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The close association between dietary salt and hypertension is well established. However, previous studies generally assessed salt intake without adjustment for body weight. Herein, we investigated the significance of body weight-adjusted salt intake in the general population. The present cross-sectional study included 7629 participants from our yearly physical checkup program, and their salt intake was assessed using a spot urine test to estimate 24-hour urinary salt excretion. Total salt intake increased with increasing body weight. Body weight-adjusted salt intake was greater in participants with hypertension than in those without hypertension. Systolic blood pressure, estimated glomerular filtration rate, and urinary albumin were independently correlated with body weight-adjusted salt intake after adjustment for possible cardiovascular risk factors. Excessive body weight-adjusted salt intake could be related to an increase in blood pressure and hypertensive organ damage. Adjustment for body weight might therefore provide clinically important information when assessing individual salt intake., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Primarily the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of proximal tubules to the blood and enhance the glucose excretion into urine. Therefore, glucose and caloric balances become negative, making the blood glucose level as well as insulin secretion both reduced. On the other hand, the proximal tubular fluid, constituting with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. On the low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, as if loop diuretics are given. Finally, blood pressure is also lowered secondarily due to the loop diuretic action by SGLT2 inhibitions. Thus, the metabolic and hemodynamic combined systems synergistically interact further to suppress the risks leading to atherosclerosis and organs damage. Precise mechanisms for SGLT2 inhibitors to work in various aspects especially in preventing organ damage and cardiovascular events must be clarified further., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Objective: The aims of this subanalysis of the COLM trial [NCT00454662] were to compare visit-to-visit variability (VVV) of blood pressure (BP) between age groups and between two treatment combinations, that is, the angiotensin II receptor blocker, olmesartan combined with a calcium channel blocker (CCB), or a diuretic and to investigate the effect of VVV of BP on cardiovascular events in elderly hypertensive patients., Methods: Hypertensive patients ages 65-84 years with a history of and/or risk factors for cardiovascular disease were randomized to receive treatment with olmesartan along with either a CCB or a diuretic for at least 3 years. This subanalysis comprised 4876 patients who had their office BP measured at least three occasions (median nine occasions) during the follow-up period. VVV of BP was defined by several metrics including the within-individual standard deviation of every visit during the follow-up period., Results: VVV of SBP was larger in the very elderly group (75-84 years) than in the elderly group (65-74 years). VVV of SBP was smaller in the olmesartan along with CCB group than in the olmesartan along with diuretic group, especially in very elderly patients and also isolated systolic hypertensive patients. The incidence rate of primary endpoint increased along with an increment in the SD of SBP in all of the age and treatment groups., Conclusion: VVV of SBP may mediate the preferable effect of combination of angiotensin II receptor blocker along with CCB on cardiovascular events in the very elderly and also isolated systolic hypertensive patients.

Background: Although there is a close relationship between dietary sodium and hypertension, the concept that persons with relatively high dietary sodium are at increased risk of developing hypertension compared with those with relatively low dietary sodium has not been studied intensively in a cohort., Methods and Results: We conducted an observational study to investigate whether dietary sodium intake predicts future blood pressure and the onset of hypertension in the general population. Individual sodium intake was estimated by calculating 24-hour urinary sodium excretion from spot urine in 4523 normotensive participants who visited our hospital for a health checkup. After a baseline examination, they were followed for a median of 1143 days, with the end point being development of hypertension. During the follow-up period, hypertension developed in 1027 participants (22.7%). The risk of developing hypertension was higher in those with higher rather than lower sodium intake (hazard ratio 1.25, 95% CI 1.04 to 1.50). In multivariate Cox proportional hazards regression analysis, baseline sodium intake and the yearly change in sodium intake during the follow-up period (as continuous variables) correlated with the incidence of hypertension. Furthermore, both the yearly increase in sodium intake and baseline sodium intake showed significant correlations with the yearly increase in systolic blood pressure in multivariate regression analysis after adjustment for possible risk factors., Conclusions: Both relatively high levels of dietary sodium intake and gradual increases in dietary sodium are associated with future increases in blood pressure and the incidence of hypertension in the Japanese general population., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial., Methods: Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140 mmHg and/or DBP at least 90 mmHg with antihypertensive treatment, or SBP at least 160 mmHg and/or DBP at least 100 mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90 mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years., Results: Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65-1.07, P = 0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38-1.02, P = 0.059, interaction P = 0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P = 0.046) experienced serious adverse events., Conclusion: Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic.

We tested the hypothesis that uric acid levels predict new-onset hypertension in the Japanese general population. Normotensive individuals who visited our hospital for a yearly health checkup (n=8157, men=61.0% and age=50.7±12.2 years) were enrolled in the present study. After baseline evaluation, participants were followed up for a median of 48.3 months (range 4.9-101.0 months), with the endpoint being the development of hypertension, defined as systolic blood pressure (BP) > or = 140 mm Hg, diastolic BP > or = 90 mm Hg or the use of antihypertensive medication. The impact of uric acid and other cardiovascular risk factors at baseline on future BP and development of hypertension was assessed. During follow-up, 19.0% of women (n=605) and 29.5% of men (n=1469) participants developed hypertension. Incident hypertension was increased across the quartiles for baseline uric acid levels (P<0.0001), and multivariate Cox proportional hazards analysis revealed a significant and independent association between the uric acid level and the onset of hypertension in both men and women participants (P<0.05). Furthermore, uric acid was independently and positively correlated with future BP (P<0.05). Thus, uric acid is an independent predictor of new-onset hypertension in both women and men.

Circadian rhythm of blood pressure (BP) is closely linked with sodium balance. With positive sodium balance the nocturnal BP is elevated, resulting in non-dipper pattern. Nocturnal BP elevation plays an important role in the cardio-renal association to cause the cardiovascular events. It is vey important, therefore, how to lower nocturnal hypertension especially in CKD.

Kidney function and cardiovascular disease are closely connected and albuminuria is a proven marker of cardiovascular risk. The present study investigated the prevalence and characteristics of albuminuria in patients with hypertension. Outpatients with essential hypertension under medical treatment were enrolled in this study (n = 350, 70.0 ± 11.4 years old). Urine samples were collected for the measurement of albumin concentration, which are expressed as the ratio of urine albumin to creatinine concentration (mg/g Cr). Cross-sectional analyses were also performed of the relationships between urinary albumin and other variables. Urinary albumin was detected in 88.3% of patients, while only 35.4% showed abnormal albuminuria (≥30 mg/g Cr). The presence of abnormal albuminuria was independently correlated with systolic blood pressure, B-type natriuretic peptide, and C-reactive protein by multivariate analysis (P < 0.05). Furthermore, multivariate regression analysis identified systolic blood pressure, serum creatinine, B-type natriuretic peptide, and C-reactive protein as the only factors showing independent correlation with urinary albumin (P < 0.05). Thus, approximately 35% of hypertensive patients had abnormal albuminuria. Urinary albumin was closely associated with blood pressure, C-reactive protein, and B-type natriuretic peptide, indicating that the severity of albuminuria parallels that of systemic inflammation, cardiac load, and blood pressure.

Background: A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved., Methods: Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0±7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization., Results: At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period., Conclusions: Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Central blood pressure is more closely associated with cardiovascular events and target organ damage than peripheral blood pressure measured over the brachium using a conventional method. This study was designed to investigate the distribution of central systolic blood pressure values estimated by Omron HEM-9000AI in the Japanese general population. A cross-sectional study were performed in 10,756 subjects without overt cardiovascular disease (male=6574; mean age 55.3±12.5 years, range 20-91 years). Of these, 7348 subjects received no antihypertensive, antidiabetic or lipid-lowering drug treatment, and were used for the present analysis. Estimated central systolic blood pressure was higher than brachial systolic blood pressure and was significantly correlated with age and brachial blood pressure. The central systolic blood pressure values obtained from subjects without cardiovascular risk factors other than hypertension were 125.8±37.2 (mean±2 s.d., n=3760) mm Hg. The values obtained from subjects with no cardiovascular risk factors were 112.6±19.2 (n=1975) mm Hg for optimal and 129.2±14.9 mm Hg for normal brachial blood pressure categories (n=697). This study is the first to show the distribution of central systolic blood pressure values estimated using the Omron HEM-9000AI, marking an important step toward implementing the clinical use of central blood pressure in the diagnosis and management of hypertension.

Objectives: Microalbuminuria is closely associated with an increased risk of renal and cardiovascular adverse outcomes. The present study tested the hypothesis that titration of telmisartan reduces urinary excretion of albumin more than does addition of amlodipine in patients treated with a standard dose of telmisartan combined with a low-dose diuretic for the same degree of blood pressure (BP) reduction., Methods: Hypertensive patients with type 2 diabetes mellitus and microalbuminuria under treatment with a combination of a standard dose of telmisartan (40 mg/day) and trichlormethiazide (1 mg/day) were randomly assigned to receive either an increased dose of telmisartan (80 mg/day) combined with trichlormethiazide [increased dose angiotensin receptor blocker (ARB) group, n = 20] or a combination consisting of telmisartan (40 mg/day), trichlormethiazide, and amlodipine (5 mg/day) (triple combination group, n = 20) for 6 months. The primary endpoint was a reduction in urinary albumin levels., Results: Although BP was reduced to a similar extent by the two regimens, patients receiving the increased dose ARB showed a higher reduction in urinary albumin (-37.4 ± 16.9%) than those on the triple combination regimen (-8.9 ± 23.7%; P < 0.0001). The reduction in urinary albumin was correlated with the drop in BP in the latter group, but not in the increased dose ARB group., Conclusion: Uptitration of telmisartan more effectively reduces urinary albumin than addition of amlodipine in hypertensive patients with diabetes treated with a combination of telmisartan and diuretic for the same degree of BP reduction.

Objective: An exaggerated elevation in blood pressure around waking potentially increases the risk of cardiovascular events, even in individuals with normal blood pressure at other-fold of day. The impact of such a transient blood pressure elevation is disproportionate to its short duration, and the reason has not been elucidated. We hypothesize that individuals with such a blood pressure abnormality receive a cardiovascular overload, even from slight physical activities that are frequently undertaken in daily life., Methods: A total of 16 patients with essential hypertension (52 ± 15 years) staying at hospital for lifestyle education participated in this study. Morning blood pressure elevation was assessed with 24 h ambulatory blood pressure monitoring. Cardiovascular responses to unloaded pedaling, including blood pressure changes, were assessed in a limited maximum exercise test using an electronically braked bicycle ergometer., Results: Changes in the systolic blood pressure caused by unloaded pedaling correlated positively with the elevation in systolic blood pressure around waking (r = 0.52, P = 0.05). Moreover, waking elevation of the systolic blood pressure correlated with changes in all of the following cardiovascular variables during unloaded pedaling: heart rate (r = 0.69, P = 0.003), oxygen consumption (r = 0.73, P = 0.001), oxygen pulse (r = 0.62, P = 0.001), and rate pressure product (r = 0.64, P = 0.008), respectively., Conclusion: These observations indicate that individuals with prominent blood pressure elevation upon awakening also experience cardiovascular overload from slight physical activities.

High salt-sensitivity and nondipper blood pressure (BP) rhythm are highly associated with each other, because both are caused by impaired renal sodium excretion capability. We proposed that nocturnal hypertension and resultant pressure natriuresis could compensate for daytime sodium retention. If so, high BP may continue until sodium is sufficiently excreted at night. In fact, it takes longer for the night-time BP to fall in patients with more severe renal dysfunction. The time appears to be an essential component of the nondipper BP rhythm and, therefore, we defined the duration as the dipping time. Also, renal function was the sole determinant of a nocturnal BP dip other than age, sex, or BMI. Furthermore, we reported that diuretic therapy or dietary salt restriction, which can prevent sodium retention, restored the circadian BP rhythm into a dipper pattern. Large-scale studies are needed to explore whether these interventions can decrease the risks.

In the present study, we tested the hypothesis that up-titrating the dose of an angiotensin receptor blocker (ARB) is superior to combined treatment with an ARB and a calcium channel blocker for the same degree of blood pressure (BP) reduction, with respect to urinary albumin excretion in diabetic patients treated with a standard dose of the ARB. Hypertensive patients with type 2 diabetes mellitus and albuminuria (≥30 mg g(-1) creatinine) were enroled in the study, and were either started on or switched to candesartan (8 mg per day) monotherapy. After a 12-week run-in period, baseline evaluations were performed and patients with BP ≥130/80 mm Hg were randomly assigned to receive either candesartan (12 mg per day) or candesartan (8 mg per day) plus amlodipine (2.5 mg per day) for a further 12 weeks. The primary end-point was a reduction in urinary albumin levels. Although there was no significant difference in the BP reduction between the two groups, the reduction in urinary albumin was greater in the up-titrated than the combination therapy group (-40±14% vs -9±38%, respectively; P<0.0001). Thus, up-titration of candesartan more effectively reduces urinary albumin excretion than combined candesartan plus amlodipine in hypertensive patients with diabetes for the same degree of BP reduction.

Objectives: The present study tested the hypothesis that glomerular filtration rate can predict the onset of hypertension in individuals with normal blood pressure in the general population., Methods: Normotensive individuals (n = 7684) who visited our hospital for a routine physical examination were enrolled in the study (4907 men; mean age 52.1 ± 11.1 years) and were followed up with the endpoint being the development of hypertension. The relationship between estimated glomerular filtration rate at baseline and the incidence of hypertension was evaluated., Results: During the follow-up period (median 4.0 years; actual follow-up 30 624 person-years), hypertension developed in 2031 participants (66.3 per 1000 person-years). After adjustment for possible risk factors, the hazard ratio of incident hypertension (first tertile as reference) in the second and third tertiles was 1.03 (95% confidence interval 0.92-1.16) and 1.40 (95% confidence interval 1.26-1.57), respectively. Multivariate Cox proportional hazard regression analysis, in which estimated glomerular filtration rate was taken as a continuous variable and adjustments were made for known risk factors, also indicated that baseline estimated glomerular filtration rate independently predicted the onset of hypertension (P < 0.0001). Furthermore, multiple regression analysis revealed that a longitudinal increase in SBP was significantly associated with baseline estimated glomerular filtration rate after adjustment for known risk factors (P < 0.01)., Conclusion: Estimated glomerular filtration rate in normotensive individuals is a good predictor of the onset of hypertension in the general population.

Objective: We have shown that as renal function deteriorates, the circadian blood pressure (BP) rhythm shifts to a nondipper pattern and the duration until nocturnal BP decline [dipping time (DT)] is prolonged. We investigated whether or not morning hypertension (BP 2 h after awakening >135/85 mmHg) in chronic kidney disease (CKD) was sustained type with a prolonged DT., Materials and Methods: Twenty-four-hour BP was monitored in 104 patients with CKD. Fifty-one of 104 participants (group A) did not exhibit morning hypertension. The patients with morning hypertension (group B, n=53) were classified into three groups: group C (n=23), participants who exhibited morning hypertension but did not meet the criteria for the surge or sustained type; group D (n=29), the sustained type (with no night-time BP readings <120/70 mmHg); and group E (n=1), the surge type (systolic BP rises >25 mmHg after awakening)., Results: The night/day BP ratio and DT were compared among groups A, C, and D because there was only one participant in group E. Night/day ratio of BP and DT were both significantly higher in group D compared with groups A and C. The prevalence of nondippers tended to be higher in group D compared with the other groups (A, 65%; C, 57%; D, 86%, P=0.09). Creatinine clearance was significantly lower in group D compared with groups A and C., Conclusion: Sustained elevation of night-time BP until the early morning and high night/day ratio of BP may contribute to the high frequency of morning hypertension, which is generally the sustained rather than the surge type in CKD.

Background: Endothelial damage is an early component of atherosclerosis; however, the impact of cardiovascular risk factors on endothelial function is not clearly understood. We investigated the impact of lipid profiles and high blood pressure on damage., Objective: Japanese male outpatients with grade I or II hypertension, along with gender and age-matched normotensive subjects (both n = 25), were enrolled. Subjects with severe cardiovascular risk factors or illness or those taking medications were excluded. Blood was sampled for laboratory analysis and endothelial function was assessed by flow-mediated dilation (FMD)., Results: Total cholesterol to high-density lipoprotein cholesterol ratio (total-C/HDL-C) was inversely correlated with the FMD value and positively correlated with both malondialdehyde-modified low-density lipoprotein and high-sensitivity C-reactive protein values. Stepwise regression analysis revealed total-C/HDL-C and systolic blood pressure were significant determinants of FMD. Hypertensive subjects had lower FMD values and similar lipid profiles to normotensive subjects. Grouping subjects according to total-C/HDL-C levels showed that those with high values had lower FMD values. Hypertensive subjects with low total-C/HDL-C had similar endothelial index values to those in normotensive subjects with high total-C/HDL-C. Logistic regression indicated hypertension and high total-C/HDL-C were significantly associated with low FMD values., Conclusion: Impaired endothelial function was associated with increased total-C/HDL-C values, possibly as the result of increased vascular oxidative stress and inflammation. In the early stages of atherosclerosis, the impact of both total-C/HDL-C and BP may be similar in terms of endothelial damage., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

When RAS inhibitors are prescribed as the first-line agent in hypertension, the combination of diuretics on them exerts several preferable effects in both blood pressure lowering and organ protection. As far as low-dose of diuretics, the unfavorable side effects such as hypokalemia and insulin resistance can be minimized by RAS inhibitors. Therefore, unless the compelling indication for Ca channel blockers exists, diuretics should be added on RAS inhibitors.

Background: The present study was designed to test the hypothesis that brachial-ankle pulse wave velocity (baPWV) predicts longitudinal increases in blood pressure (BP) and new onset of hypertension in individuals with normal BP., Methods: baPWV was measured using a semiautomated device in 2,496 participants (27-84 years) without hypertension who visited our hospital for a yearly health check-up. They were followed up for 4 years with the endpoint being development of hypertension., Results: During the follow-up period (median, 733 days; actual follow-up, 5,215 person-years), hypertension developed in 698 participants (133.8/1,000 person-years). Kaplan-Meier analysis revealed that risk for hypertension was increased across the tertiles of baseline baPWV. The hazard ratio (first tertile as reference) was 2.02 (95% confidence interval (CI) 1.55-2.64) and 3.49 (95% CI 2.66-4.57) in the second and third tertiles, respectively, after adjustment for possible risk factors. Multivariate Cox proportional hazard regression analysis adjusted for known risk factors, where baPWV was used as a continuous variable, also indicated that the baseline value of baPWV independently predicted new onset of hypertension (P < 0.001). Furthermore, baseline baPWV was significantly associated with a longitudinal increase in BP after adjustment for known risk factors in multiple regression analysis (P < 0.001)., Conclusion: This study provides the first evidence that baPWV is an independent predictor of longitudinal increases in BP as well as of new onset of hypertension.

Objectives: Effective blood pressure (BP) control is difficult to achieve in diabetic patients. This study investigated factors that exacerbate resistance to antihypertensive medication in patients with diabetes., Methods: Hypertensive patients with type 2 diabetes (n = 108, 67 ± 9 years) were subjected to a step-wise upward titration of medication (step 1, routine dose of angiotensin receptor blocker; step 2, routine doses of angiotensin receptor blocker and calcium channel blocker; step 3, step 1 + double dose of calcium channel blocker; step 4, double doses of angiotensin receptor blocker and calcium channel blocker; step 5, step 4 + routine dose of diuretic; step 6, step 5 + routine dose of β-blocker; step 7, step 6 + routine dose of α-blocker; step 8, step 6 + double dose of α-blocker) implemented with a target home BP of below 130/80 mmHg. The step number at which target BP was achieved was considered the amount of antihypertensive medications needed for BP control., Results: All patients reached the target BP at step 4.0 ± 1.5. Multivariate regression analysis identified estimated glomerular filtration rate, but not measures of glycemic control, as an independent predictor of the number of drugs needed for BP control (P < 0.0001)., Conclusion: The number of antihypertensive medications needed for BP control in patients with diabetes mellitus is largely dependent on estimated glomerular filtration rate. Impaired kidney function could produce resistance to antihypertensive therapy in diabetic patients.

Some cardiovascular disorders disturb circadian variation of endothelial function. We investigated whether deterioration of renal function alters circadian variation of endothelial function in patients with hypertension. Endothelial function was assessed by the peak forearm blood flow (FBF) response to reactive hyperemia, and 24-hour ambulatory blood pressure monitoring was performed in 25 patients with essential hypertension (61 ± 17 years). Relationships among renal function, 24-hour blood pressure, and endothelial function were analyzed. The ratio of nighttime to daytime mean arterial pressure was inversely correlated with estimated glomerular filtration rate (eGFR) (r = -0.43, P = .03). The FBF response to reactive hyperemia examined at 21:00, but not at 6:30 or 11:30, was significantly correlated with eGFR (r = 0.44, P = .03). Furthermore, the ratio of FBF response measured at 21:00 to that measured at 6:30 was independently correlated with eGFR (β = 0.47, P = .02). Renal dysfunction is associated with the derangement of circadian variation of both endothelial function and blood pressure. Nocturnal blood pressure is elevated, and evening endothelial function deteriorates in parallel with a decline in renal function in hypertensive patients., (American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (<140 mm Hg) is superior to moderate blood pressure control (> or =140 mm Hg to <150 mm Hg) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension. We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension (sitting blood pressure 160 to 199 mm Hg) into 2 groups, according to strict or moderate blood pressure treatment. A composite of cardiovascular events was evaluated for > or =2 years. The strict control (1545 patients) and moderate control (1534 patients) groups were well matched (mean age: 76.1 years; mean blood pressure: 169.5/81.5 mm Hg). Median follow-up was 3.07 years. At 3 years, blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg, respectively. The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg. The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group (hazard ratio: 0.89; [95% CI: 0.60 to 1.34]; P=0.38). In summary, blood pressure targets of <140 mm Hg are safely achievable in relatively healthy patients > or = 70 years of age with isolated systolic hypertension, although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets.

In healthy subjects, blood pressure (BP) drops by 10-20% during the night. Conversely, in patients with the salt-sensitive type of hypertension or chronic kidney disease, nighttime BP does not fall, resulting in an atypical pattern of circadian BP rhythm that does not dip. This pattern is referred to as the 'non-dipper' pattern. Loss of renal functional reserve, due to either reduced ultrafiltration capacity or enhanced tubular sodium reabsorption, induces the salt-sensitive type of hypertension. When salt intake is excessive in patients with salt-sensitive hypertension, the defect in sodium excretory capability becomes evident, resulting in elevated BP during the night. This nocturnal hypertension compensates for diminished natriuresis during the daytime and enhances pressure natriuresis during the night. Nocturnal hypertension and the non-dipper pattern of circadian BP rhythm cause cardiovascular events. When excess salt intake is loaded in patients who are in a salt-sensitive state, glomerular capillary pressure is also elevated, resulting in glomerular sclerosis and eventual renal failure. In this way, salt sensitivity and excess salt intake contribute to both cardiovascular and renal damage at the same time. We propose that salt sensitivity of BP and excess salt intake have important roles in the genesis of the cardiorenal connection. Salt sensitivity and circadian rhythm of BP are the keys to understanding the connections between cardiovascular and renal complications.

Anti-hypertensive medication with an angiotensin II receptor blocker (ARB) is effective in slowing the progression of chronic kidney disease. The present study was designed to investigate whether calcium channel blockers (CCBs) in combination with an ARB differentially affect kidney function. Elderly hypertensive patients with chronic kidney disease (n = 17, 72 +/- 6 years old) were instructed to self-measure blood pressure. They were randomly assigned to receive either benidipine (4-8 mg/day) or amlodipine (5-10 mg/day) combined with olmesartan (10 mg/day). After 3 months, CCBs were switched in each patient and the same protocol was applied for another 3 months. At baseline, significant correlation was obtained between urine albumin (22.8 +/- 16.7 (median +/- median absolute deviation) mg/g creatinine) and self-measured blood pressure (170 +/- 23/87 +/- 10 (mean +/- SD) mmHg, r = 0.65, p < 0.01). Both regimens reduced blood pressure to a similar extent (139 +/- 22/75 +/- 11 mmHg and 133 +/- 17/72 +/- 10 mmHg, respectively; both p < 0.001), while urine albumin decreased only after combination therapy including benidipine (11.7 +/- 6.1 mg/g creatinine, p < 0.05). Benidipine, but not amlodipine, in combination with olmesartan, reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease. The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease.

Increased B-type natriuretic peptide (BNP) expression precedes the development of hypertension in spontaneously hypertensive rats. We therefore tested the hypothesis that elevated plasma BNP levels predict the onset of hypertension in normotensive subjects. Japanese normotensive participants who were at our hospital for a yearly physical check-up (mean age 52.7 years, 35.9% women, n=5,026) were enrolled in the study. Blood pressure and BNP were measured at baseline and subjects were followed up for 5 years (median 1,114 d), with the endpoint being the development of hypertension. We evaluated the relationship between plasma BNP levels at baseline and the incidence of hypertension during the follow-up period. Hypertension was defined as systolic or diastolic blood pressure > or =140 or > or =90 mmHg, respectively, or the use of antihypertensive medications. During the follow-up period, hypertension developed in 23.4% (77.0 per 1,000 person-years) and 14.9% (51.0 per 1,000 person-years) of male and female subjects, respectively. Cox proportional hazard regression analysis demonstrated that after adjustment for known risk factors, the risk of hypertension was increased from the first to fourth quartiles of baseline BNP levels. However, after additional adjustment for baseline blood pressure, BNP did not predict the new onset of hypertension. Baseline BNP levels are closely associated with the risk of hypertension in individuals with normal blood pressure, but the prediction of hypertension with BNP is largely dependent on baseline blood pressure. Measurements of BNP may serve as a complementary method for the prediction or confirmation of hypertension.

Nifedipine has been shown to improve endothelial function. Recent studies have indicated that endothelial function is correlated with the number of circulating endothelial progenitor cells (EPCs), but it is unclear whether nifedipine affects the number and function of EPCs. The aims of this study were to determine the effects of nifedipine on the number and function of EPCs and to investigate the relationship between improvement of endothelial function and EPC numbers in patients with hypertension. Stage 1 hypertensive men (n=37) were randomly divided into the nifedipine group and the control untreated group. The nifedipine group was administered slow-release nifedipine (20 mg) once daily. At baseline and after 4 weeks, flow-mediated dilation, blood pressure, biochemical data, and number of circulating CD34+CD133+ progenitor cells and EPCs were measured. The direct effects of nifedipine on EPC number and function were assessed in vitro. In the nifedipine group, flow-mediated dilation and the numbers of circulating CD34+CD133+ progenitor cells and EPCs were increased, along with a decrease of serum malondialdehyde low-density lipoprotein. The improvement of flow-mediated dilation by nifedipine was correlated with the increase of circulating CD34+CD133+ progenitor cells. Nifedipine also improved angiogenesis-related functions of EPCs (differentiation, migration, and resistance to oxidative stress) in vitro. Thus, nifedipine improved endothelial function and EPC function in stage 1 hypertensive subjects. The latter action may be mediated by reduction of oxidative stress and suppression of EPC apoptosis. These results demonstrate that nifedipine preserves endothelial integrity in patients with hypertension, at least partly, by enhancing EPC numbers and activity.

Each component of the metabolic syndrome is not necessarily clustered coincidentally. Thus, subjects who have obesity, dyslipidemia or impaired glucose tolerance may be at high risk for the development of hypertension. We studied the predictive value of the following for the development of hypertension: obesity (body mass index > or =25.0 kg/m2), dyslipidemia (high-density lipoprotein-cholesterol <40 mg/dL, triglyceride > or =150 mg/dL, or use of anti-dyslipidemic drugs), high normal blood pressure (130 mmHg < or = systolic <140 mmHg, or 85 mmHg < or = diastolic <90 mmHg), and impaired glucose tolerance (fasting plasma glucose > or =110 mg/dL or use of anti-diabetic agents). This observational study included 5,785 subjects without hypertension recruited from participants in our health checkup program. They were followed up for 1,097+/-365 d, with the endpoint being the development of hypertension. During the follow-up, hypertension developed in 1,168 subjects (74.1 per 1,000 person-years). The incidence of hypertension was higher in subjects who had obesity (106.2 vs. 67.8), dyslipidemia (96.1 vs. 69.0), high normal blood pressure (166.0 vs. 40.1), or impaired glucose tolerance (130.5 vs. 65.3 per 1,000 person-years) than in those without these disorders at baseline. The risk of hypertension was increased as the number of metabolic disorders in an individual increased. Multiple regression analysis indicated that obesity, high normal blood pressure, and impaired glucose tolerance remained independent predictors of the onset of hypertension. Thus, the presence of individual components of the metabolic syndrome predicts the development of hypertension. Prediction of the development of hypertension may lead to effective prevention of both hypertension and resulting cardiovascular diseases.

Recent progress in antihypertensive therapy has widened the selection of drugs, and large clinical trials have attracted attention to newer classes of antihypertensives. Consequently, the use of diuretics as antihypertensive agents has been relatively reduced, particularly since the newer drugs are associated with fewer adverse metabolic reactions. However, diuretics have a specific activity of removing sodium from the body fluid, thereby rendering the blood pressure insensitive to sodium intake, relieving the overload to systemic circulation, and normalizing the circadian rhythm of blood pressure from a non-dipper to a dipper pattern. At low doses, diuretics are known to be as effective as all other antihypertensive agents for reducing nearly all types of cardiovascular events. In this brief review, the indication for thiazide diuretics will be discussed based on the pathophysiology of hypertension and antihypertensive therapy with diuretics mainly from the point of view of sodium metabolism. Low-dose diuretics will continue to be an important agent in the treatment of hypertension, mostly in combination with vasodilators such as modulators of the reninangiotensin system and calcium channel blockers.

Objective: To assess whether an association between sodium-sensitive hypertension and metabolic syndrome exists; and whether, in patients with metabolic syndrome, the nocturnal fall of blood pressure decreases and salt restriction affects the circadian blood pressure rhythm., Methods: Japanese patients with essential hypertension, who were treated without any antihypertensive agent, were maintained on a high-sodium diet and a low-sodium diet for 1 week each. On the last day of each diet, the 24-h blood pressures were measured. A diagnosis of metabolic syndrome was made according to the International Diabetes Foundation definition, Results: Among the 56 patients with essential hypertension, 15 patients were complicated with metabolic syndrome while 41 patients were not. The nocturnal blood pressure fall was significant in patients without metabolic syndrome, while it was not so in patients with metabolic syndrome. Only in patients with metabolic syndrome was the nocturnal blood pressure fall enhanced by sodium restriction. The prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than in those without metabolic syndrome (70.6 versus 36.0%, respectively; P = 0.017). A multiple logistic regression analysis revealed central obesity to be an independent risk factor for sodium-sensitive hypertension (odds ratio, 1.41; 95% confidence interval, 1.04-1.91)., Conclusions: In patients with essential hypertension, an inter-relationship exists among metabolic syndrome, enhanced sodium sensitivity of the blood pressure and non-dipping. The elevated risk of cardiovascular diseases in patients with metabolic syndrome may be related to sodium-sensitive hypertension and non-dipping.

Microalbuminuria is a sensitive marker of early renal damage in essential hypertension as well as diabetes mellitus. Elevated urinary albumin excretion has positive correlations with other cardiovascular risk factors. Microalbuminuria has an independent value to predict cardiovascular disease in the patients with not only diabetes mellitus but also with essential hypertension and even in general population. The seventh report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure (JNC 7) has adopted microalbuminuria or estimated glomerular filtration rate < 60 ml/min as one of the major cardiovascular risk factors. It is an important future task whether decrease in urinary albumin excretion with treatment improves prognosis of individual patients.

Blood pressure-lowering mechanisms of the Dietary Approaches to Stop Hypertension (DASH) diet, rich in fruits, vegetables, and low-fat dairy foods, were analyzed based on the pressure-natriuresis relationship. Participants (n=375) were randomly assigned to control or DASH diet groups by using a parallel-group design. They then ate their assigned diet for 3 consecutive 30-day intervention feeding periods, during which sodium intake varied among 3 levels by a randomly assigned sequence. Urinary sodium excretion rate and mean arterial pressure were measured at the end of each sodium intake level. Mean arterial pressure and urinary sodium excretion were plotted on x and y axes, respectively, for participants eating control and DASH diets and were modeled as linear relationships for simplicity to allow the estimation of the extrapolated x-intercept and slope of the relationships. The DASH diet steepened the slope of the relationship (29.5+/-3.4 vs 64.9+/-13.1 [mmol/d]/mm Hg, P=0.0002) without significantly shifting the x-intercept (94.1+/-0.5 vs 93.2+/-0.6 mm Hg, NS) of the relationship. These data suggest a natriuretic action of the DASH diet.

Recently, we found that the circadian rhythms of natriuresis as well as of glomerular filtration rate were disturbed similar to the blood pressure in non-dipper type of essential hypertension during intake of a high-sodium diet. In this study, we examined circadian rhythms of the urinary albumin excretion rate (AER), which is recognized as a marker of glomerular capillary hydraulic pressure, in addition to those of urinary sodium excretion and blood pressure in 27 patients with essential hypertension. The patients were maintained on relatively high (10-12 g) on low (1-3 g) sodium (NaCl) diets for 1 week. On the last day of each diet, the 24-hour blood pressure was measured every 30 min noninvasively, and during the last 3 days, urine samples were collected for determination of both daytime (07:00-21.30 h) and nighttime (21.30-07.00 h) sodium and AER variations. During the high-sodium diet, nocturnal falls in urinary sodium excretion and blood pressure were observed in dippers (n = 7), while they were not observed in non-dipper (n = 20). The nocturnal decline in AER was also observed in dippers (day: 37 x// 6 microg/min vs. night: 22 x// 5 microg/min; p < 0.02), while it was not observed in non-dippers (day: 49 x// 6 microg/min vs. night: 40 x// 8 microg/min; NS). During intake of the low-sodium diet, on the other hand, a nocturnal decline in AER was observed in both types of hypertension. Sodium restriction significantly reduced only the nighttime AER in non-dippers (p < 0.01). These findings indicate that changes in dietary sodium intake modified the circadian rhythms of both blood pressure and AER in non-dippers. Renal sodium handling may contribute to determining the circadian rhythm of blood pressure, and furthermore an elevated glomerular capillary hydraulic pressure during the night may enhance the nocturnal albumin excretion in non-dippers., (Copyright 2002 S. Karger AG, Basel)