Discovery of orexin 2 receptor selective and dual orexin receptor agonists based on the tetralin structure: Switching of receptor selectivity by chirality on the tetralin ring.

A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (-)-6 having a (S)-1-amino-tetralin skeleton showed a OX2R selective agonist activity (EC50 = 2.69 nM for OX2R, OX1R/OX2R = 461) yet its enantiomer (R)-(+)-6 showed a potent OX1/2R dual agonist activity (EC50 = 13.5 nM for OX1R, 0.579 nM for OX2R, OX1R/OX2R = 23.3). These results suggested that upward orientation of the amide side chain against the tetralin scaffold (S-configuration) would be selective for OX2R activation, and the downward orientation (R-configuration) would be significant for dual agonist activity. To our best knowledge, there have been no reports thus far that the stereochemistry of one carbon center on the agonist structure regulates the orexin receptor selectivity. Our results would provide important information for the development of OX1R selective agonists.

Differences in brain natriuretic peptide and other factors between Japanese peripheral arterial disease patients with critical limb ischemia and intermittent claudication.

AIM: The goal of this study was to analyze differences in risk factors, including the level of brain natriuretic peptide (BNP) and the distribution of lesions, between cases of critical limb ischemia (CLI) and intermittent claudication (IC) among patients with peripheral arterial disease. METHODS: Risk factors and clinical characteristics were prospectively investigated in 817 consecutive patients, including 185 patients with CLI and 632 patients with IC. RESULTS: The patients in the CLI group were older than those in the IC group (p＜0.001). The prevalence of diabetes and cerebral infarction and the proportion of women were higher in the CLI group (p＜0.05). The plasma BNP levels in the CLI group were higher than those observed in the IC group (333±538 vs. 136±354 pg/mL, p＜0.001). In contrast, the levels of homocysteine and fibrinogen were higher and the levels of albumin and the estimated glomerular filtration rate were lower in the CLI group (p＜0.05). According to a multiple logistic analysis, the BNP level, diabetes, female gender, the albumin level, body mass index (BMI) and ankle-brachial pressure index (ABI) were associated with CLI (p＜0.05). Aortoiliac artery lesions were less common, whereas femoropopliteal and below-the-knee (BK) lesions were more common, in the CLI group (p＜0.05). The number of affected BK arteries was also higher in the CLI group (p＜0.001). Correlations were found between the presence of aortoiliac lesions and smoking and a low HDL cholesterol level, while femoropopliteal lesions were found to correlate with age, BMI and hypertension and BK lesions were found to correlate with diabetes, age, female gender and BMI (p＜0.05). The plasma BNP level correlated with the number of affected BK arteries (p＜0.05). CONCLUSIONS: A high BNP level, diabetes, female gender, a low albumin level, ABI and BMI are risk factors for CLI. In this study, differences in the levels of anatomical lesions and correlated risk factors were found between the CLI and IC groups.

Effects of mineralocorticoid receptor antagonist spironolactone on cardiac sympathetic nerve activity and prognosis in patients with chronic heart failure.

BACKGROUND: Aldosterone prevents norepinephrine uptake and promotes structural remodeling of the heart. Spironolactone is well known to have an anti-aldosteronergic effect, and this agent could improve cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF). On the other hand, we previously reported that the delta washout rate (WR) determined from serial (123)I-MIBG scintigraphic studies is the best currently available prognostic value in patients with CHF. METHODS: In total 208 patients with CHF (left ventricular ejection fraction [LVEF] <45%), but no cardiac events for at least 5 months, were identified on the basis of a history of decompensated acute heart failure requiring hospitalization. These patients underwent (123)I-MIBG scintigraphy and echocardiography just before leaving the hospital and after 6 months of treatment. The patients were retrospectively divided into a spironolactone (n=82) and a non-spironolactone (n=126) group. RESULTS: The extents of changes in (123)I-MIBG scintigraphic and echocardiographic parameters in the spironolactone group were significantly better than those in the non-spironolactone group. Of the 208 patients, 56 experienced fatal cardiac events during the study. The mean follow-up period was 4.45+/-1.82 years. On Kaplan-Meier analysis, the rate freedom from cardiac death was 81.7% (67/82) in the spironolactone group and 67.5% (85/126) in the non-spironolactone group (P<0.05). Moreover, stepwise multivariate analyses showed spironolactone therapy to have the most independent and significant negative relationship with delta-WR, during the period from hospital discharge until 6 months after starting treatment, in patients with CHF (P<0.001). CONCLUSIONS: Spironolactone treatment improves CSNA and prevents LV remodeling in patients with CHF. Furthermore, this agent is potentially effective for reducing the incidence of fatal cardiac events in CHF patients.

Prevalence and risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease.

OBJECTIVE: The purpose of the study was to examine the prevalence and risk factors for cerebral infarction (CI) and carotid artery stenosis (CAS) in patients with peripheral arterial disease (PAD) compared with normal controls. METHOD: A cross-sectional analysis was performed in 857 subjects (PAD: 543, controls: 314). CI and lacunar infarction (LI) were evaluated using brain computed tomography. Intima-media thickening (IMT) and CAS were measured with ultrasound. RESULTS: The prevalences of CI and LI were higher in patients with PAD than in controls (15.0% vs. 9.8%, 41.0% vs. 13.4%, respectively, p < 0.05). In multiple logistic analysis, CI was associated with diabetes mellitus, low HDL cholesterol and CAS ≥ 70% (p < 0.05). LI was associated with age, PAD, diabetes mellitus, and estimated glomerular filtration rate (p < 0.05). The prevalences of CAS ≥ 70% and CAS ≥ 50% were higher in patients with PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%, respectively, p < 0.01). Mean and max IMT differed significantly between the two groups (PAD vs. controls: 1.01 ± 0.45 vs. 0.90 ± 0.28, 2.67 ± 2.00 vs. 1.73 ± 1.05 mm, respectively, p < 0.001). CAS ≥ 70% correlated with high LDL cholesterol, and CAS ≥ 50% with age and PAD. IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (p < 0.05). CONCLUSIONS: Prevalences of CI and CAS were markedly higher in patients with PAD than in controls, indicating that PAD is a meaningful risk factor for CI, LI, and CAS. This suggests that screening for CI and CAS is important for managements in PAD, as with screening for PAD in patients with stroke.

Sex-related differences in Japanese patients with peripheral arterial disease.

OBJECTIVE: The goal of the study was to examine possible sex-related differences in the clinical characteristics and risk factors in Japanese patients with peripheral arterial disease (PAD). METHODS: Sex-related differences in clinical profiles, risk factors and treatments were examined in 730 consecutive patients with PAD (148 women (20.3%) and 582 men (79.7%)). RESULTS: The mean age of the women was higher than that of the men (73.6 ± 11.2 vs. 70.9 ± 9.1 years old, p = 0.002) and the proportion of subjects aged ≥ 75 years old was also higher in women (P=0.005). Women more frequently had critical limb ischemia (P < 0.001) and diabetes mellitus (P = 0.026), but less frequent smoking and alcohol intake, compared to men (P< 0.001). Total cholesterol (P < 0.001) and LDL cholesterol (P = 0.014) were higher in women. Fontaine stages were correlated with age, diabetes, cerebral infarction and women (p < 0.001). The prevalence of iliac artery lesions was higher in men (p< 0.001), whereas that for below the knee lesions was higher in women (p < 0.001). The number of affected below the knee arteries was also higher in women than in men (p < 0.001). The prevalence of medical treatment was higher in women (P = 0.009) and major amputation tended to be higher in women (p = 0.056). CONCLUSIONS: Women had more severe symptomatic states and uncontrolled risk factors. The prevalence of iliac artery lesions was lower, but below the knee lesions were more severe in women.

Effects of spironolactone on cardiac sympathetic nerve activity and left ventricular remodelling after reperfusion therapy in patients with first ST-segment elevation myocardial infarction.

OBJECTIVE: To evaluate the effects of spironolactone on cardiac sympathetic nerve activity (CSNA) and left ventricular (LV) remodelling in patients with ST-segment elevation myocardial infarction (STEMI). DESIGN: Single-centre, prospective, randomised evaluation study. SETTING: Patients with a first STEMI and single-vessel disease undergoing primary coronary angioplasty. PATIENTS: Sixty patients randomly assigned to two groups before angioplasty. INTERVENTIONS: Patients were randomly assigned to receive or not the spironolactone before primary coronary angioplasty. MAIN OUTCOME: The extent score (ES) was determined by use of (99m)Tc-pyrophosphate scintigraphy to evaluate the area of initial myocardial damage 3-5 days after primary angioplasty. The LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LV ejection fraction were determined by echocardiography, and plasma procollagen type III aminoterminal peptide (PIIINP) was measured before and 3 weeks after treatments. The delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS) and washout rate (WR) were determined from ¹²³I-meta-iodobenzylguanidine scintigraphy after 3 weeks. RESULTS: After primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine kinase concentration, recanalisation time and ES were similar in the two groups. However, in the spironolactone group, the TDS and WR were significantly lower (TDS: mean (SD) 22.5 (8.0) vs 29.5 (10.1), p<0.005, WR: 30.5 (8.7)% vs 40.0 (10.9)%, p<0.001) and the H/M ratio was significantly higher (2.18 (0.37) vs 1.96 (0.30), p<0.05) than in the non-spironolactone group. Moreover, significant correlations were found between the degree of change in PIIINP concentration and change in LVEDV (r=0.559, p=0.001), or LVESV (r=0.546, p=0.002) in the spironolactone group. CONCLUSION: Administration of spironolactone improves CSNA and prevents LV remodelling in patients with a first STEMI.

Prognostic value of cardiac sympathetic nerve activity evaluated by [123I]m-iodobenzylguanidine imaging in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Many studies have shown that cardiac sympathetic nerve activity evaluated by [(123)I]m-iodobenzylguanidine ([(123)I]MIBG) scintigraphic study during a stable period is useful for determining the prognosis of patients with chronic heart failure. OBJECTIVE: To examine whether results of this imaging method performed 3 weeks after the onset of ST-segment elevation myocardial infarction (STEMI) are a reliable prognostic marker for patients with STEMI. METHODS: The study analysed findings for 213 consecutive patients with STEMI undergoing [(123)I]MIBG scintigraphy. The left ventricular (LV) end-diastolic and end-systolic volume and LV ejection fraction (EF) were determined by left ventriculography or echocardiography 3 weeks after the onset of STEMI. The delayed total defect score, heart-to-mediastinum ratio and washout rate (WR) were also determined from [(123)I]MIBG scintigraphy at the same time. RESULTS: Of the 213 patients, 46 experienced major adverse cardiac events (MACE) during the study. The median follow-up period was 982 days. Patients were divided into an event-free group (n = 167; 78.4%) and a MACE group (n = 46; 21.6%). The LV and [(123)I]MIBG scintigraphic parameters in the event-free group were better than those in the MACE group. Multivariate Cox regression analyses revealed that WR was a significant predictor of MACE along with oral nicorandil (ATP-sensitive potassium channel opener) treatment and undergoing percutaneous coronary intervention. On Kaplan-Meier analysis, the event-free rate of patients with a WR<40% was significantly higher than that in patients with a WR ≥ 40% (p<0.001). Even when confined to patients with LVEF>45%, WR was a predictor of MACE, pump failure death, cardiac death and progression of heart failure in patients with STEMI. CONCLUSION: WR evaluated by [(123)I]MIBG scintigraphy 3 weeks after the onset of STEMI is a significant predictor of MACE in patients with STEMI, independent of LVEF.

Serial cardiac 123I-metaiodobenzylguanidine scintigraphic studies are more useful for predicting cardiac death than one-time scan in patients with chronic heart failure: sub-analysis of our previous report.

BACKGROUND: Many studies have shown a one-time ¹²³I-metaiodobenzylguanidine (MIBG) scan during a stable period to be useful for determining the prognosis of patients with chronic heart failure (CHF). However, we recently reported that the delta washout rate (WR) determined from serial ¹²³I-MIBG scintigraphic studies is the best prognostic value in patients with CHF. METHODS: A total of 208 patients with CHF (left ventricular ejection fraction <45%), but no cardiac events for at least 5 months, were identified on the basis of a history of decompensated acute heart failure requiring hospitalization. The patients underwent ¹²³I-MIBG scintigraphy and echocardiography just before leaving the hospital and after 6 months of treatment. We evaluated two models for predicting cardiac death using the Cox proportional hazards regression analysis. In addition to clinical characteristics, New York Heart Association functional class and pharmacotherapy, one model included variables of baseline scintigraphic and echocardiographic parameters (model A), and the other model included those of delta (i.e. follow-up minus baseline) scintigraphic and echocardiographic parameters (model B). RESULTS: Of the 208 patients, 56 experienced fatal cardiac events during the study. In model A, a Cox proportional hazards analysis showed baseline WR ≥50% to be the only independent predictor of cardiac death (hazard ratio=2.335, 95% confidence interval=1.142-4.774, P=0.020). In model B, delta-WR≥-5% was the only incremental predictor of cardiac death (hazard ratio=4.444, 95% confidence interval=1.511-13.069, P=0.009). The survival rates of patients with a delta-WR of less than -5% were significantly higher for those with a baseline WR of less than 50% (P=0.036). Moreover, high delta-WR was the best predictor compared with single scan, single echocardiography, and their combination evaluated by the global χ² analysis. CONCLUSION: Baseline WR and delta-WR obtained from ¹²³I-MIBG scintigraphy can be used as independent predictors of cardiac death, and two ¹²³I-MIBG scintigraphic studies are more useful than a one-time scan in stabilized patients with CHF.

Long-term effects of telmisartan on blood pressure, the renin-angiotensin-aldosterone system, and lipids in hypertensive patients.

We prospectively evaluated long-term (12 months) effects of telmisartan on blood pressure (BP), circulating renin-angiotensin-aldosterone levels, and lipids in hypertensive patients. There were 13 men and 11 women, 59 +/- 8.7 years of age (mean +/- SEM), with untreated essential hypertension. The 20-60 mg doses of telmisartan were administered once daily in the morning until BP130/85 was obtained. Blood pressure and plasma renin activity, plasma angiotensin (Ang) I and Ang II, serum angiotensin-converting enzyme (ACE) activity, plasma aldosterone concentration, plasma human atrial natriuretic peptide (hANP) concentration, and serum lipids were obtained 6 and 12 months after starting telmisartan administration. Systolic and diastolic BP were significantly (P < 0.001, P < 0.001) decreased from 162 +/- 3.3 and 97.7 +/- 2.1 mmHg to 128 +/- 3.8 and 79.6 +/- 2.0 mmHg after 12 months of treatment, respectively. Plasma Ang I and Ang II were unchanged at 12 months. Plasma renin activity and serum ACE activity were significantly (P < 0.001, P < 0.05) increased and plasma aldosterone concentration was unchanged during the study period. Total cholesterol levels were unchanged, but serum triglycerides levels were significantly decreased at 12 months (P < 0.01). Plasma hANP showed no significant alteration throughout the 12-month period. In hypertensive patients, telmisartan is a beneficial antihypertensive drug that also lowers serum triglycerides.

Effects of raloxifene on brachial arterial endothelial function, carotid wall thickness, and arterial stiffness in osteoporotic postmenopausal women.

The beneficial effects of raloxifene, a selective estrogen receptor modulator, on cardiovascular risks and events have been investigated. Brachial arterial flow-mediated vasodilatation (FMD), carotid intima-media thickness (IMT), and pulse wave velocity (PWV) have been widely used in clinical settings as surrogate markers of atherosclerosis. This study investigated the simultaneous effects of raloxifene on brachial arterial FMD, carotid IMT, and PWV in osteoporotic postmenopausal women. A total of 31 postmenopausal women with osteoporosis or osteopenia were divided into 2 groups: a raloxifene group (n = 15; mean age +/- SD, 66.1 +/- 8.2 years) was treated with raloxifene hydrochloride (60 mg/day) orally for 12 months, and an untreated control group (n = 16; 64.1 +/- 7.8 years). Brachial arterial FMD, carotid IMT, and brachial-ankle PWV (baPWV) were measured at baseline and at 12 months after the start of the study. The brachial arterial FMD increased significantly, from 4.5 +/- 1.8% to 9.2 +/- 3.0%, in the raloxifene group (P < 0.01) but did not change in the control group. Nitroglycerin-induced vasodilatation did not change in either group. The carotid IMT decreased significantly, from 0.82 +/- 0.15 mm to 0.72 +/- 0.11 mm, in the raloxifene group (P < 0.01) but did not change in the control group. The baPWV did not change in either group. In conclusion, raloxifene may have beneficial effects on brachial arterial endothelial function and carotid wall thickness in osteoporotic postmenopausal women.

Effects of raloxifene on the renin-angiotensin-aldosterone system and blood pressure in hypertensive and normotensive osteoporotic postmenopausal women.

AIM: An increase in blood pressure after menopause has been documented. The renin-angiotensin-aldosterone system (RAAS) plays a central role in the regulation of blood pressure and in the pathophysiology of hypertension. This study investigated the effects of raloxifene, a selective estrogen receptor modulator, on components of the RAAS and blood pressure in hypertensive and normotensive osteoporotic postmenopausal women. METHODS: A total of 41 hypertensive or normotensive postmenopausal women with osteoporosis or osteopenia were divided into four groups. Eleven hypertensive and eight normotensive women received raloxifene hydrochloride (60 mg/day) p.o. for 6 months, and 12 hypertensive and 10 normotensive women did not receive raloxifene hydrochloride for 6 months. In all of the hypertensive women, blood pressure had been controlled prior to the start of the study using a variety of antihypertensive drugs other than angiotensin-converting enzyme (ACE) inhibitors, angiotensin (Ang)II type 1 receptor antagonists or diuretics. Plasma renin activity (PRA), serum ACE activity, plasma AngI, AngII and aldosterone concentrations, and blood pressure were measured before and 6 months after the start of the study. RESULTS: No significant changes in PRA, ACE activity, or the AngI, AngII or aldosterone levels were observed in any of the groups. In all the groups, blood pressure remained unchanged. CONCLUSION: Raloxifene may have no significant effect on the RAAS or blood pressure in hypertensive and normotensive osteoporotic postmenopausal women.

Relationship between carotid atherosclerosis and lumbar spine bone mineral density in postmenopausal women.

Osteoporosis and increased carotid intima-media thickness (IMT) have been associated with atherosclerosis. We investigated the correlation between carotid IMT and lumbar spine bone mineral density (BMD) in postmenopausal women. We studied the carotid IMT in 175 postmenopausal women, including 43 women (control) with normal spinal BMD, 73 women with osteopenia, and 59 women with osteoporosis. Carotid IMT was assessed by ultrasonography. BMD at the lumbar spine (lumbar 2 to 4 vertebrae) was measured by dual-energy X-ray absorptiometry. Age, years since menopause, and carotid IMT were significantly greater in the osteoporosis group than in the control (all p<0.01) and osteopenia groups (all p<0.01). Estradiol was significantly lower in the osteoporosis group than in the control group (p<0.05). BMD was significantly lower in the osteoporosis group than in the osteopenia or control group (both p<0.01) and in the osteopenia group than in the control group (p<0.01). After adjusting for age, years since menopause, and estradiol, women with osteoporosis had significantly greater carotid IMT than controls (p<0.05). The univariate linear regression analysis revealed that carotid IMT was significantly positively correlated with age, years since menopause, and low-density lipoprotein (LDL) cholesterol (all p<0.05) and was significantly negatively correlated with estradiol and BMD (all p<0.05), but showed no significant association with other clinical variables. In multivariate regression analysis, the carotid IMT was significantly positively correlated with LDL cholesterol (p<0.01) and negatively correlated with BMD (p<0.01), but not with other variables. Carotid atherosclerosis might be associated with lumbar spine bone mass in postmenopausal women, suggesting that postmenopausal women with osteoporosis may have more advanced carotid atherosclerosis than those with a normal bone mass.

Prognostic value of serial cardiac 123I-MIBG imaging in patients with stabilized chronic heart failure and reduced left ventricular ejection fraction.

UNLABELLED: Many studies have shown that a one-time 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphic study during a stable period is useful for determining the prognosis of patients with chronic heart failure (CHF). However, the findings from this imaging modality are well known to be improved by medical treatment for heart failure. Accordingly, this study was performed to determine whether serial 123I-MIBG scintigraphic studies represent a reliable prognostic marker for patients with CHF. METHODS: A total of 208 patients with CHF (left ventricular ejection fraction [LVEF] < 45%) and with no cardiac events for at least 5 mo were identified on the basis of a history of decompensated acute heart failure requiring hospitalization. The delayed percentage of denervation (% denervation), delayed heart-to-mediastinum count (H/M) ratio, and washout rate (WR) were determined from the patients' 123I-MIBG images just before they left the hospital and after they had received 6 mo of treatment. The left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and LVEF were also determined by echocardiography at the same time points. RESULTS: Of the 208 patients, 56 experienced fatal cardiac events during the study. The mean follow-up period was 4.45 +/- 1.82 y. The baseline H/M ratio and WR; follow-up % denervation, H/M ratio, and WR; Delta-% denervation, H/M ratio, and WR; baseline LVEF; follow-up LVEDV, LVESV, and LVEF; and Delta-LVEDV, Delta-LVESV, and Delta-LVEF were significantly worse in the cardiac death group. A Cox regression analysis showed that the Delta-WR was an independent predictor of cardiac death. Moreover, sudden death occurred in 13 of the 56 patients with cardiac death. A Cox regression analysis also showed that the Delta-WR was an incremental predictor of sudden death. The cardiac death-free rate and sudden death-free rate were significantly higher in patients with Delta-WR less than -5% and Delta-WR less than -2% than in patients with Delta-WR greater than or equal to -5% and Delta-WR greater than or equal to -2%. CONCLUSION: Delta-WR obtained from serial 123I-MIBG scintigraphic studies can be useful for predicting cardiac death and sudden death in stabilized patients with CHF.

Additive effects of spironolactone and candesartan on cardiac sympathetic nerve activity and left ventricular remodeling in patients with congestive heart failure.

UNLABELLED: The activation of the renin-angiotensin-aldosterone system prevents the uptake of norepinephrine in the myocardium. However, the additive effects of combined spironolactone and candesartan on cardiac sympathetic nerve activity (CSNA) have not been determined. We investigated the effects of the angiotensin-receptor blocker candesartan alone and in combination with spironolactone on CSNA in patients with congestive heart failure (CHF). METHODS: Fifty patients with CHF (left ventricular ejection fraction [LVEF] < 45%) were randomly assigned to candesartan plus spironolactone (group A; n = 25) or to candesartan alone (group B; n = 25). All patients were also treated with a loop diuretic. The delayed percent denervation, delayed heart-to-mediastinum count (H/M) ratio, and washout rate (WR) were determined from (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, and plasma brain natriuretic peptide (BNP) concentration was measured before and 6 mo after treatment. The LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LVEF were also determined by echocardiography. RESULTS: After 6 mo, all of these parameters were improved in both groups. However, the degree of change in the percent denervation was -14 +/- 12 in group A and -7 +/- 10 in group B (P < 0.05); the change in the H/M ratio was 0.19 +/- 0.18 in group A and 0.08 +/- 0.14 in group B (P < 0.05), the change in WR was -12% +/- 8% in group A and -5% +/- 13% in group B (P < 0.05), and the change in plasma BNP was -100 +/- 83 pg/mL in group A and -43 +/- 97 pg/mL in group B (P < 0.05). The degree of change in LVEDV, LVESV, and LVEF in group A tended to be better than that in group B, but these changes were not statistically significant. Moreover, there were significant correlations between changes in the (123)I-MIBG scintigraphic findings and changes in the LVEDV (% denervation, r = 0.692, P < 0.001; H/M ratio, r = -0.437, P < 0.05; and WR, r = 0.505, P < 0.01) or the LVESV (% denervation, r = 0.663, P < 0.001; H/M ratio, r = -0.438, P < 0.05; and WR, r = 0.532, P < 0.01) in group A. In contrast, there was no relationship between these parameters in group B. CONCLUSION: These findings indicate that the combination of spironolactone and candesartan may be more beneficial for CSNA and LV performance than candesartan alone in patients with CHF.

Long-term nicorandil therapy improves cardiac sympathetic nerve activity after reperfusion therapy in patients with first acute myocardial infarction.

UNLABELLED: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, reduces plasma norepinephrine concentration in patients with ischemic heart disease. However, long-term effects on cardiac sympathetic nerve activity (CSNA) as evaluated by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy have not been determined for patients with acute myocardial infarction (AMI). METHODS: We studied 40 patients with their first AMI who were treated with intravenous nicorandil before and after primary coronary angioplasty. After suspension of the initial intravenous nicorandil treatment, 20 patients were randomized to receive oral nicorandil (15 mg/d) (group A) and the other 20 patients received a placebo (group B). All patients were also treated with an angiotensin-converting enzyme (ACE) inhibitor or beta-blockers. The delayed heart-to-mediastinum count ratio (H/M ratio), delayed total defect score (TDS), and washout rate (WR) were determined from (123)I-MIBG scintigraphy 3 wk and 6 mo after angioplasty. The left ventricular (LV) end-diastolic volume (EDV), LV end-systolic volume (ESV), and LV ejection fraction (EF) were determined by contrast left ventriculography, whereas plasma procollagen type III amino-terminal peptide (PIIINP) concentrations were also measured at the same time points. RESULTS: Three weeks after angioplasty, TDS, H/M ratios, WR, LVEDV, LVESV, and LVEF were similar in both groups. After 6 mo, all of these parameters had improved in both groups. However, the extent of change in TDS was -9 +/- 6 in group A and -5 +/- 6 in group B (P < 0.05), whereas that in the H/M ratio was 0.15 +/- 0.13 and 0.07 +/- 0.11 (P < 0.05) and that in the WR was -12% +/- 8% and -5% +/- 11% (P < 0.05). The extent of change in LVEDV, LVESV, and LVEF in group A tended to exceed that in group B, but these changes were not statistically significant. We found significant correlations between the percent change in PIIINP and that of TDS from baseline to 6 mo in group A (r = 0.456, P < 0.05). CONCLUSION: Long-term nicorandil therapy can be more beneficial for CSNA and LV remodeling than short-term therapy in patients with AMI.

Relationship between brachial arterial endothelial function and lumbar spine bone mineral density in postmenopausal women.

BACKGROUND: Osteoporosis and endothelial dysfunction have been associated with atherosclerosis. The correlation between brachial arterial endothelial function and lumbar spine bone mineral density (BMD) in postmenopausal women will be investigated. METHODS AND RESULTS: The endothelial function in 85 postmenopausal women, including 28 women with normal spinal BMD, 27 women with osteopenia, and 30 women with osteoporosis were studied. Brachial arterial flow-mediated vasodilatation (FMD) after reactive hyperemia was assessed by ultrasonography. The BMD at the lumbar spine (lumbar 2 to 4 vertebrae) was measured by dual-energy X-ray absorptiometry. Age, years since menopause, and FMD were significantly greater in the osteoporosis group than in the normal BMD group (p<0.01, p<0.05, and p<0.05, respectively). The BMD was significantly lower in the osteoporosis group than in the osteoporosis or normal BMD group (both p<0.01). After adjusting for age and years since menopause, women with osteoporosis had significantly lesser FMD than those with normal BMD (p<0.05). The univariate linear regression analysis revealed that brachial arterial FMD was significantly positively correlated with BMD (r=0.31, p<0.01), but showed no significant association with other clinical variables. In multivariate regression analysis, the FMD was significantly positively correlated with BMD (p<0.01), but not with other variables. CONCLUSIONS: Postmenopausal women with osteoporosis might have impaired brachial arterial endothelial function, suggesting that brachial artery endothelial function might be associated with lumbar spine bone mass in postmenopausal women.

Evaluation of cardiac sympathetic nerve activity and left ventricular remodelling in patients with dilated cardiomyopathy on the treatment containing carvedilol.

AIMS: It has been reported that carvedilol improves cardiac sympathetic nerve activity (CSNA) in patients with dilated cardiomyopathy (DCM). However, the influence of carvedilol on cardiac (123)I-meta-iodobenzylguanidine (MIBG) scintigraphic findings and left ventricular (LV) remodelling has not been determined in DCM patients. METHODS AND RESULTS: In 30 patients with DCM and 10 normal controls, the delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate (WR) were determined by (123)I-MIBG scintigraphy. In addition, the left ventricular end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were calculated by echocardiography. In the DCM patients, the regional defect score index (RDSI), regional washout rate index (RWRI), and wall motion score index (WMSI) were also determined to evaluate regional adrenergic dysfunction and wall motion. Examinations were repeated in all DCM patients after standard treatment containing carvedilol at a dose of 10-20 mg/day (mean dose: 16 +/- 4 mg/day) for a mean of 12 +/- 1 months. Both the (123)I-MIBG scintigraphic and echocardiographic parameters were significantly worse in the DCM patients than the normal control subjects. After treatment, all of these parameters improved significantly in the DCM patients. There was a significant correlation between the changes of (123)I-MIBG findings and changes of the LVEDV and LVESV after treatment. Moreover, there was a significant correlation between changes of the WMSI and those of the RDSI or RWRI in DCM patients. CONCLUSION: Both (123)I-MIBG scintigraphic parameters and echocardiographic parameters were improved in the DCM patients. There was a significant correlation between the changes of (123)I-MIBG scintigraphic and echocardiographic findings after treatment. These findings implicate that long-term, including carvedilol, therapy can improve both CSNA and LV remodelling in patients with DCM.

Effects of intravenous atrial natriuretic peptide on cardiac sympathetic nerve activity and left ventricular remodeling in patients with first anterior acute myocardial infarction.

OBJECTIVES: We sought to evaluate the effects of atrial natriuretic peptide (ANP) on cardiac sympathetic nerve activity (CSNA) and left ventricular (LV) remodeling in patients with first anterior acute myocardial infarction (AMI) after primary coronary angioplasty. BACKGROUND: The activation of the renin-angiotensin-aldosterone system (RAAS) prevents the uptake of norepinephrine in the myocardium. Atrial natriuretic peptide, a circulating hormone of cardiac origin, has vasodilatory and diuretic properties, and can inhibit the RAAS. METHODS: We studied 50 patients with first anterior AMI who were randomly assigned to receive ANP (group A) or isosorbide dinitrate (group B) before and after primary coronary angioplasty. The ANP or ISDN was continuously infused >48 h. The extent score (ES) was determined from 99mTc-pyrophosphate scintigraphy to evaluate the area of initial myocardial damage 3 to 5 days after primary angioplasty. The LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF) were determined by left ventriculography 2 weeks later. The delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate (WR) were determined from 123I-meta-iodobenzylguanidine scintigraphy after 3 weeks. RESULTS: After primary angioplasty, age, gender, risk factors, peak serum creatine phosphokinase concentration, recanalization time, and ES were similar in the 2 groups. However, in group A (n = 25), the TDS was significantly lower (34 +/- 8 vs. 41 +/- 8; p < 0.05), the H/M ratio was significantly higher (1.96 +/- 0.18 vs. 1.74 +/- 0.23; p < 0.05), and the WR was significantly lower (35 +/- 8% vs. 44 +/- 12%; p < 0.005) than in group B (n = 25). Moreover, the LVEDV and LVEF in group A were better than in group B (LVEDV: 85.5 +/- 28.5 ml vs. 106.3 +/- 39.4 ml [p < 0.05]; LVEF: 47.9 +/- 10.2% vs. 41.5 +/- 11.8% [p < 0.05]). CONCLUSIONS: Intravenous ANP improves CSNA and prevents LV remodeling in patients with first anterior AMI.

Different effects of oral conjugated estrogen and transdermal estradiol on arterial stiffness and vascular inflammatory markers in postmenopausal women.

AIMS: We compared the effects of oral conjugated equine estrogen (CEE) therapy and transdermal estradiol therapy on pulse wave velocity (PWV) and circulating levels of vascular inflammatory markers in postmenopausal women and we also explored the interrelationship between the change in PWV and the changes in vascular inflammatory markers. METHODS AND RESULTS: In a randomized 12-month trial, 28 postmenopausal women received a continuous oral CEE plus cyclic medroxyprogesterone acetate (MPA), 28 received a continuous transdermal estradiol patch plus cyclic MPA, and 27 did not receive either therapy. In each subject, we measured the brachial-ankle PWV (baPWV) using an automated device, the blood pressure, and the circulating levels of vascular inflammatory markers (C-reactive protein [CRP], cell adhesion molecules [CAMs], monocyte chemoattractant protein-1 [MCP-1], and matrix metalloproteinase [MMP-9]) before and 12 months after the start of the study. Oral CEE therapy did not change the baPWV but significantly increased the CRP and MMP-9 levels (P<0.05, each) and significantly decreased the CAMs and MCP-1 levels (P<0.05, each). Transdermal estradiol therapy significantly decreased the baPWV, and the CAMs and MCP-1 levels (P<0.05, each) but had no effect on the CRP or MMP-9 levels. No significant changes were seen in the control group. The blood pressures of the subjects remained unchanged. In the transdermal estradiol group, the change in baPWV was not significantly correlated with the changes in vascular inflammatory markers. CONCLUSION: Transdermal estradiol, but not oral CEE therapy, may have antiatherosclerotic effects by improving arterial stiffness. The reduction in baPWV may contribute to the direct effect of estrogen, but not to the decrease in estrogen-induced vascular inflammatory markers.

Effect of transdermal hormone replacement therapy on carotid artery wall thickness and levels of vascular inflammatory markers in postmenopausal women.

Carotid intima-media thickness (IMT) and vascular inflammatory markers have been shown to be involved in atherosclerosis. This study was designed to investigate the effect of transdermal hormone replacement therapy (HRT) on carotid IMT and vascular inflammatory markers in postmenopausal women and to explore the interrelationship between the change in carotid IMT and the changes in vascular inflammatory markers. Thirty-five postmenopausal women (mean age 57.0+/-7.7 years) received transdermal HRT (continuous 17beta-estradiol patch [36 microg/day] plus cyclic oral medroxyprogesterone acetate [2.5 mg/day, for 12 days/ month]) for 12 months, and 32 controls (mean age 58.0+/-7.5 years) did not. Carotid IMT, assessed by ultrasound, and circulating vascular inflammatory markers, i.e., C-reactive protein (CRP), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, E-selectin, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinase (MMP)-9 were measured before and after 12 months of treatment. In the HRT group, carotid IMT decreased significantly (p<0.01), from 0.71+/-0.13 mm to 0.65+/-0.12 mm, and the ICAM-1, VCAM-1, E-selectin, and MCP-1 levels decreased significantly (p<0.01 for all), but the CRP and MMP-9 levels remained unchanged. Carotid IMT and vascular inflammatory markers were unchanged in the control group. In the HRT group, the change in carotid IMT was significantly correlated with the change in serum E-selectin (r=0.38, p<0.05), but not with the changes in other vascular inflammatory markers. These results suggest that transdermal HRT reduced carotid artery wall thickness, and that the reduction may have been induced by an antiatherosclerotic effect combined with the direct effect of estrogen and decreased levels of estrogen-induced E-selectin.