Takuma Etoh

Increased plasma adrenomedullin levels in chronic congestive heart failure

Adrenomedullin is a potent vasodilator peptide and occurs in circulating blood of human beings and experimental animals. Because it is produced in intact aorta of rats and in cultured vascular endothelial cells, adrenomedullin seems to participate in regulation of local vascular tone. To determine the pathophysiological roles of adrenomedullin, we investigated its plasma concentrations in 49 patients with heart failure. Plasma adrenomedullin levels increased significantly with advancing severity of the disease (New York Heart Association functional class I, 4.1 +/- 1.0; II, 5.6 +/- 1.6; III, 6.4 +/- 0.8; IV, 13.2 +/- 6.8 (fmol/l). Plasma adrenomedullin was correlated with pulmonary artery pressure (r = 0.44, p = 0.0114) and pulmonary capillary wedge pressure (r = 0.53, p = 0.0002). These findings indicate that adrenomedullin may play some important role in the pathophysiologic makeup of heart failure by its vasodilating effects against the concomitant exaggeration of humor pressor agents such as catecholamine and the renin-angiotensin system. Hemodynamic changes in pulmonary circulation may have some influence on the increased synthesis and secretion of plasma adrenomedullin in chronic congestive heart failure.

One-year effectiveness and safety of open-label losartan/hydrochlorothiazide combination therapy in Japanese patients with hypertension uncontrolled with ARBs or ACE inhibitors

The long-term antihypertensive efficacy and safety of losartan/hydrochlorothiazide (HCTZ) combinations have not been appropriately evaluated in Japan. In this study, treated hypertensive patients taking angiotensin-receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) regimens not at blood pressure (BP) goals proposed by the Japanese Society of Hypertension (JSH) were switched to losartan/HCTZ combinations and followed for 1 year. Data analysis included 244 patients aged 64.5±10.7 years, 56% male, 27% with diabetes mellitus and 36% with dyslipidemia. Pre-switching BP 157±16/88±10 mm Hg promptly decreased and maintained a steady state, reaching 132±15/77±9 mm Hg (P<0.001) 1 year later. After 1 year of treatment, 50% of patients cleared the goals of the JSH guideline for systolic BP and 79% for diastolic BP. Patients with maximal doses of ARBs tended to show larger decreases in BP (159±11/90±10 to 128±10/75±8 mm Hg, P<0.001, n=32). Clinical and laboratory adverse events were reported for 29 patients (11%), but serious abnormalities were not observed. In particular, plasma levels of uric acid (UA) were well-maintained for 1 year, and significant decreases in UA were observed in patients with higher levels of UA (⩾7.0 mg dl−1). Losartan/HCTZ combinations showed strong and steady hypotensive abilities and acceptable safety and tolerability in patients currently not at BP goals with regimens including ARBs or ACEIs in Japan.

Synergistic effect of chronic kidney disease and high circulatory norepinephrine level on stroke risk in Japanese hypertensive patients.

OBJECTIVE Evidence is now available about the association between chronic kidney disease (CKD) and stroke. However, less is known about the underlying mechanisms, and there is currently no reliable marker for identifying stroke-prone high-risk patients among CKD patients. METHODS A total of 514 hypertensive patients aged >50 years (mean, 72.3 years; 37% men) underwent 24-h BP monitoring and measurement of circulatory high-sensitivity C-reactive protein (hs-CRP) and norepinephrine at baseline. CKD was defined as eGFR<60 ml/min/1.73 m(2) using the Cockcroft-Gault equation. RESULTS AND CONCLUSION During an average of 41 months (1751 person-years), there were 43 stroke events. Compared with hypertensive patients without CKD, those with CKD (n=225) had higher levels of sleep systolic BP (SBP) (125 mmHg vs. 129 mmHg), circulatory hs-CRP (0.12 mg/L vs. 0.20 mg/L) and norepinephrine (332.2 pg/ml vs. 372.8 pg/ml; all P<0.05). On multivariable analysis, the hazard ratio (HR) (95% CI) for stroke in CKD vs. non-CKD was 2.7 (1.2-6.9) (P<0.05). CKD, as well as the baseline presence of silent cerebral infarction, sleep SBP increase, and high hs-CRP level (highest quartile: ≥0.42 mg/L) were independently and additively associated with stroke events; above all, there was a synergistic effect of CKD and high norepinephrine level (highest quartile: ≥538 pg/ml) on stroke risk (all P<0.05). Among hypertensive patients with CKD, those within the highest quartiles of norepinephrine had a greater stroke risk compared to those who were in the lower quartiles of norepinephrine (HR (95% CI): 2.2 (1.0-4.5); P=0.045). In conclusion, CKD is an independent predictor of stroke in Japanese hypertensive patients; in particular, hypertensive patients with CKD and a high norepinephrine level have a synergistically augmented stroke risk.

Three-Year Safety and Effectiveness of Fixed-Dose Losartan/Hydrochlorothiazide Combination Therapy in Japanese Patients with Hypertension Under Clinical Setting (PALM-1 Extension Study)

Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 ± 16/88 ± 11 mm Hg to 132 ± 13/75 ± 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1-year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension.

Diuretics enhance effects of increased dose of candesartan on ambulatory blood pressure reduction in Japanese patients with uncontrolled hypertension treated with medium-dose angiotensin II receptor blockers

Abstract Although blockade of the renin–angiotensin system by increasing the dose of angiotensin II receptor blockers (ARBs) is recommended to achieve clinical benefits in terms of blood pressure (BP) control and cardiovascular and renal outcomes, the effect of this increased dose on ambulatory BP monitoring has not been evaluated completely in Japanese patients with uncontrolled hypertension undergoing medium-dose ARB therapy. The primary objective of this study was to examine the effect of the relatively high dose of the ARB candesartan (12 mg/day) on 24-h systolic BP and the attainment of target BP levels in uncontrolled hypertension treated with a medium dose of ARBs. A total of 146 hypertensive patients (age: 69.9 ± 9.3 years; females: 65.8%) completed the study. After switching to candesartan at 12 mg/day, all these BP measurements decreased significantly (p < 0.001). Attainment of the target office BP (p = 0.0014) and 24-h BP levels (p = 0.0296) also improved significantly. Subgroup analysis indicated that the reduction of 24-h systolic BP was larger in patients treated with diuretics than those without (p = 0.0206). Multivariate analysis revealed a significant correlation between the combined ARB and diuretic therapy, and the change in 24-h systolic BP irrespective of preceding ARBs. In conclusion, the switching therapy to increased dose of candesartan caused significant reductions in office and ambulatory BP levels, and improved the attainment of target BP levels in patients with uncontrolled hypertension treated with a medium dose of ARBs. Combination with diuretics enhanced this effect.

Differences in 24-h blood pressure profile of Japanese hypertensive patients under ARB treatment.

Abstract Blood pressure (BP) control throughout the entire day is recommended for cardiovascular protection. Angiotensin-II receptor blockers (ARBs) are widely used in hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in 24-h BP profiles among ARBs. We examined ambulatory blood pressure monitoring (ABPM) among 211 Japanese hypertensive patients (age, 69.4 ± 9.6 years; female, 59.2%) under treatment with five different ARBs. Patients were divided into five groups according to ARBs prescribed. Patient backgrounds were almost identical in all the groups and there were no differences in office, 24-h and daytime BP; however, nighttime BP with olmesartan was significantly lower than with other ARBs. Office BPs with candesartan and telmisartan, but not other ARBs, correlated well with 24-h BP (p < 0.01). Also, there were higher correlations between daytime and nighttime BP with candesartan and telmisartan. In all patients, pulse pressure with office BP was significantly correlated with ambulatory arterial stiffness index (p = 0.001) and fluctuation of systolic BP on ABPM (p = 0.002). In conclusion, different ARB treatments produced meaningful differences in 24-h profiles.

566 EFFECT OF SWITCHING THERAPY FROM MEDIUM-DOSE OF ANGIOTENSIN II RECEPTOR BLOCKERS TO HIGH DOSE CANDESARTAN ON AMBULATORY BLOOD PRESSURE IN JAPANESE PATIENTS WITH UNCONTROLED HYPERTENSION

Objectives: Although blockade of renin-angiotensin system by increased dose of angiotensin II receptor blockers (ARBs) is recommended from the perspectives of clinical benefits on cardiovascular and renal outcomes, effect of high-dose ARBs on ambulatory blood pressure monitoring (ABPM) was not fully evaluated in Japanese patients with hypertension. The aim of present study was to examine the effect of switching therapy from medium-dose of ARBs to high-dose candesartan 12 mg on ABPM and office BP. Methods: 164 hypertensive patients (age, 69.9 ± 9.3 years; female, 65.8%) were enrolled. At baseline and 3- to 6-month-period after the switching, we examined ABPM, office BP and drug-related adverse effects. Results: Baseline values of 24-hour, day-time, night-time BPs obtained from ABPM and office BP were 139 ± 14/79 ± 9, 144 ± 15/82 ± 9, 129 ± 17/73 ± 10, 148 ± 17/82 ± 11 mmHg, respectively. After the switching therapy, 24-hour BP (135 ± 15/76 ± 9, p < 0.001), day-time BP (139 ± 15/80 ± 10, p < 0.001), night-time BP (125 ± 17/70 ± 10, p < 0.001) and office BP (134 ± 16/75 ± 10, p < 0.0001) decreased significantly. The attaining target level of office BP and that of ABPM also significantly improved (p < 0.05, respectively). Multivariate analysis indicated that there were significant correlations observed between baseline 24-hour systolic BP (ß = −0.29, p < 0.0001), past history of cardiovascular diseases (ß = 4.7, p < 0.05), diuretics use (ß = −5.4, p < 0.05) and the change in 24-hour systolic BP during the follow-up period. The estimated glomerular filtration rate was slightly but significantly decreased, however none of the patients exhibited clinically progressive renal dysfunction. Conclusions: Switching therapy from medium-dose ARBs to high-dose candesartan effectively decreased out of office BPs throughout 24-hour-period as well as office BP.

557 INTER-DRUG DIFFERENCES OF ARBS IN UNCONTROLLED HYPERTENSIVE PATIENTS

Background: Angiotensin-II receptor blockers (ARBs) are widely used for hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in clinical effects among each ARB or not. Methods: We enrolled uncontrolled hypertensive patients treated by any ARB alone or combined for clinical trials. Data of basic characteristics, blood test and ambulatory blood pressure monitoring (ABPM) were collected. We analyzed the data by each ARB. Results: We enrolled 211 patients treated with candesartan (74), valsartan (62), telmisartan (30), losartan (28) and olmesartan (17). Average office blood pressure (BP) was 150.7 ± 15.3 /83.0 ± 11.2 mmHg, and average 24-hour BP was 139.5 ± 13.9/78.2 ± 9.0 mmHg. There were no differences in office BP, 24-hour BP and day time BP among ARBs. But night time BP was significantly low in patients with olmesartan (p < 0.01), and the difference of BP between day time and night time was also large in patients with olmesartan. Although there were no differences in office and ambulatory BPs, ambulatory arterial stiffness index (AASI), a marker of arterial stiffness, was significantly high in patients with candesartan (candesartan 0.57 ± 0.12 vs. others 0.52 ± 0.10, p = 0.002). This difference was significant after adjustment of background. Conclusion: Although office BP distributes similar ranges, there may be some differences in 24-hour profile of ambulatory BP within each ARB, and the differences could be related future organ damages.