factors, but the effects of pioglitazone and metformin on IGT are not well described. We tested the hypothesis that each drug would exhibit antiatherogenic and anti-inflammatory effects in subjects with IGT and early diabetes. The study design was a prospective, randomized, open label, cross-over study. Blood tests, including a 75-g oral glucose tolerance test (OGTT), were performed at baseline and after each treatment. Pioglitazone 15 mg/day or metformin 500-750 mg/day was given for 3 months. Biochemical markers to assess insulin resistance as well as lipid, inflammatory, neurohumoral, and hemostatic factors were included. Twenty-five subjects (17 male, 8 female; age [mean+/-SD]: 61+/-9 years; 84% hypertensive) completed the protocol. Of 25 subjects, 14 were diagnosed as IGT and 11 as diabetes with 75-g OGTT. Pioglitazone significantly reduced fasting glucose (p<0.05), and homeostasis model assessment of insulin resistance (HOMA-IR) (p<0.05) and metformin (p<0.01) reduced cholesterol. Both drugs significantly reduced aldosterone (both p<0.05) and von Willebrand factor (vWF) (both p<0.05). Plasma adiponectin was increased only by pioglitazone (p<0.001). Neither drug affected BP levels. In conclusion, pioglitazone was superior to metformin for the improvement of insulin resistance and adiponectin, and both drugs were equally effective in reducing vWF and aldosterone in subjects with IGT and early diabetes. Early intervention with pioglitazone or metformin therapy may reduce the incidence of future cardiovascular disease in subjects with impaired glucose tolerance or early diabetes.

Patients with obstructive sleep apnea syndrome (OSAS) have been reported to be at greater risk for cardiovascular events, and midnight surge of blood pressure (BP) may be a mechanism of sleep apnea-related cardiovascular risk. However, there has been no accurate noninvasive technique to detect intermittent BP surge at the time of each sleep apnea episode. We therefore developed an experimental system to detect apnea-related short-term BP surge based on BP measurement triggered by peripheral (finger-tip) oxygen desaturation (a desaturation-triggered BP monitoring system). In 16 patients with OSAS, this new system successfully detected BP surges at the time of the sleep apnea, and the BP values were found to be significantly higher than those detected using a conventional fixed interval BP monitoring system (systolic BP [SBP] difference: 13 +/- 5.8 mmHg, p = 0.039; diastolic BP [DBP] difference: 10 +/- 6.8 mmHg, p = 0.032). The maximum SBP time rate (velocity of BP surge) showed a strong positive correlation with the apnea-hypopnea index (r = 0.855, p < 0.0001). In conclusion, we developed a noninvasive oxygen desaturation-triggered BP monitoring system that can successfully detect sleep apnea-related BP surge. The midnight BP surge detected by this new method was significantly associated with the severity of OSAS.

Morning blood pressure (BP) level may play an important role in the pathogenesis of cardiovascular events; however, morning BP detected by home BP monitoring may remain uncontrolled in medicated hypertensive patients even when clinic BP is well controlled (masked morning hypertension: MMHT). We studied the determinants of MMHT in stably medicated hypertensive outpatients. In the Jichi Morning Hypertension Research (J-MORE) study, 969 consecutive hypertensive outpatients were recruited by 43 doctors in 32 different institutes. They had been under stable antihypertensive medication status at least for 3 months. Clinic BP was measured on 2 different days and self-measured BP monitoring was conducted twice consecutively in the morning and evening for 3 days. Four-hundred and five patients had well-controlled clinic BP (systolic BP [SBP]<140 mmHg and diastolic BP [DBP]<90 mmHg). Among them, 246 patients (60.7%) had MMHT (morning SBP > or =135 mmHg and/or DBP > or =85 mmHg). Compared with the patients with normal clinic BP and morning BP, the patients with MMHT had a significantly higher prevalence of regular alcohol drinkers (35.0% vs. 23.3%, p=0.012), a significantly higher number of antihypertensive drug classes (1.83 +/- 0.82 vs. 1.66 +/- 0.84, p = 0.04) and a significantly higher clinic BP level (SBP: 130.4 +/- 7.6 mmHg vs. 127.8 +/- 8.4 mmHg, p = 0.001; DBP: 75.5 +/- 7.6 mmHg vs. 73.6 +/- 7.6 mmHg, p = 0.013). In logistic regression analysis, independent determinants for MMHT were regular alcohol drinking (odds ratio [OR]: 1.76; 95% confidence interval [CI]: 0.99-3.12; p = 0.05) and higher-normal clinic BP (130/85 mmHg < clinic SBP/DBP < 140/90 mmHg) (OR: 1.60; 95% CI: 1.05-2.44; p = 0.03) after adjustment for confounding factors. The patients who both drank alcohol regularly and had a higher-normal clinic BP had 2.71 times higher risk for MMHT than those who did not drink alcohol regularly and had a relatively lower-normal clinic BP (<130/85 mmHg) (p < 0.01). In conclusion, regular alcohol drinking is an independent determinant for MMHT detected by home BP monitoring in medicated hypertensive patients with well-controlled clinic BP.

Stroke occurs most frequently in the morning hours, but the impact of the morning blood pressure (BP) level on stroke risk has not been fully investigated in hypertensives. We studied stroke prognosis in 519 older hypertensives in whom ambulatory BP monitoring was performed, and who were followed prospectively. During an average duration of 41 months (range: 1-68 months), 44 stroke events occurred. The morning systolic BP (SBP) was the strongest independent predictor for stroke events among clinic, 24-h, awake, sleep, evening, and pre-awake BPs, with a 10 mmHg increase in morning SBP corresponding to a relative risk (RR) of 1.44 (p<0.0001). The average of the morning and evening SBP (Av-ME-SBP; 10 mmHg increase: RR=1.41, p=0.0001), and the difference between the morning and evening SBP (Di-ME-SBP; 10 mmHg increase: RR=1.24, p=0.0025) were associated with stroke risks independently of each other. The RR of morning hypertension (Av-ME-SBP > or = 135 mmHg and Di-ME-SBP > or = 20 mmHg) vs. sustained hypertension (Av-ME-SBP > = 135 mmHg and Di-ME-SBP < or = 20 mmHg) for stoke events was 3.1 after controlling for other risk factors (p=0.01). In conclusion, morning hypertension is the strongest independent predictor for future clinical stroke events in elderly hypertensive patients, and morning and evening BPs should be monitored in the home as a first step in the treatment of hypertensive patients.

Morning blood pressure is reported to be more closely related to hypertensive organ damages such as left ventricular mass index, microalbuminuria and silent cerebral infarcts, than blood pressure at other times of the day. Morning blood pressure may play an important role in the pathogenesis of hypertensive target organ damage. Increased sympathetic nerve activity is reported to be one of the mechanisms of morning hypertension; however, there are no available data that show whether strict home blood pressure control, especially in the morning period, can reduce target organ damage. The Japan Morning Surge-1 (JMS-1) study includes hypertensive outpatients with elevated morning systolic blood pressure (>or=135 mmHg) as assessed by self-measured blood pressure monitoring at home. All enrolled patients are under stable antihypertensive medication status. Exclusion criteria are arrhythmia, chronic inflammatory disease, and taking alpha-blockers or beta-blockers. The target number of patients to be enrolled in the JMS-1 study is 600, and the aim is to evaluate differences in the markers of hypertensive target organ damage, such as brain natriuretic peptide and the urinary albumin excretion/creatinine ratio. All of the patients are randomized to an experimental group or a control group, with randomization to be carried out by telephone interviews with the patients' physicians. In the experimental group, patients begin taking additional antihypertensive medication just before going to bed. This consists of doxazosin 1 mg/day, which then is increased to 2 mg/day and 4 mg/day, with a beta-blocker added after a 1-month interval until the morning systolic blood pressure is controlled to less than 135 mmHg. Patients in the control group continue the treatment they are receiving at the enrollment for 6 months. Blood pressure levels, adverse effects, and hypertensive target organ damage before and after the study are evaluated. In the JMS-1 study, we will evaluate whether strict morning blood pressure control by sympathetic nervous system blockade using an alpha-blocker, doxazosin, and with the addition of a beta-blocker if needed, can reduce hypertensive target organ damage.

Collagen metabolism in the extracellular matrix (ECM) is related to the pathogenesis of cardiovascular stiffness and remodeling in hypertension. We evaluated the association between collagen metabolism markers and the newly developed parameter, brachial-ankle pulse wave velocity (baPWV), in older hypertensive patients with left ventricular hypertrophy (LVH). We performed echocardiography and baPWV measurement using a new device, form PWV/ABI (Colin Medical Technology, Komaki, Japan), and measured plasma levels of markers of collagen metabolism such as procollagen type I C-terminal propeptide (PICP: a marker of collagen synthesis), collagen type I pyridinoline cross-linked C-terminal telopeptide (ICTP: a marker of collagen type I degradation), matrix metalloproteinase-1 (MMP-1: a marker of collagen degradation) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in 46 hypertensive patients with LVH. BaPWV was correlated with the plasma level of PICP (r=0.33, p=0.03) and ICTP (r=0.29, p=0.05) and the total TIMP-1/MMP-1 ratio (an index of collagen turnover; r=0.30, p=0.04). BaPWV was negatively correlated with the E/A ratio of left ventricular inflow (r=-0.36, p<0.05), while baPWV was not correlated with left ventricular mass index (LVMI; r=-0.175, p=0.25) or deceleration time of the mitral E wave (DCT; r=0.15, p=0.31). The measures of hypertensive heart disease, such as the E/A ratio, DCT or LVMI were not correlated with any collagen markers in this study. In multiple regression analysis adjusted for confounding factors such as age, sex, pulse pressure, mean blood pressure, pulse rate, LVMI, E/A ratio and DCT, the positive correlation between baPWV and total TIMP-1/MMP-1 ratio remained significant (p<0.05). In conclusion, arterial stiffness in high-risk older hypertensive patients may involve ECM collagen metabolism.

Cilnidipine is a novel and unique 1,4-dydropyridine derivative calcium antagonist that exerts potent inhibitory actions not only on L-type but also on N-type voltage-dependent calcium channels. Blockade of the neural N-type calcium channel inhibits the secretion of norepinephrine from peripheral neural terminals and depresses sympathetic nervous system activity. The purpose of this study was to assess the effect of cilnidipine and amlodipine on ambulatory blood pressure (BP) levels. We performed 24-h ambulatory BP monitoring before and after once-daily use of cilnidipine (n=55) and amlodipine (n=55) in 110 hypertensive patients. Both drugs significantly reduced clinic and 24-h systolic BP (SBP) and diastolic BP (DBP) (p < 0.005). However, the reductions of 24-h (-1.19+/-6.78 vs. 1.55+/-6.13 bpm, p=0.03), daytime (-1.58+/-6.72 vs. 1.68+/-7.34 bpm, p=0.02) and nighttime (-1.19+/-5.72 vs. 1.89+/-6.56 bpm, p=0.01) pulse rate (PR) were significantly greater in the cilnidipine group than the amlodipine group. There was no correlation between the degree of daytime SBP change and that of daytime PR change after amlodipine treatment (r=-0.08, n.s.), but there was a significant negative correlation between the degree of daytime SBP change and that of day-time PR change after cilnidipine treatment (r=-0.27, p<0.05). N-type calcium channel blockade by cilnidipine may not cause reflex tachycardia, and may be useful for hypertensive treatment.

To investigate how cigarette smoking and antihypertensive drug therapy may interact to affect cardiovascular disease, in this prospective study we administered amlodipine to hypertensive smokers and non-smokers and compared blood pressure reduction and indices of arterial stiffness. We measured blood pressure (BP), heart rate (HR), brachial-ankle pulse wave velocity (baPWV), and the carotid augmentation index (AIx) by using a non-invasive automated device in 101 hypertensive patients at baseline and at 1, 3, and 6 months of amlodipine administration (5.0 mg). At baseline, the AIx was significantly lower in smokers (n=27) than in non-smokers (n=74) (27.3% +/- 13.3% vs. 33.3% +/- 11.4%). After amlodipine administration, in both the groups, the mean BP, baPWV, and AIx were significantly reduced; however, the HR did not show a statistically significant difference. The reduction in the baPWV (cm/s) at 1 and 3 months was less marked in smokers than in non-smokers (mean +/- SD: -186.6 +/- 36.5 vs. -283.6 +/- 24.5 at 1 month; -136.6 +/- 42.2 vs. -280.1 +/- 29.6 at 3 months, respectively, both p<0.05). At 6 months, these intergroup differences in the reductions of baPWV disappeared. The blunted reduction of baPWV, particularly at 3 months, was significantly associated with the extent of smoking (lifetime pack-years smoked). Changes observed in the AIx and mean BP were similar between groups throughout the study period. In the short term, cigarette smoking blunts the effect of amlodipine on the reduction of arterial stiffness, independently of the mean BP level.

To investigate the impact of arterial properties on orthostatic blood pressure (BP) dysregulation in older hypertensives, orthostatic BP dysregulation, a common phenomenon in elderly hypertensives, is associated with target organ damage and falls. However, the mechanism of orthostatic BP dysregulation remains unclear. The pulse wave velocity (PWV), related arterial stiffness, and the augmentation index (AI), a measure of arterial wave reflection, were measured in 365 older hypertensives. We classified the study patients into an orthostatic hypertension (OHT) group with orthostatic increase of systolic BP (SBP) of > or = 220 mmHg (n = 27) and an orthostatic normotension (ONT) group with an orthostatic increase of SBP of < 20 mmHg and orthostatic SBP decrease of < 20 mmHg (n = 338). Orthostatic AI was significantly greater in the OHT group than in the ONT group (OHT: 6.5 +/- 12% vs. ONT: -5.6 +/- 12%, p < 0.001), while supine AI and supine and orthostatic pulse rate were comparable between the two groups. There was no significant difference in the PWV between the OHT and ONT groups. Orthostatic hypertension was affected by altered aortic properties and associated with augmented wave reflection of arterial pressure.

Arterial stiffness is a strong determinant of cardiovascular risk. Pulse wave velocity (PWV) and the augmentation index (AIx) are widely used as arterial stiffness indices. We studied the reproducibility of these indices and their association with cardiovascular risk factors in hypertensives. We measured brachial blood pressure (BP), brachial-ankle PWV (baPWV) and carotid AIx (cAIx) twice (at the baseline and 4 weeks after the baseline) using an automatic device in 103 hypertensives. The mean intraobserver-intersession difference was 29.0 cm/s with an SD of 201.6 cm/s for baPWV, and 0.5% with an SD of 5.9% for cAIx, and the Bland-Altman plots demonstrated the good reproducibility of baPWV and cAIx. Both baPWV and cAIx (the average of the 1st and the 2nd measurements) were significantly correlated with age, systolic BP (SBP), and pulse pressure (all, p <0.005); however, these factors were not correlated with each other (r =0.06, NS). cAIx was correlated with height, heart rate (HR), total cholesterol, and low density lipoprotein cholesterol (LDL-C) (all, p <0.05). In multiple regression analysis, age, SBP, and HR emerged as significant independent predictors of baPWV (adjusted R(2)=0.43, p <0.0001), while height, SBP, HR, and LDL-C emerged as significant independent predictors of cAIx (adjusted R(2)=0.58, p <0.0001). Both PWV and AIx measured using an automatic device were fairly reproducible, and their associated risk factors appeared to be different. Automated simultaneous measurement of these arterial stiffness indices may be useful for risk stratification of hypertensives.

We aimed to investigate the relationships between smoking and silent cerebrovascular damage. We performed brain MRI to evaluate silent cerebral infarct (SCI) and periventricular hyperintensity (PVH), and carotid-ultrasonography to investigate carotid atherosclerotic plaque in 170 high-risk community-dwelling subjects (mean age: 67.2 years; men: 28.7%) who met more than 3 of the following 9 criteria: 1) high blood pressure (BP); 2) hypercholesterolemia; 3) left ventricular hypertrophy; 4) high hemoglobin A1c; 5) proteinuria; 6) high waist-to-hip ratio; 7) smoking > or =30 cigarettes/day; 8) heavy alcohol intake; 9) family history of stroke. The subjects with SCI (SCI group) were older (70 years vs. 66 years, p=0.004) and had higher systolic BP (SBP) (160 vs. 148 mmHg, p <0.001) and higher carotid plaque score (2.3 vs. 1.5/person, p <0.05) than those without SCI. Among the variables, smoking status (r =0.34, p <0.001), SBP (r =0.28, p <0.001), male gender (r =0.29, p <0.001), left ventricular mass index (r =0.25, p =0.001), and serum creatinine (r =0.20, p =0.006) were significantly correlated with the number of SCIs. Among smokers, the number of SCIs was significantly higher in current smokers than in past smokers (1.9+/-2.2 vs. 0.5+/-0.8, p <0.01). In multiple regression analysis, smoking status (beta =0.183, p =0.045) and SBP (beta =0.196, p =0.011) were independent determinants of the increased number of SCIs. In conclusion, smoking status was an independent determinant of multiple SCIs in a high-risk Japanese community-dwelling population.

Greater change of postural blood pressure (BP) is often seen in elderly hypertensives and is recognized as a risk factor for cognitive decline and poorer cerebrovascular outcome, but its clinical significance still remains to be clarified. We performed a head-up tilting test, ambulatory BP monitoring, and brain MRI in 59 hypertensives and 27 normotensive subjects. We measured plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels at rest to assess cardiac burden. The 59 hypertensive patients were classified into 3 groups: an orthostatic hypertension (OHT) group with orthostatic increase in systolic BP (SBP) > or = 10 mmHg (n=16); an orthostatic hypotension (OHYPO) group with orthostatic SBP decrease < or = -10 mmHg (n=18); and an orthostatic normotension (ONT) group with neither of these two patterns (n=25). A group of 27 normotensive subjects (NT) was also included as a control. Plasma BNP (72 +/- 92 vs. 29 +/- 24 pg/ml, p < 0.05) and BNP/ANP ratio (4.6 +/- 3.3 vs. 2.4 +/- 1.5, p < 0.05) were significantly higher in the OHYPO than in the NT group. The BNP/ANP ratio was also higher in the OHT than in the NT group (5.1 +/- 3.9 vs. 2.4 +/- 1.5, p < 0.01). The number of silent cerebral infarct (SCI), prevalence of SCI and number of multiple SCIs was the highest in the OHT group, followed in order by the OHYPO, ONT and NT groups. Blood pressure and left ventricular mass index were not significantly different among the 3 hypertensive groups. In conclusion, hypertensive patients with greater change of postural BP (OHT and OHYPO) were shown to have increased risk of advanced silent brain lesions and greater cardiac burden.