Yoshiaki Takayama

Effect of spironolactone on cardiacsympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy

Abstract Objectives We sought to evaluate the effects of spironolactone on cardiac sympathetic nerve activity and left ventricular (LV) remodeling in patients with dilated cardiomyopathy (DCM). Background Aldosterone prevents the uptake of norepinephrine and promotes structural remodeling of the heart. Spironolactone, an aldosterone receptor blocker, improves LV remodeling in patients with DCM, but its influence on cardiac sympathetic nerve activity has not been determined. Methods We selected 30 patients with DCM who were treated with an angiotensin-converting enzyme inhibitor and a loop diuretic. Fifteen patients were assigned to receive spironolactone additionally, whereas the remaining 15 patients continued their current regimen. The delayed heart/mediastinum (H/M) count ratio, delayed total defect score (TDS), and washout rate (WR) were determined from iodine-123 ( 123 I)-meta-iodobenzylguanidine (MIBG) images before and six months after treatment. The left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) were determined by echocardiography, and New York Heart Association (NYHA) functional class was estimated. Results In the spironolactone group, the TDS decreased from 36 ± 9 to 24 ± 13 (p 123 I-MIBG findings and changes in LVEDV with spironolactone treatment (TDS: r = 0.684, p = 0.0038; H/M ratio: r = −0.878, p Conclusions Spironolactone improves cardiac sympathetic nerve activity and LV remodeling in patients with DCM.

Effect of long-term hormone replacement therapy on angiotensin-converting enzyme activity and bradykinin in postmenopausal women with essential hypertension and normotensive postmenopausal women.

ObjectiveHormone replacement therapy (HRT) reduces the incidence of cardiovascular disease in postmenopausal women. Three-month short-term HRT in postmenopausal women with essential hypertension increased the plasma concentrations of bradykinin with decreased serum angiotensin-converting enzyme (ACE) activity, which may be partially responsible for the cardioprotective effects of HRT. The objective was to determine whether 12-month long-term HRT in postmenopausal women with essential hypertension would maintain the decreased ACE activity and increased bradykinin levels and whether long-term HRT would increase the plasma bradykinin concentrations of normotensive postmenopausal women who had shown no significant changes in the 3-month HRT study, despite their decreased serum ACE activity. DesignTwenty hypertensive and 15 normotensive postmenopausal women were treated with conjugated estrogens (0.625 mg/day) and medroxyprogesterone (2.5 mg/day) for 12 months. Twenty hypertensive and 15 normotensive postmenopausal women were used as controls. The controls were not treated with HRT. Serum ACE activity and plasma bradykinin concentrations were measured at baseline and at 12 months. ResultsLong-term HRT in both hypertensive and normotensive postmenopausal women significantly decreased serum ACE activity from 15.5 ± 0.7 IU/L and 16.0 ± 0.9 IU/L, respectively, at baseline to 13.3 ± 0.5 IU/L and 14.2 ± 0.9 IU/L, respectively, 12 months after the start of HRT (p < 0.05 and p < 0.05, respectively). Long-term HRT in both hypertensive and normotensive postmenopausal women also significantly increased plasma bradykinin concentrations from 22.1 ± 4.4 pg/mL and 19.2 ± 3.0 pg/mL, respectively, at baseline to 86.7 ± 21.2 pg/mL and 73.5 ± 23.0 pg/mL, respectively, 12 months after the start of HRT (p < 0.01 and p < 0.05, respectively). No significant changes in serum ACE activity or plasma bradykinin concentrations were observed in the control groups. ConclusionsLong-term HRT in hypertensive and normotensive postmenopausal women decreases their serum ACE activity and increases their plasma bradykinin concentrations. Thus, maintenance of elevated bradykinin with decreased serum ACE activity by HRT may be useful in reducing the risk of cardiovascular disease in both hypertensive and normotensive postmenopausal women.

Additive Effects of Spironolactone and Candesartan on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients with Congestive Heart Failure

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 123I-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 123I-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.

Comparative effects of valsartan and enalapril on cardiac sympathetic nerve activity and plasma brain natriuretic peptide in patients with congestive heart failure

Objective: To evaluate the effects of valsartan on cardiac sympathetic nerve activity, plasma brain natriuretic peptide (BNP) concentration, cardiac function, and symptoms in patients with congestive heart failure (CHF) by comparison with those of enalapril. Methods: 50 patients with CHF (left ventricular ejection fraction (LVEF) < 40%) were randomly assigned to valsartan (80 mg/day; n  =  25) or enalapril (5 mg/day; n  =  25). All patients were also treated with a loop diuretic. The delayed heart to mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate were determined from 123I-meta-iodobenzylguanidine (MIBG) images. Plasma BNP concentrations were measured before and after six months of treatment. The left ventricular end diastolic volume (LVEDV) and LVEF were also determined by echocardiography. Results: In patients receiving valsartan, TDS decreased from a mean (SD) of 43 (8) to 39 (10) (p < 0.01), H/M ratio increased from 1.70 (0.17) to 1.78 (0.22) (p < 0.05), washout rate decreased from 46 (11)% to 41 (10)% (p < 0.05), and plasma BNP concentration decreased from 237 (180) pg/ml to 143 (93) pg/ml (p < 0.05). In addition, LVEDV decreased from 172 (42) ml to 151 (45) ml (p < 0.05) and LVEF increased from 31 (7)% to 39 (10)% (p < 0.001). However, these parameters did not change significantly in patients receiving enalapril. Conclusion: Plasma BNP concentration and 123I-MIBG scintigraphic and echocardiographic parameters improved significantly after six months of treatment with valsartan. These findings indicate that valsartan can improve cardiac sympathetic nerve activity and left ventricular performance in patients with CHF.

Effects of torasemide on cardiac sympathetic nerve activity and left ventricular remodelling in patients with congestive heart failure

Objective: To determine the effect of torasemide, a loop diuretic with antialdosteronergic properties, compared with furosemide on cardiac sympathetic nerve activity in patients with congestive heart failure (CHF). Methods: 40 patients with non-ischaemic CHF (left ventricular ejection fraction (LVEF) < 45%) were randomly assigned to torasemide (4–8 mg/day; n  =  20) or furosemide (20–40 mg/day; n  =  20). All patients were also treated with angiotensin-converting enzyme inhibitor. The delayed heart to mediastinum count (H/M) ratio, delayed total defect score (TDS) and washout rate were determined from iodine-123 meta-iodobenzylguanidine measured before and 6 months after treatment. Left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV) and LVEF were also determined by echocardiography. Results: After treatment, in patients receiving torasemide, TDS decreased from 44 (8) to 36 (8) (p < 0.001), H/M ratio increased from 1.61 (0.19) to 1.77 (0.24) (p < 0.001), and washout rate decreased from 52 (12)% to 41 (14)% (p  =  0.001). In addition, LVEDV decreased from 173 (22) ml to 147 (30) ml (p < 0.001) and LVESV decreased from 117 (19) ml to 95(24) ml (p < 0.001). Although LVEF tended to increase, the change was not significant (from 31 (7)% to 34 (7)%, NS). Conversely, these parameters did not change significantly in patients receiving furosemide. Moreover, percentage change of TDS was significantly correlated with percentage change of LVEDV (r  =  0.473, p < 0.05) and of LVESV (r  =  0.579, p < 0.01) after torasemide treatment. Conclusion: These findings indicate that torasemide treatment can ameliorate cardiac sympathetic nerve activity and left ventricular remodelling in patients with CHF.

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 17β-estradiol patch [36 μg/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.

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 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 [123I]m-iodobenzylguanidine ([123I]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 [123I]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 [123I]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 [123I]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 [123I]MIBG scintigraphy 3 weeks after the onset of STEMI is a significant predictor of MACE in patients with STEMI, independent of LVEF.

Long-Term Nicorandil Therapy Improves Cardiac Sympathetic Nerve Activity After Reperfusion Therapy in Patients with First Acute Myocardial Infarction

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 123I-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 β-blockers. The delayed heart-to-mediastinum count ratio (H/M ratio), delayed total defect score (TDS), and washout rate (WR) were determined from 123I-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.

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.