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Objectives: The randomized Jikei Heart Study has demonstrated that the addition of valsartan to conventional treatments prevents more cardiovascular events in Japanese patients with hypertension. This substudy analyses the sex difference in cardiovascular disease risk reduction in the Jikei Heart Study., Methods: Treatment effects were evaluated by sex (1038 women and 2043 men) as hazard ratios with 95% confidence intervals (CIs) using Cox regression models adjusted for age, BMI, smoking, dyslipidemia, diabetes, antihypertensives, and statin use at baseline., Results: Women were older, had higher SBP, total and low-density lipoprotein cholesterol but were less frequently smokers or diabetics, and had a lower DBP and incidence of coronary artery disease. A greater incidence of primary endpoint, a composite of cardiovascular events, occurred in men versus women [hazard ratio 1.37 (95% CI 1.02-1.85)]. Men in the valsartan group had a significant reduction in the primary endpoint [hazard ratio 0.6 (95% CI 0.44-0.82), P = 0.001], whereas a nonsignificant effect was found in women [hazard ratio 0.64 (95% CI 0.39-1.06), P = 0.075]. However, statistical heterogeneity of this valsartan effect was not found between sexes, and women of at least 55 years of age, mostly after menopause, in the valsartan group showed a significant risk reduction for the primary endpoint [hazard ratio 0.60 (95% CI 0.36-0.99)]., Conclusion: The valsartan effect was significant in men and in elderly women but consistent in both sexes. A potential cardiovascular protection by valsartan therapy might be attributed to the cardiovascular risk level but not to the sex difference.

Background: Recent studies suggest that B-type natriuretic peptide (BNP) is an important predictor of cardiac events in hypertensive patients., Methods and Results: The relationship between the plasma BNP level and various clinical parameters was examined in 154 untreated hypertensive patients without heart failure or atrial fibrillation (mean age: 58.0+/-10.7; mean blood pressure: 164.5+/-15.2/99.1+/-9.7 mmHg; mean BNP: 32.7+/-36.7 pg/ml). First, the patients were divided into 2 groups based on BNP: normal (<18.5 pg/ml, mean 9.7+/-5.7, n=69); or elevated (>18.5 pg/ml, mean 51.4+/-40.4, n=85). The elevated BNP group had a significantly greater electrocardiographic voltage index (SV1+RV5; 3.7+/-1.2 vs 3.2+/-0.8 mV, p=0.0029), cardiothoracic ratio/chest radiography (CTR; 49.1 vs 46.9%, p=0.0037), left ventricular mass index (LVMI; 122.2+/-31.7 vs 103.1+/-26.4 g/m2, p=0.0005) and deceleration time (DT; 241+/-39 vs 208+/-30 ms, p=0.0001), as well as a smaller E-wave to A-wave (E/A ratio) (0.80+/-0.22 vs 0.96+/-0.28, p=0.0003), compared with the normal BNP group. There were no significant differences in casual blood pressure, body mass index, serum creatinine and ejection fraction between the 2 groups. Next, the patients were divided into 3 groups based on BNP: normal (<18.5, n=69), moderate (18.5 to 40, mean 27.0+/-5.7, n=43) and high (40<, mean 76.3+/-45.3, n=42). In the high BNP group, most clinical parameters indicated the most severe organ damage compared with other groups, including SV1+RV5, DT and LVMI. In all patients, logarithmic BNP was positively correlated with the age, pulse pressure, SV1+RV5, CTR, ventricular wall thickness, DT, LVMI and negatively correlated with hemoglobin, renin and E/A ratio. Using multiple regression analysis, renin and DT were significantly associated with BNP. No gender differences in the relationship between BNP and clinical parameters were found., Conclusions: Results suggest that BNP is a useful indicator for the initial assessment of the severity of essential hypertension, detecting both cardiac hypertrophy and diastolic dysfunction, and may also be valuable for risk stratification.

Background: Drugs that inhibit the renin-angiotensin-aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease., Methods: We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20-79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40-160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328., Findings: After a median follow-up of 3.1 years (range 1-3.9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21.3 vs 34.5 per 1000 patient years; hazard ratio 0.61, 95% CI 0.47-0.79, p=0.0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0.60, 0.38-0.95, p=0.028), angina pectoris (19 vs 53; 0.35, 0.20-0.58, p<0.0001), and heart failure (19 vs 36; 0.53, 0.31-0.94, p=0.029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups., Interpretation: The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

Background: Angiotensin II receptor blockers (ARB) are now commonly used to treat hypertension because of their beneficial effects on cardiovascular remodeling. However, ARB treatment can not inhibit the left ventricular (LV) remodeling sufficiently, which may be related with aldosterone secretion. To inhibit the action of aldosterone during ARB treatment, the additional effects of an aldosterone blocker and spironolactone (SPRL) on LV hypertrophy in patients with essential hypertension was studied., Methods and Results: The patients with essential hypertension were randomly divided into 2 groups; 1 group was treated with an ARB, candesartan (8 mg/day), for 1 year (ARB group) and other group was treated with the ARB for the first 6 months and with the ARB plus SPRL (25 mg/day) for the next 6 months (combination group). Seventy patients who underwent echocardiography every 6 months were analyzed and were also classified into 4 subgroups of LV geometric pattern according to the LV mass index (LVMI) and the relative wall thickness (RWT). The ARB treatment and the addition of SPRL significantly reduced the blood pressure, however, both treatments did not affect the LV geometry in both groups. The ARB treatment in the subgroups of concentric LV remodeling (RWT>or=0.45 and LVMI<125) and concentric LV hypertrophy (RWT>or=0.45 and LVMI>or=125) significantly reduced RWT. However, ARB treatment in all subgroups did not affect LVMI. The addition of SPRL only in the concentric LV hypertrophy subgroup significantly reduced the LVMI, despite similar changes in blood pressure., Conclusions: These results indicated that the addition of SPRL treatment during the ARB treatment and conventional treatments is clinically useful to reduce the LVMI in hypertensive patients with concentric LV hypertrophy; however, does not improve the eccentric LV hypertrophy.

Background: Several recent clinical trials have demonstrated that angiotensin II receptor blockers (ARBs) have cardiovascular as well as renal protective effects. Asian patients including Japanese were under-represented in these trials, however, and no large-scale clinical trials of ARBs have yet been performed in Japan. It is therefore important to verify that the results of these studies are also valid for Japanese patients. The JIKEI HEART Study has been designed to investigate whether concomitant treatment with valsartan, an angiotensin II receptor blocker, in addition to conventional treatment, will improve the prognosis of Japanese patients with cardiovascular diseases (hypertension, ischemic heart disease, congestive heart failure)., Method and Evaluation of Results: Around 3,000 patients with hypertension, ischemic heart disease and/or congestive heart failure will be randomized to receive either additional treatment with valsartan (80 mg/day) or conventional therapy. The follow-up period will be three years. The primary endpoint will be the onset of any cardiovascular event. Secondary endpoints will include death from any cause, changes in left ventricular size and function, renal function, changes in neuro-hormonal levels and quality-of-life assessments. Sub-studies will explore the effect in patients with diabetes mellitus, hyperlipidemia and the effects of combination of drugs., Conclusion: Improved prognosis would confirm the role of angiotensin II receptor blockers in the treatment of the cardiovascular disease in Japanese patients.

To clarify the correlation between intracellular Ca2+ dynamics and level of Ca2+-regulatory proteins, changes in Ca2+ handling and these proteins were investigated in a whole-heart experimental model of pressure-overload hypertrophy. We used 17-18-week-old male Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) fed a high-salt diet. We monitored the fura-2 fluorescence ratio, an index of cytoplasmic Ca2+ concentration ([Ca2+]i), using a Ca2+ analyzer in a retrograde perfused heart. Left ventricular pressure (LVP) and an electrocardiogram were simultaneously recorded. Ca2+ handling was assessed by exposing the hearts to 2 min of low-Na+ (70 mmol/l) perfusion to produce an increase in [Ca2+]i (n = 6), which was sensitive to Ni2+, a blocker of the Na+/Ca2+ exchanger (NCX). In another series, the hearts were stimulated at 2.5 to 5 Hz to determine the Ca2+-force-frequency relationship (n = 6). DS rats showed marked cardiac hypertrophy without any signs of failure. The time-to-peak Ca2+ transient was prolonged in DS compared with that in DR during normal beating. During low-Na+ exposure, the time-to-peak diastolic [Ca2+]i (TTP) and the decay-time from peak [Ca2+]i (DT) were prolonged in DS compared with DR (TTP, 43.3 +/- 4.0 vs. 32.5 +/- 2.5 s, p < 0.05; DT, 70.0 +/- 8.8 vs. 29.2 +/- 2.7 s, p < 0.005). Following pretreatment with 10 mmol/l caffeine to inhibit sarcoplasmic reticulum (SR) function, TTP and DT were still prolonged in DS compared with DR (TTP, 64.2 +/- 9.7 vs. 37.0 +/- 5.8 s, p < 0.05; DT, 55.8 +/- 12.6 vs. 26.0 +/- 5.7 s, p < 0.05). The force (LVP)-frequency relationship was initially positive in DR but was negative at all times in DS (%LVP/2.5 Hz: DS, 90.3 +/- 2.0%; DR, 112.2 +/- 4.5%; p < 0.05). Elevation of diastolic [Ca2+]i (percent increase of baseline) was greater in DS than in DR with increased stimulation (5 Hz: DS, 80.7 +/- 6.7%; DR, 52.1 +/- 5.9%; p < 0.05). In Western blot analysis, the protein level of NCX was equivalent, whereas that of SR Ca2+ ATPase (SERCA2) was significantly decreased in DS compared with DR. These results suggest that slowing of cellular Ca2+ mobilization and removal is related to impaired Ca2+ handling in late-phase cardiac hypertrophy. Both the activity of the NCX and that of the SR may be affected. The SR dysfunction may be associated with change in protein level of SERCA2.

Studies have shown that the renin-angiotensin system (RAS) plays an important role in cardiac remodeling induced by hypertension. However, the role of this system on myocyte remodeling remains unclear. In the present study, we have assessed the effect of perindopril, an angiotensin converting enzyme (ACE) inhibitor, in spontaneously hypertensive rats (SHRs) as a means to evaluate the role of RAS in myocyte remodeling. We also investigated the effect of beta blockade on myocyte remodeling. We used female SHRs at 12 weeks of age. They were divided into four experimental groups: a control group, group C; low dose perindopril group (0.3 mg/kg/day, p.o.), group PL; high dose perindopril group (3 mg/kg/day, p.o.), group PH; and bisoprolol group (60 mg/kg/day, p.o.), group B. We isolated myocytes from these rats after 4 weeks. LV myocyte volume and cross-sectional area decreased in groups PL and PH compared to group C. LV myocyte length decreased in group PH compared to group C. However, there was no morphological change in LV myocytes in group B compared to group C. In summary, ACE inhibitors reversed cardiac hypertrophy mainly by a reduction in LV myocyte volume; however, beta blockade did not reverse myocyte remodeling. These results suggest that RAS plays an important role in myocyte remodeling in the hypertensive heart.

Renin-angiotensin system activity has been shown to affect insulin sensitivity. However, the relationship between I/D polymorphism and insulin resistance is controversial. Therefore, we examined the relationship between the ACE genotype and insulin sensitivity in 51 Japanese hypertensive patients using the glucose clamp technique. The ACE genotype distribution in the hypertensive subjects was: 7 subjects with DD, 20 subjects with ID, and 24 subjects with II. Insulin sensitivity in terms of the glucose disposal rate was not significantly different among the three ACE genotypes, although there was a tendency for insulin sensitivity to decrease in the order of II, ID and DD, DD being the lowest. These findings are contrary to previous reports that insulin sensitivity was increased in normotensive subjects with the DD genotype who were Caucasian or African-American. There might be a difference due to race and whether the subjects are hypertensive or obese. We concluded that insulin sensitivity was not different among the ACE genotypes in the Japanese hypertensive subjects, supporting a previous report on the Chinese population. To date, insulin sensitivity has not been found to differ with ACE genotypes in the oriental population.

To determine the effects of insulin on intracellular calcium and platelet aggregatory responses in hypertensive subjects with insulin resistance, we measured insulin sensitivity in terms of glucose disposal rate (GDR) by the hyperinsulinemic euglycemic clamp technique (GC) in 14 non-diabetic untreated hypertensive subjects, and determined basal ([Ca2+]i) and thrombin-stimulated (T-[Ca2+]i) platelet-free calcium concentrations and thrombin-stimulated platelet aggregatory response (AG) before (PRE[Ca2+]i, T-PRE[Ca2+]i, and PRE AG, respectively) and during (POST[Ca2+]i, T-POST[Ca2+]i, and POST AG, respectively) GC. As a control for GC, vehicle (normal saline) was infused on another day. No significant difference was observed between PRE[Ca2+]i and POST[Ca2+]i, T-PRE[Ca2+]i and T-POST[Ca2+]i, or PRE AG and POST AG, GDR inversely correlated with delta[Ca2+]i (POST [Ca2+]i-PRE[Ca2+]i, r = -0.75, p < 0.02), delta T-[Ca2+]i, (T-POST[Ca2+]i-T-PRE[Ca2+]i, r = -0.63, p < 0.02) and delta AG (POST AG-PRE AG, r = -0.67, p < 0.01). No significant changes were observed in these variables during vehicle infusion. [Ca2+]i, T-[Ca2+]i, and AG decreased during GC as compared with baseline in hypertensive subjects with normal insulin sensitivity, but were unchanged in those with insulin resistance, suggesting that the vasodilatory and anti-platelet aggregatory effects of insulin are impaired in patients with insulin-resistant hypertension.

Insulin sensitivity in terms of glucose disposal rate was measured by the hyperinsulinemic/euglycemic clamp technique in 10 hypertensive patients and 7 normotensive control subjects before and after 12 weeks of doxazosin therapy. Supine blood pressure fell significantly, from 150/98 mmHg before treatment to 136/90 mmHg after treatment (systolic P < 0.001/diastolic P < 0.01). The average dose of doxazosin at the end of the study was 3.3 +/- 0.4 mg/day. The glucose disposal rate during the last 30 minutes of the glucose clamp procedure was significantly increased, from 5.8 +/- 0.7 mg/kg/min before to 7.8 +/- 0.7 mg/kg/min after treatment (P < 0.02). Insulin sensitivity was 8.7 +/- 0.4 mg/kg/min in the normotensive subjects, which represented a significant difference when compared with that of the hypertensive subjects before treatment (P < 0.01). Steady-state serum insulin concentrations, as measured during the glucose clamp procedure, were 172 +/- 10.4 microU/ml before and 176 +/- 13.5 microU/ml after doxazosin treatment; these levels were significantly higher than the 137 +/- 7.0 microU/ml reading obtained in the normotensive subjects (P < 0.05). Study results show that hypertensive patients tend to be insulin resistant and that treatment with doxazosin improves insulin sensitivity.

In order to assess myocardial hypertrophic activity during the process of hypertensive cardiac hypertrophy in the presence and absence of treatment with anti-hypertensive agents, we analyzed myocardial polyamine concentrations in spontaneous hypertensive (SHR) rats and control rats of Wistar Kyoto (WKY) strain. The anti-hypertensive agents studied were diltiazem, hydralazine and captopril, each of which was administered for 5 weeks. In comparison with WKY rats, SHR rats showed elevated blood pressure and enlarged hearts with higher myocardial spermidine concentration. Although blood pressure was lowered in the diltiazem-treated SHR rats, heart weight and myocardial spermidine concentration increased as in untreated SHR rats. In the hydralazine-treated group increases in both blood pressure and myocardial spermidine concentration were suppressed, while an increase in heart weight was not. In the captopril-treated group, increases in blood pressure, heart weight and spermidine concentration were all suppressed. Since spermidine level appears to be a sensitive indicator of hypertrophic activity in the heart, this study suggests that captopril exerts an inhibitory effect on hypertensive cardiac hypertrophy whereas diltiazem does not. It also suggests that hypertrophy may reach a certain plateau level earlier in the hydralazine-treated animals than in others.