Takuji Toyama

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 atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction

Atrial natriuretic peptide (ANP) is a member of the natriuretic peptide family that exerts various biological effects via acting on the receptor-guanylyl cyclase system, increasing the content of intracellular cyclic guanosine monophosphate (cGMP). ANP was first identified as a diuretic/natriuretic and vasodilating hormone, but subsequent studies revealed that ANP has a very important function in the inhibition of the renin-angiotensin-aldosterone system (RAAS), endothelin synthesis, and sympathetic nerve activity. Evidence is also accumulating from recent work that ANP exerts its cardioprotective functions not only as a circulating hormone but also as a local autocrine and/or paracrine factor. ANP inhibits apoptosis and hypertrophy of cardiac myocytes, and inhibits proliferation and fibrosis of cardiac fibroblasts. Reperfusion of the ischaemic myocardium by percutaneous coronary intervention (PCI) reduces the infarct size and improves left ventricular (LV) function in patients with acute myocardial infarction (AMI). However, the benefits of PCI in AMI are limited by reperfusion injury. Animal studies have shown that ANP inhibits ischaemia/reperfusion injury, and reduces infarct size. We and others have recently shown that the intravenous administration of ANP inhibits RAAS, sympathetic nerve activity and reperfusion injury, prevents LV remodelling, and improves LV function in patients with AMI. ANP has a variety of cardioprotective effects and is considered to be a very promising adjunct drug for the reperfusion therapy in patients with AMI.

Plasma connective tissue growth factor is a novel potential biomarker of cardiac dysfunction in patients with chronic heart failure.

Connective tissue growth factor (CTGF) has been recently reported as a mediator of myocardial fibrosis; however, the significance of plasma CTGF concentration has not been evaluated in patients with heart failure. The aim of this study was to investigate the clinical utility of plasma CTGF concentration for the diagnosis of heart failure.

Impact of lesion calcification on clinical and angiographic outcome after sirolimus-eluting stent implantation in real-world patients

BACKGROUND Previous studies have demonstrated similar efficacy of the drug-eluting stent (DES) in patients with and without calcified lesions. However, most of the randomized trials have excluded patients with severe calcified lesions. This study aimed to examine the impact of lesion calcium on clinical and angiographic outcome after sirolimus-eluting stent (SES) implantation in real-world patients. METHODS Consecutive 380 patients with 556 lesions treated with SES were enrolled. Lesions were divided into Calc lesions (moderate or sever calcification; 195 lesions) and non-Calc lesions (none or mild calcification; 361 lesions) according to the lesion calcium. Quantitative coronary angiography (QCA) parameters, binary restenosis rate (%restenosis), target lesion revascularization (TLR) rate, and major adverse cardiac events (MACE) during follow-up were compared between the two groups. All patients were contacted at 1, 6, and 12 months after the procedure. RESULTS Lesion success rate was similar in the two groups. %Restenosis (9.2% vs. 3.6%; P<.05) and TLR (7.3% vs. 2.8%; P<.05) were significantly higher in Calc lesions. Stent thrombosis was observed in 0.7% of overall lesions with no difference between the two groups. The MACE rate in Calc patients (13.8%) was significantly higher than in non-Calc patients (6.1%). By multivariate analysis, hemodialysis (HD) and requirement of rotational atherectomy (RA) were predictive factors of TLR in the Calc lesions. CONCLUSIONS Coronary lesions with calcification comprise a high-risk cohort and are associated with a higher TLR and binary restenosis rates in real-world patients treated with SES. Moreover, patients with calcified lesions and on HD are associated with higher MACE rate.

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.

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.

Combined therapy with carvedilol and amiodarone is more effective in improving cardiac symptoms, function, and sympathetic nerve activity in patients with dilated cardiomyopathy: Comparison with carvedilol therapy alone

BackgroundCarvedilol therapy has been reported to be more effective than other beta-blockers in patients with chronic heart failure (CHF). Amiodarone is an anti-arrhythmic medicine that has also been reported to be effective in patients with CHF. But the usefulness of combined therapy with carvedilol and amiodarone has not been reported.MethodsWe compared 15 patients (M/F=3/12, age=57±8 y) with dilated cardiomyopathy (DCM) receiving carvedilol and amiodarone with 15 patients (M/F=3/12, age=61±9 y) receiving carvedilol alone. Patients were studied before and after 1 year of treatment (1Y). NYHA class and exercise capacity based on the specific-activity-scale (SAS), were assessed. Cardiac sympathetic nerve activity was estimated using total defect score (TDS), H/M ratio and washout rate (WR) of 123I-MIBG imaging. Cardiac function was evaluated using 99mTc-MIBI QGS.ResultsCombined, therapy improved several parameters much more than carvedilol alone (p<0.05) including delta-TDS (15.0±8.6 vs. 7.6±7.2) and delta- WR (15.9±11.0% vs. 7.3±10.0%) for 123I-MIBG imaging, delta-LVEF (26.1±11.4% vs. 15.5±13.8%), delta-endsystolic volume (100±63.8 ml vs. 58.9±47.3 ml), 1Y NYHA class (1.5±0.5 vs. 1.9±0.5), 1Y SAS (7.3±0.7 Mets vs. 6.2±1.0 Mets), and delta-SAS (3.4±0.8 Mets vs. 2.6±1.1 Mets).ConclusionCombined therapy with carvedilol and amiodarone is more effective in improving cardiac symptoms, exercise capacity, cardiac function and cardiac sympathetic nerve activity in patients with DCM.

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.