Sodium-Glucose Cotransporter 2 Inhibitor Combined with Conventional Diuretics Ameliorate Body Fluid Retention without Excessive Plasma Volume Reduction.

We previously reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake. However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. In this study, we examined the comparative effects of the SGLT2 inhibitor dapagliflozin (SGLT2i group, n = 53) and the combined use of dapagliflozin and conventional diuretics, including loop diuretics and/or thiazides (SGLT2i + diuretic group, n = 23), on serum copeptin, a stable, sensitive, and simple surrogate marker of vasopressin release and body fluid status. After six months of treatment, the change in copeptin was significantly lower in the SGLT2i + diuretic group than in the SGLT2i group (-1.4 ± 31.5% vs. 31.5 ± 56.3%, p = 0.0153). The change in the estimated plasma volume calculated using the Strauss formula was not significantly different between the two groups. Contrastingly, changes in interstitial fluid, extracellular water, intracellular water, and total body water were significantly lower in the SGLT2i + diuretic group than in the SGLT2i group. Changes in renin, aldosterone, and absolute epinephrine levels were not significantly different between the two groups. In conclusion, the combined use of the SGLT2 inhibitor dapagliflozin and conventional diuretics inhibited the increase in copeptin levels and remarkably ameliorated fluid retention without excessively reducing plasma volume and activating the renin-angiotensin-aldosterone and sympathetic nervous systems.

Fluid homeostatic action of dapagliflozin in patients with chronic kidney disease: the DAPA-BODY Trial.

Sodium glucose cotransporter 2 (SGLT2) inhibitors have both glucose-lowering and diuretic effects. We recently reported that the SGLT2 inhibitor dapagliflozin exerts short-term fluid homeostatic action in patients with chronic kidney disease (CKD). However, the long-term effects of SGLT2 inhibitors on body fluid status in patients with CKD remain unclear. This was a prospective, non-randomized, open-label study that included a dapagliflozin treatment group (n = 73) and a control group (n = 24) who were followed for 6 months. Body fluid volume was measured using a bioimpedance analysis device. The extracellular water-to-total body water ratio (ECW/TBW), a predictor of renal outcomes, was used as a parameter for body fluid status (fluid retention, 0.400 ≤ ECW/TBW). Six-month treatment with dapagliflozin significantly decreased ECW/TBW compared with the control group (-0.65% ± 2.03% vs. 0.97% ± 2.49%, p = 0.0018). Furthermore, dapagliflozin decreased the ECW/TBW in patients with baseline fluid retention, but not in patients without baseline fluid retention (-1.47% ± 1.93% vs. -0.01% ± 1.88%, p = 0.0017). Vasopressin surrogate marker copeptin levels were similar between the control and dapagliflozin groups at 6 months (32.3 ± 33.4 vs. 30.6 ± 30.1 pmol/L, p = 0.8227). However, dapagliflozin significantly increased the change in copeptin levels at 1 week (39.0% ± 41.6%, p = 0.0010), suggesting a compensatory increase in vasopressin secretion to prevent hypovolemia. Renin and aldosterone levels were similar between the control and dapagliflozin groups at 6 months, while epinephrine and norepinephrine (markers of sympathetic nervous system activity) were significantly lower in the dapagliflozin group than in the control group. In conclusion, the SGLT2 inhibitor dapagliflozin ameliorated fluid retention and maintained euvolemic fluid status in patients with CKD, suggesting that SGLT2 inhibitors exert sustained fluid homeostatic actions in patients with various fluid backgrounds. Clinical trial registration: https://www.umin.ac.jp/ctr/, identifier [UMIN000048568].

The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic action. We recently reported that the SGLT2 inhibitor dapagliflozin ameliorates extracellular volume expansion with a mild increase in urine volume. However, the impact of the pretreatment extracellular volume status on the body fluid response to SGLT2 inhibitors remains unclear. METHODS: Thirty-six diabetic kidney disease (DKD) patients were treated with dapagliflozin. The body fluid volume, including intracellular water (ICW), extracellular water (ECW) and total body water (TBW), were measured on baseline and day 7 using a bioimpedance analysis (BIA) device. The ECW/TBW and ECW were used as markers of the extracellular volume status. For a comparison, the extracellular volume status responses to loop diuretic furosemide (n = 16) and vasopressin V2 receptor antagonist tolvaptan (n = 13) were analyzed. RESULTS: The body weight, brain natriuretic peptide and body fluid parameters measured by a BIA (ICW, ECW, TBW, and ECW/TBW) were significantly decreased for 1 week after dapagliflozin administration. The change in the ECW/TBW in the high-ECW/TBW group (over the median value of 0.413) was significantly higher than in the low-ECW/TBW group (- 2.1 ± 0.4 vs. - 0.5 ± 0.4%, p = 0.006). Only with dapagliflozin treatment (not furosemide or tolvaptan treatment) was the baseline ECW/TBW significantly correlated with the changes in the ECW/TBW (r = - 0.590, p < 0.001) and ECW (r = - 0.374, p = 0.025). CONCLUSIONS: The pretreatment extracellular volume status predicts the body fluid response to the SGLT2 inhibitor dapagliflozin in DKD patients. The diminished extracellular fluid reduction effect of dapagliflozin in patients without severe extracellular fluid retention may contribute to maintaining a suitable body fluid status.

Morning hypertension: the strongest independent risk factor for stroke in elderly hypertensive patients.

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.

Regular alcohol drinking is a determinant of masked morning hypertension detected by home blood pressure monitoring in medicated hypertensive patients with well-controlled clinic blood pressure: the Jichi Morning Hypertension Research (J-MORE) study.

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.

Nocturnal hypoxia is associated with silent cerebrovascular disease in a high-risk Japanese community-dwelling population.

BACKGROUND: Sleep-disordered breathing (SDB) is recognized as a risk factor for cerebrovascular disease. The objective of this study was to investigate the relationship between nocturnal hypoxia and silent cerebral infarct (SCI) in the general population. METHODS: In the 2001 annual health check in Nishiarita, Japan, 170 individuals at high risk were screened who met more than three of the following criteria: high blood pressure, hypercholesterolemia, left ventricular hypertrophy by electrocardiography, hemoglobinA(1)c >6.5%, proteinuria, central obesity, heavy smoking habit, heavy drinking, and family history of stroke. Overnight pulse oximetry, brain magnetic resonance imaging, and carotid/cardiac ultrasonography were performed in 146 (mean age 67.4 +/- 9.0 years) of the 170 individuals in whom pulse oximetry was successfully performed. RESULTS: Subjects were classified into a nocturnal hypoxia group (n = 36) and a nonhypoxia group (n = 110) based on a 3% oxygen desaturation index (ODI) 5.6 times per hour during sleep (highest quartile) by pulse oximetry. The presence of silent cerebral infarct (SCI) (57% v 35%, P = .03) was significantly higher in the hypoxia group than in the nonhypoxia group. The number of SCI was positively correlated with age (r = 0.23, P < .01), systolic blood pressure (r = 0.196, P < .05), and 3% ODI (r = 0.318, P < .001). Even after adjustment for confounding factors using logistic regression analysis, nocturnal hypoxia (odds ratio = 2.2, 95% confidence interval = 1.10 to 5.30, P = .026) as well as systolic blood pressure and age (10-year increase: odds ratio = 1.22, 95% confidence interval 1.00 to 1.48, P = .048) were independently associated with SCI in the study subjects. CONCLUSIONS: Based on the study results, SDB assessed by overnight pulse oximetry was associated with silent cerebral disease in a high-risk, community-dwelling Japanese population.

Determinants of exaggerated difference in morning and evening blood pressure measured by self-measured blood pressure monitoring in medicated hypertensive patients: Jichi Morning Hypertension Research (J-MORE) Study.

BACKGROUND: Morning blood pressure (BP) surge in ambulatory BP monitoring was a risk factor for stroke in our previous study. We studied the determinants of the morning minus evening systolic BP difference (ME difference) in self-measured BP monitoring, as a possible risk factor for stroke in medicated hypertensive patients. METHODS: Nine hundred sixty-nine hypertensive outpatients receiving stable antihypertensive drug treatment were studied using self-measured BP monitoring in the morning and evening. RESULTS: The ME difference ranged from -37.3 to 53.3 mm Hg (mean 7.9 mm Hg). The highest quartile (Q4) of the ME difference group (>15.0 mm Hg) had older age (68.0+/-9.8 years v 66.2+/-10.3 years, P=.01) and higher prevalence of men (48.3% v 39.9%, P=.02), regular alcohol drinkers (34.7% v 26.0%, P=.01) and beta-blocker use (26.9% v 19.9%, P=.03) than the other quartile groups (Q1 to Q3), whereas there was no significant difference in the average of morning and evening (ME average) BP. In logistic regression analysis controlling for ME average and other confounding factors, independent risks for Q4 of ME difference were older age (10 years older: odds ratio [OR] 1.21, P=.01, 95% confidence interval (CI) 1.04-1.42), regular alcohol drinker (OR 1.51, P=.04, 95% CI 1.01-2.26), and beta-blocker use (OR 1.50, P=.02, 95% CI 1.06-2.12). CONCLUSIONS: Older age, beta-blocker use, and regular alcohol drinking were significant determinants of the exaggerated ME difference in medicated hypertensive patients.

Altered aortic properties in elderly orthostatic hypertension.

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.

Diabetic brain damage in hypertension: role of renin-angiotensin system.

Diabetes and hypertension are potent risk factors for cerebrovascular disease. We studied the effects of an angiotensin II type 1 receptor blockade (ARB) on brain damage in hypertensives in relation to diabetes. We studied cerebral metabolism (by proton magnetic resonance spectroscopy) and hemodynamics (by phase-contrast magnetic resonance angiography) before and 3 to 4 months after candesartan therapy in 20 diabetic hypertensives (DHTs) and 20 matched nondiabetic hypertensives (HTs). Silent multiple cerebral infarcts detected by brain MRI were more common in DHTs than in HTs (50% versus 25%). Cerebral N-acetyl aspartate (NAA; an indicator of functional neuronal mass) was lower in DHTs than in HTs (8.35 versus 9.58 mmol/kg; P=0.007). Baseline quantitative volume flow in the internal carotid arteries (ICAs) and the middle cerebral arteries (MCAs) was comparable between the 2 groups, whereas cerebrovascular reserve (CVR) assessed using acetazolamide (a cerebral arteriolar dilator) in ICAs (25% versus 35%; P=0.03) and MCAs (20% versus 31%; P=0.01) was lower in DHTs than in HTs. These baseline CVR and NAA values of DHT group were lower than those of 12 matched normotensives (CVR: 44% for ICA; 41% for MCA; NAA: 10.5 mmol/kg; all P<0.005). After candesartan therapy, CVR in ICAs and MCAs was significantly increased (P=0.001) independently of the reduction of the 24-hour blood pressure level, whereas the cerebral NAA level did not change. In conclusion, brain damage is advanced in DHTs. ARB partly improved the impaired cerebral microvascular function in DHTs.

Type 2 diabetes is associated with left ventricular concentric remodeling in hypertensive patients.

BACKGROUND: Left ventricular (LV) geometric remodeling is associated with cardiovascular prognosis in hypertensive patients. It is uncertain how LV remodeling is modulated by diabetes in hypertensive patients. In this study, we investigated the impact of diabetes and ambulatory blood pressure (BP) on LV geometric remodeling in hyptensives with/without diabetes. METHODS: Ambulatory BP monitoring and echocardiography were performed to compare 24-h BP levels and LV measurements in 400 uncomplicated hypertensives (mean age, 67 years, 152 men and 248 women) between diabetic (n = 161) and nondiabetic (n = 239) patients. RESULTS: The age (67 v 68 years), percentage of men (43% v 34%), body mass index (24.5 v 24.0 kg/m(2)), 24-h systolic BP (144/80 v 144/82 mm Hg), LV mass index (128 v 130 g/m(2)) were similar between the groups. Diabetic patients had higher relative wall thickness (0.50 v 0.44, P < .001) and higher prevalence of concentric LV hypertrophy (39.4% v 26.8%, P < .001) than nondiabetic patients. The presence of diabetes (odds ratio [OR] = 2.76; 95% confidence interval [CI] = 1.73-4.41, P < .001) and 24-h systolic BP (OR for 10 mm Hg increase = 1.17; 95% CI = 1.01-1.37, P < .05) were independently associated with the higher relative wall thickness (>/=0.45). On the other hand, 24-h systolic BP was independently associated with LV hypertrophy (OR for 10 mm Hg increase = 1.32; 95% CI = 1.14-1.52, P < .05). CONCLUSIONS: Among hypertensive patients, type 2 diabetes was associated with concentric LV geometry independent of ambulatory BP.

Collagen metabolism in extracellular matrix may be involved in arterial stiffness in older hypertensive patients with left ventricular hypertrophy.

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.

Morning blood pressure surge and hypertensive cerebrovascular disease: role of the alpha adrenergic sympathetic nervous system.

BACKGROUND: The morning surge of blood pressure (BP) is associated with alpha-adrenergic activity. We studied the association between the alpha-adrenergic morning surge in BP and silent cerebrovascular disease in elderly patients with hypertension. METHODS: We conducted ambulatory BP monitoring three times (twice at baseline and after nighttime dosing of the alpha1-blocker doxazosin) in 98 elderly hypertensive patients in whom the presence of silent cerebral infarcts (SCI) was assessed by brain magnetic resonance imaging. The morning BP surge (MBPS) was calculated as the mean systolic BP during the 2 h after waking minus the mean systolic BP during 1 h that included the lowest sleep BP. The alpha-adrenergic MBPS was calculated as the reduction of MBPS by doxazosin. RESULTS: The prevalence of multiple SCI was higher in the Surge group (top quartile: MBPS > or = 45 mm Hg, n = 24) than in the Nonsurge group (MBPS < 45 mm Hg, n = 74) (54% v 31%, P = .04), and in the higher alpha-adrenergic surge group (top quartile: alpha-adrenergic MBPS > or = 28 mm Hg, n = 25) than in the lower alpha-adrenergic surge group (< 28 mm Hg, n = 73) (68% v 26%, P < .0001). In the Surge group, subjects with higher alpha-adrenergic surge (n = 17) had a markedly higher frequency of multiple SCI, whereas none in the lower alpha-adrenergic surge group had multiple SCI (n = 7) (77% v 0%, P = .001). The alpha-adrenergic MBPS was closely associated with multiple SCI (10 mm Hg increase: OR = 1.96, P = .006), independently of age, MBPS, 24-h systolic BP, and other confounding factors. CONCLUSION: The morning BP surge, particularly that dependent on alpha-adrenergic activity, is closely associated with advanced silent hypertensive cerebrovascular disease in elderly individuals.

Greater change of orthostatic blood pressure is related to silent cerebral infarct and cardiac overload in hypertensive subjects.

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.

Sleep pulse pressure and awake mean pressure as independent predictors for stroke in older hypertensive patients.

BACKGROUND: It remains uncertain which is the stronger predictor for stroke in older hypertensives, ambulatory pulse pressure (PP) or mean blood pressure (MBP). METHODS: We studied the prognosis for stroke in 811 older hypertensives in whom ambulatory BP monitoring was performed. We also assessed silent cerebral infarct (SCI) by brain magnetic resonance imaging. RESULTS: Silent cerebral infarcts were found in 50% of 515 subjects (64% of the total population) in whom we assessed SCI using brain magnetic resonance imaging. During a mean of a 42-month follow-up period, stroke events occurred in 59 subjects. After adjustment for covariates, for each 10 mm Hg increase in sleep PP, there was an independent 43% (95% confidence interval [CI]:16%-75%, P =.001) increase in the stroke risk, and sleep MBP was not a significant factor after controlling for sleep PP. On the other hand, for each 10 mm Hg increase in awake MBP, there was an independent 48% (95% CI: 21%-81%, P =.0002) increase in the stroke risk, and awake PP was not a significant factor after controlling for awake MBP. After adjusting for SCI (a strong predictor, P <.0001) at baseline, the effects of awake MBP (38% risk increase for each 10 mm Hg, P =.007) and sleep PP (32% risk increase for each 10 mm Hg, P =.016) remained significant. CONCLUSIONS: In older hypertensives, the impacts of PP and MBP on stroke risk are different during sleep and awake periods. Sleep PP and awake MBP are both predictors of stroke events independently of SCI.

Comparison of valsartan and amlodipine on ambulatory and morning blood pressure in hypertensive patients.

BACKGROUND: Cardiovascular events occur most frequently in the morning. We aimed to study the effects of monotherapy with the long-acting angiotensin II receptor blocker valsartan compared with the long-acting calcium antagonist amlodipine on ambulatory and morning blood pressure (BP). METHODS: We performed ambulatory BP monitoring before and after once-daily dose of valsartan (valsartan group, n = 38) and amlodipine (amlodipine group, n = 38) therapy in 76 hypertensive patients. To achieve the target BP of < or =140/90 mm Hg, valsartan was titrated from 40 mg/day to 160 mg/day (mean dose 124 mg/day) and amlodipine was titrated from 2.5 mg/day to 10 mg/day (mean dose 6.4 mg/day). RESULTS: Both drugs significantly reduced clinic and 24-h systolic BP (SBP) and diastolic BP (DBP) (P <.002). However, the antihypertensive effect of amlodipine was superior to that of valsartan in clinical SBP (-26 mm Hg v -13 mm Hg, P =.001) and 24-h SBP (-14 mm Hg v -7 mm Hg, P =.008). In addition, morning SBP was significantly reduced by amlodipine from 156 to 142 mm Hg (P <.001) but not by valsartan. Both agents reduced lowest night SBP to a similar extent (amlodipine 121 to 112 mm Hg, P <.001; valsartan 123 to 114 mm Hg, P <.002). Reduction in morning SBP surge (morning SBP minus lowest night SBP) was significantly greater in patients treated with amlodipine compared with those treated with valsartan (-6.1 mm Hg v +4.5 mm Hg, P <.02). CONCLUSIONS: Amlodipine monotherapy was more effective than valsartan monotherapy in controlling 24-h ambulatory BP and morning BP in hypertensive patients.

Smoking is associated with silent cerebrovascular disease in a high-risk Japanese community-dwelling population.

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.

Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study.

BACKGROUND: Cardiovascular events occur most frequently in the morning hours. We prospectively studied the association between the morning blood pressure (BP) surge and stroke in elderly hypertensives. METHODS AND RESULTS: We studied stroke prognosis in 519 older hypertensives in whom ambulatory BP monitoring was performed and silent cerebral infarct was assessed by brain MRI and who were followed up prospectively. The morning BP surge (MS) was calculated as follows: mean systolic BP during the 2 hours after awakening minus mean systolic BP during the 1 hour that included the lowest sleep BP. During an average duration of 41 months (range 1 to 68 months), 44 stroke events occurred. When the patients were divided into 2 groups according to MS, those in the top decile (MS group; MS > or =55 mm Hg, n=53) had a higher baseline prevalence of multiple infarcts (57% versus 33%, P=0.001) and a higher stroke incidence (19% versus 7.3%, P=0.004) during the follow-up period than the others (non-MS group; MS <55 mm Hg, n=466). After they were matched for age and 24-hour BP, the relative risk of the MS group versus the non-MS group remained significant (relative risk=2.7, P=0.04). The MS was associated with stroke events independently of 24-hour BP, nocturnal BP dipping status, and baseline prevalence of silent infarct (P=0.008). CONCLUSIONS: In older hypertensives, a higher morning BP surge is associated with stroke risk independently of ambulatory BP, nocturnal BP falls, and silent infarct. Reduction of the MS could thus be a new therapeutic target for preventing target organ damage and subsequent cardiovascular events in hypertensive patients.