CLINICAL STUDY: HEART FAILURE
Effect of spironolactone on cardiacsympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy
Shu Kasama, MD*,*,
Takuji Toyama, MD*,
Hisao Kumakura, MD ,
Yoshiaki Takayama, MD,
Shuichi Ichikawa, MD,
Tadashi Suzuki, MD* and
Masahiko Kurabayashi, MD*
* Second Department of Internal Medicine, Gunma University School of Medicine, MaebashiJapan
Kitakanto Cardiovascular Hospital, Gunma, Japan
Manuscript received July 10, 2002;
revised manuscript received October 17, 2002,
accepted October 31, 2002.
* Reprint requests and correspondence: Dr. Shu Kasama, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371-0034, Japan.
s-kasama{at}bay.wind.ne.jp
 |
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 (123I)-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 < 0.0001), the H/M ratio increased from 1.64 ± 0.20 to 1.86 ± 0.27 (p < 0.0001), and WR decreased from 55 ± 12% to 41 ± 15% (p < 0.0005). In addition, the LVEDV decreased from 187 ± 26 to 154 ± 41 ml (p < 0.005), and LVEF increased from 33 ± 6% to 39 ± 6% (p < 0.005). However, there were no significant changes in these parameters in the control group. There was a significant correlation between changes in the 123I-MIBG findings and changes in LVEDV with spironolactone treatment (TDS: r = 0.684, p = 0.0038; H/M ratio: r = –0.878, p < 0.0001; and WR: r = 0.737, p = 0.0011). The NYHA functional class improved in both groups but showed a greater improvement in the spironolactone group than in the control group (p < 0.01).
CONCLUSIONS: Spironolactone improves cardiac sympathetic nerve activity and LV remodeling in patients with DCM.
|
Abbreviations and Acronyms
| | ACE | | angiotensin-converting enzyme | | CHF | | congestive heart failure | | DCM | | dilated cardiomyopathy | | H/M | | heart/mediastinum count | | LV | | left ventricular | | LVEDV | | left ventricular end-diastolic volume | | LVEF | | left ventricular ejection fraction | | MIBG | | meta-iodobenzylguanidine | | NYHA | | New York Heart Association | | SPECT | | single-photon emission computed tomography | | TDS | | total defect score | | WR | | washout rate |
|
Since the Randomized ALdactone Evaluation Study (RALES) (1) reported the effectiveness of spironolactone in the treatment of patients with congestive heart failure (CHF), this drug has often been used in patients with severe CHF. Aldosterone plays an important role in the pathophysiology of CHF (2–5). Aldosterone promotes retention of sodium, loss of magnesium and potassium, myocardial and vascular fibrosis, baroreceptor dysfunction, vascular damage and arterial noncompliance, structural remodeling, sympathetic activation, and parasympathetic inhibition (5–9). RALES reported that the addition of spironolactone (an aldosterone receptor blocker) reduces the risk of death from cardiac causes among patients who have severe left ventricular (LV) systolic dysfunction and who are receiving standard therapy, including an angiotensin-converting enzyme (ACE) inhibitor. Spironolactone also improves the symptoms of heart failure, as measured by changes in the New York Heart Association (NYHA) functional class.
Myocardial imaging with iodine-123 (123I)-meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine, is a useful tool for detecting abnormalities of the myocardial adrenergic nervous system in patients with dilated cardiomyopathy (DCM) (10–14). A correlation between the myocardial norepinephrine concentration and 123I-MIBG uptake in patients with DCM has been reported (12). However, there are no reports on cardiac 123I-MIBG scintigraphic changes in response to long-term spironolactone therapy in patients with DCM. However, spironolactone is reported to improve LV remodeling in patients with DCM (15).
In the present study, we evaluated whether spironolactone improves cardiac sympathetic nerve activity and LV remodeling in patients with DCM.
|
Methods
|
|---|
Patients.
Thirty patients (17 men and 13 women; age 65 ± 15 years [range 40 to 84]) with DCM were included in the study. A detailed history and physical examination, chest radiography, standard electrocardiography, echocardiography, thallium-201 and 123I-MIBG scintigraphy, coronary angiography, and left ventriculography were performed in all patients. Patients with acute or chronic myocarditis, previous myocardial infarction, coronary artery disease, or valvular disease were excluded from the study. Patients were in NYHA functional class II or III. All patients were being treated with an ACE inhibitor and a loop diuretic. Treatment with digitalis and vasodilators was allowed, but the use of potassium-sparing diuretics was not permitted. The study was approved by the Ethics Review Board of our institution, and written, informed consent was obtained from all patients.
Study protocol
Fifteen patients were randomized to receive spironolactone additionally (25 mg/day), and the remaining 15 patients continued their current drug regimen. We performed a series of examinations before and six months after treatment. In this study, no patients received beta-blockers.
Cardiac 123I-MIBG scintigraphy
The 123I-MIBG scintigram was obtained commercially (Daiichi-Radioisotope Laboratories, Tokyo, Japan). Patients were injected intravenously with 123I-MIBG (111 MBq) while in an upright position. Anterior planar and single-photon emission computed tomographic (SPECT) images were acquired 15 min after injection and repeated 4 h later. SPECT imaging was performed with a dedicated single-headed imaging system (Millennium MPR, GE Medical Systems, Waukesha, Wisconsin). The energy, uniformity, and linearity were continuously corrected. Images were acquired for 40 s each at 32 steps over a 180° orbit and were recorded at a digital resolution of 128 x 128 pixels from the anterior planar 123I-MIBG image.
The heart/mediastinum count (H/M) ratio was determined from anterior planar delayed 123I-MIBG images (Fig. 1). The washout rate (WR) was calculated by the following formula:  , where H = mean count/pixel in the left ventricle; and M = mean count/pixel in the upper mediastinum. In our laboratory, the normal value for the delayed H/M ratio is 2.00 to 2.80, and the normal WR value is 22% to 32%.
View larger version (15K):
[in this window]
[in a new window]
|
Figure 1 Cardiac 123I-MIBG uptake was quantified as the H/M ratio 4 h after injection, using regions of interest positioned over the heart (H) and upper mediastinum (M).
|
|
The myocardial delayed SPECT images for each patient were divided into 20 segments (Fig. 2). The short-axis images at the basal, middle, and apical ventricular levels were divided into six segments. The apical segment of the vertical long-axis image was divided into two segments. Regional tracer uptake was assessed semiquantitatively using a 4-point scoring system (0 = normal uptake; 1 = mildly reduced uptake; 2 = moderately reduced uptake; 3 = severely reduced uptake). The total defect score (TDS) was calculated as the sum of the scores for all 20 segments. Interobserver variability was determined in a blinded manner by two independent observers. The interobserver correlation was represented by r = 0.90 (p < 0.001).
Echocardiography
Echocardiographic measurements were performed using standard methods in a blinded manner before and six months after treatment. Left ventricular end-diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) were calculated by using the modified Simpson method (16).
Statistical analysis
Statistical analysis was performed using Statview for Macintosh (Abacus Concepts, Berkeley, California). Numeric results are expressed as the mean ± SD. The differences between continuous variables were evaluated using a paired t test. Changes in NYHA functional class were assessed using the Wilcoxon matched-pairs, singed-rank test. Linear regression analysis was used to determine the relationship between continuous variables. A value of p < 0.05 was considered statistically significant.
|
Results
|
|---|
Clinical characteristics.
There were no significant differences in the hemodynamic characteristics of the two groups. Before treatment, the TDS, H/M ratio, WR, LVEDV, LVEF, and NYHA functional class were similar in both groups (Table 1).
Comparison of cardiac 123I-MIBG scintigraphic findings before and after treatment
The TDS, H/M ratio, and WR are summarized in Table 2. In the spironolactone group, the TDS decreased significantly after six months (24 ± 13) from the baseline value (36 ± 9; p < 0.0001). In contrast, in the control group, there was no significant difference between the baseline TDS and that after six months of treatment. Furthermore, after six months of treatment, the TDS in the spironolactone group was significantly lower than that in the control group (p < 0.01). Although uptake tended to improve in the inferior wall, the difference was not significant. In the spironolactone group, the H/M ratio increased significantly after six months (1.86 ± 0.27), compared with baseline (1.64 ± 0.20; p < 0.0001). In contrast, in the control group, there were no significant differences between the value at baseline and that after six months of treatment. Furthermore, after six months of treatment, the H/M ratio in the spironolactone group was significantly higher than that in the control group (p < 0.05). In the spironolactone group, the WR decreased significantly after six months (41 ± 15%), compared with baseline (55 ± 12%; p < 0.0005). In contrast, in the control group, there were no significant differences between values at baseline and after six months of treatment. Furthermore, after six months of treatment, the WR in the spironolactone group was significantly lower than that in the control group (p < 0.05).
View this table:
[in this window]
[in a new window]
|
Table 2 Changes in Total Defect Score, H/M Ratio, and WR for 123I-MIBG Imaging in Patients With Dilated Cardiomyopathy
|
|
Comparison of echocardiographic findings before and after treatment
The changes in LVEDV and LVEF are summarized in Table 3. In the spironolactone group, the LVEDV decreased significantly after six months (154 ± 41 ml), compared with the baseline value (187 ± 26 ml; p < 0.005). In contrast, in the control group, there were no significant differences between values at baseline and after six months of treatment. Furthermore, after six months of treatment, the LVEDV in the spironolactone group was significantly lower than that in the control group (p < 0.05). In the spironolactone group, the LVEF increased significantly after six months (39 ± 6%), compared with baseline (33 ± 6%; p < 0.005). In contrast, in the control group, there were no significant differences between values at baseline and after six months of treatment. Furthermore, after six months of treatment, the LVEF in the spironolactone group was significantly higher than that in the control group (p < 0.05).
Comparison of NYHA functional class before and after treatment
The NYHA functional classes of the patients are summarized in Table 3 and Figure 3. Patients in both groups showed improvement after six months of treatment, compared with baseline values (in the spironolactone group, NYHA class from 2.8 ± 0.4 to 1.7 ± 0.5 [p < 0.0005]; in the control group, from 2.8 ± 0.4 to 2.3 ± 0.7 [p < 0.05]). After treatment, the NYHA functional class of patients in the spironolactone group was better than that in the control group (p < 0.01).
View larger version (18K):
[in this window]
[in a new window]
|
Figure 3 Changes in New York Heart Association (NYHA) functional class during treatment in the two groups.
|
|
Relationship between LVEDV and 123I-MIBG scintigraphic findings before and after treatment
There was a significant correlation between changes in the 123I-MIBG scintigraphic findings and changes in the LVEDV (Fig. 4) with spironolactone treatment (TDS: r = 0.684, p = 0.0038; H/M ratio: r = –0.878, p < 0.0001; and WR: r = 0.737, p = 0.0011). In contrast, there was no relationship between these parameters in the control group.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 4 Correlation between the changes in the 123I-MIBG scintigraphic findings and changes in left ventricular end-diastolic volume (LVEDV) after six months of spironolactone treatment in 15 patients with dilated cardiomyopathy. Delta LVEDV = LVEDV value after six months – pretreatment value of LVEDV; delta TDS = total defect score (TDS) value after six months – pretreatment value of TDS; delta H/M ratio = H/M ratio after six months – pretreatment value of H/M ratio; delta WR = washout rate (WR) value after six months – pretreatment value of WR.
|
|
|
Discussion
|
|---|
Aldosterone causes myocardial and vascular fibrosis (17,18), direct vascular damage (9), and baroreceptor dysfunction by altering Na, K-ATPase activity (7) and preventing myocardial uptake of norepinephrine (5,19). A large proportion of the low basal uptake of norepinephrine is probably due to the loss of neuronal norepinephrine uptake in the failing myocardium. However, some of the reduction in norepinephrine uptake appears to be functional and reversible and is mediated by hormonal factors, such as aldosterone. Struthers et al. (5,19) reported that once norepinephrine is taken up into cardiac cells, it is rapidly metabolized and inactivated so that uptake is equivalent to the local disposal in the myocardium.
The RALES investigators (1) reported that spironolactone reduces the risk of cardiac death in patients with CHF. Spironolactone may prevent myocardial fibrosis by blocking the effect of aldosterone. Based on the RALES trial, Zannad et al. (20) reported that adding spironolactone to an ACE inhibitor decreases the concentrations of several markers of cardiac fibrosis in patients with CHF. Myocardial fibrosis may predispose patients to alterations in the ventricular conduction time and therefore also to the development of reentrant ventricular arrhythmias (19,21–23). Spironolactone may also prevent sudden death by increasing the myocardial uptake of norepinephrine (1). Myocardial uptake of norepinephrine has been shown to be a strong prognostic marker for overall mortality in CHF (13). Barr et al. (5) reported that spironolactone increases cardiac neuronal uptake of 123I-MIBG in patients with CHF. However, that study included a small number of patients and the observation period was relatively short, and all patients had CHF caused by coronary artery disease. Therefore, in this study, we examined whether long-term spironolactone therapy improves cardiac sympathetic nerve activity by using 123I-MIBG imaging in patients with DCM.
Iodine-123–MIBG, an analogue of the adrenergic neuron-blocking agent guanethidine, is thought to utilize the same mechanism of myocardial uptake and release as norepinephrine (24). The myocardial norepinephrine concentration and 123I-MIBG uptake are correlated in patients with DCM (12). Therefore, cardiac 123I-MIBG imaging is a useful tool for detecting abnormalities of the myocardial adrenergic nervous system in patients with DCM (10–14). Several reports have suggested that the treatment of heart failure can improve cardiac sympathetic nerve activity, based on cardiac 123I-MIBG scintigraphic studies in patients with DCM (25–30). In this study, the TDS, H/M ratio, and WR, as determined by cardiac 123I-MIBG scintigraphy, improved in the spironolactone treatment group compared with the control group. Therefore, spironolactone may mediate its effect by increasing myocardial uptake of norepinephrine.
Tsutamoto et al. (15) reported that spironolactone improves cardiac function and LV remodeling in patients with mild to moderate nonischemic CHF. Moreover, cardiac sympathetic nerve activity and cardiac function are correlated in patients with DCM (31). In this study, spironolactone improved LV volume and cardiac function, as well as 123I-MIBG uptake in patients with DCM. The reduction of LV volume may have been due to blocking of the mineralocorticoid receptor, which is known to be expressed in the human heart (32,33). However, with respect to the effect of spironolactone treatment in patients with DCM, it is not known whether the reduction in LV volume (due to the antiproliferative/antifibrotic effect of spironolactone) increases the myocardial uptake of norepinephrine or whether increasing the myocardial uptake of norepinephrine causes a reduction in LV volume. Further studies are necessary to clarify the relationship between the reduction in LV volume and the increase in myocardial uptake of norepinephrine.
In this study, delayed MIBG images were used to determine the TDS and H/M ratio. There are two types of norepinephrine and MIBG uptake: uptake-1 (neuronal uptake), which occurs even if the concentration of norepinephrine or MIBG is low, is dependent on sodium and ATP and is suppressed by tricyclic antidepressants; uptake-2 (extraneuronal uptake), which takes place only when the norepinephrine or MIBG concentration is high, occurs by diffusion and is unaffected by tricyclic agents (34–36). Early imaging detects both uptake-1 and uptake-2 (37,38), whereas delayed imaging involves less uptake-2 and therefore primarily reflects the status of cardiac sympathetic nerve activity. For these reasons, we used delayed MIBG imaging in this study. Previous reports suggest that WR is the most clinically useful parameter for assessing the severity and improvement of CHF (39,40). Increased norepinephrine turnover in cardiac sympathetic nerve endings may decrease the uptake in delayed images, such that the increase in turnover (i.e., increase in WR) reflects the severity of CHF. In this study, all three parameters (delayed TDS, delayed H/M ratio, and WR) improved with spironolactone therapy. We hypothesize that one mechanism responsible for functional improvement in patients with DCM is increased myocardial uptake of norepinephrine mediated by spironolactone.
Study limitations.
The small number of patients with DCM included in this study was a limitation. In addition, the present study employed a fixed spironolactone dose of 25 mg/day. The dose-response effects of spironolactone on MIBG scintigraphic findings and LV remodeling must be evaluated in future studies.
It is known that spironolactone therapy increases the plasma aldosterone concentration (5,15). It has been reported that aldosterone is produced in the ventricles of the failing human heart (41). Furthermore, it has been reported that the aldosterone synthase gene is expressed in cardiac tissue (42). We did not measure plasma renin activity or aldosterone concentrations. However, aldosterone may be produced in cardiac tissue, even if the plasma aldosterone concentration is normal. Therefore, we believe that it is important to inhibit aldosterone produced in cardiac tissue by adding spironolactone to an ACE inhibitor in patients with DCM.
Conclusions
The TDS, H/M, and WR, as determined by 123I-MIBG scintigraphy, were significantly improved after six months of spironolactone treatment. In addition, LV volume improved with spironolactone therapy. There was a significant correlation between changes in the 123I-MIBG scintigraphic findings and changes in the LVEDV with spironolactone treatment. These findings indicate that long-term spironolactone treatment can improve cardiac sympathetic nerve activity and LV remodeling in patients with DCM.
|
Acknowledgments
|
|---|
The authors thank Takayoshi Honjo, Akira Nakaya, Hiromitsu Takahashi, and Hiroyuki Takada for their technical assistance.
|
References
|
|---|
1. the Randomized Aldactone Evaluation Study InvestigatorsPitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–717[Abstract/Free Full Text]
2. Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the renin-angiotensin-aldosterone system to clinical state in congestive heart failure. Circulation. 1981;63:645–651[Free Full Text]
3. the CONSENSUS Trial Study GroupSwedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation. 1990;82:1730–1736[Abstract/Free Full Text]
4. Weber KT, Villarreal D. Aldosterone and antialdosterone therapy in congestive heart failure. Am J Cardiol. 1993;71:3–11A
5. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995;76:1259–1265[CrossRef][Medline]
6. MacFadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res. 1997;35:30–34[Abstract/Free Full Text]
7. Wang W. Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension. 1994;24:571–575[Abstract/Free Full Text]
8. Duprez DA, De Buyzere ML, Rietzschel ER, et al. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J. 1998;19:1371–1376[Abstract/Free Full Text]
9. Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension. 1998;31:451–458[Abstract/Free Full Text]
10. Henderson EB, Kahn JK, Corbett JR, et al. Abnormal I-123 metaiodobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive cardiomyopathy. Circulation. 1988;78:1192–1199[Abstract/Free Full Text]
11. Yamakado K, Takeda K, Kitano T, et al. Serial change of iodine-123 metaiodobenzylguanidine (MIBG) myocardial concentration in patients with dilated cardiomyopathy. Eur J Nucl Med. 1992;19:265–270[Medline]
12. Schofer J, Spielmann R, Schuchert A, Weber K, Schluter M. Iodine-123 meta-iodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1988;12:1252–1258[Abstract]
13. Merlet P, Valette H, Dubois-Rande JL, et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med. 1992;33:471–477[Abstract/Free Full Text]
14. Imamura Y, Ando H, Mitsuoka W, et al. Iodine-123 metaiodobenzylguanidine images reflect intense myocardial adrenergic nervous activity in congestive heart failure independent of underlying cause. J Am Coll Cardiol. 1995;26:1594–1599[Abstract]
15. Tsutamoto T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001;37:1228–1233[Abstract/Free Full Text]
16. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography by the American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2:358–367[Medline]
17. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991;83:1849–1865[Abstract/Free Full Text]
18. Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res. 1990;67:1355–1364[Abstract/Free Full Text]
19. Struthers AD. Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in chronic heart failure. J Card Fail. 1996;2:47–54[CrossRef][Medline]
20. the RALES InvestigatorsZannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized ALdactone Evaluation Study. (RALES)Circulation. 2000;102:2700–2706[Abstract/Free Full Text]
21. Klug D, Robert V, Swynghedauw B. Role of mechanical and hormonal factors in cardiac remodeling and the biologic limits of myocardial adaptation. Am J Cardiol. 1993;71:46–54A
22. Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol. 1993;25:563–575[CrossRef][Medline]
23. Barr CS, Naas A, Freeman M, Lang CC, Struthers AD. QT dispersion and sudden unexpected death in chronic heart failure. Lancet. 1994;343:327–329[CrossRef][Medline]
24. Wieland DM, Wu JI, Brown LE, Manger TJ, Swanson DP, Beierwaltes WH. Radiolabeled adrenergic neuron-blocking agents: adrenomedullary imaging with [131I]iodobenzylguanidine. J Nucl Med. 1980;21:349–353[Abstract/Free Full Text]
25. Takeishi Y, Atsumi H, Fujiwara S, Takahashi K, Tomoike H. ACE inhibition reduces cardiac iodine-123–MIBG release in heart failure. J Nucl Med. 1997;38:1085–1089[Abstract/Free Full Text]
26. Watanabe K, Takahashi T, Nakazawa M, et al. Effects of carvedilol on cardiac function and cardiac adrenergic neuronal damage in rats with dilated cardiomyopathy. J Nucl Med. 2002;43:531–535[Abstract/Free Full Text]
27. Fukuoka S, Hayashida K, Hirose Y, et al. Use of iodine-123 metaiodobenzylguanidine myocardial imaging to predict the effectiveness of beta-blocker therapy in patients with dilated cardiomyopathy. Eur J Nucl Med. 1997;24:523–529[Medline]
28. Kakuchi H, Sasaki T, Ishida Y, Komamura K, Miyatake K. Clinical usefulness of 123I meta-iodobenzylguanidine imaging in predicting the effectiveness of beta-blockers for patients with idiopathic dilated cardiomyopathy before and soon after treatment. Heart. 1999;81:148–152[Abstract/Free Full Text]
29. Suwa M, Otake Y, Moriguchi A, et al. Iodine-123 metaiodobenzylguanidine myocardial scintigraphy for prediction of response to beta-blocker therapy in patients with dilated cardiomyopathy. Am Heart J. 1997;133:353–358[CrossRef][Medline]
30. Toyama T, Aihara Y, Iwasaki T, et al. Cardiac sympathetic activity estimated by 123I-MIBG myocardial imaging in patients with dilated cardiomyopathy after beta-blocker or angiotensin-converting enzyme inhibitor therapy. J Nucl Med. 1999;40:217–223[Abstract/Free Full Text]
31. Parthenakis FI, Prassopoulos VK, Koukouraki SI, et al. Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: relationship to regional wall motion and myocardial perfusion abnormalities. J Nucl Cardiol. 2002;9:15–22[CrossRef][Medline]
32. Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Mol Cell Cardiol. 1994;26:809–820[CrossRef][Medline]
33. Lombes M, Oblin ME, Gasc JM, Baulieu EE, Farman N, Bonvalet JP. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ Res. 1992;71:503–510[Abstract/Free Full Text]
34. Sisson JC, Wieland DM, Sherman P, Mangner TJ, Tobes MC, Jacques S Jr. Metaiodobenzylguanidine as an index of the adrenergic nervous system integrity and function. J Nucl Med. 1987;28:1620–1624[Abstract/Free Full Text]
35. Tobes MC, Jaques S Jr, Wieland DM, Sisson JC. Effect of uptake-1 inhibitors on the uptake of norepinephrine and metaiodobenzylguanidine. J Nucl Med. 1985;26:897–907[Abstract/Free Full Text]
36. Gasnier B, Roisin MP, Scherman D, Coornaert S, Desplanches G, Henry JP. Uptake of meta-iodobenzylguanidine by bovine chromaffin granule membranes. Mol Pharmacol. 1986;29:275–280[Abstract]
37. Kline RC, Swanson DP, Wieland DM, et al. Myocardial imaging in man with I-123 meta-iodobenzylguanidine. J Nucl Med. 1981;22:129–132[Abstract/Free Full Text]
38. Nakajo M, Shimabukuro K, Yoshimura H, et al. Iodine-131 metaiodobenzylguanidine intra- and extravesicular accumulation in the rat heart. J Nucl Med. 1986;27:84–89[Abstract/Free Full Text]
39. Momose M, Kobayashi H, Iguchi N, et al. Comparison of parameters of 123I-MIBG scintigraphy for predicting prognosis in patients with dilated cardiomyopathy. Nucl Med Commun. 1999;20:529–535[Medline]
40. Ogita H, Shimonagata T, Fukunami M, et al. Prognostic significance of cardiac (123)I metaiodobenzylguanidine imaging for mortality and morbidity in patients with chronic heart failure: a prospective study. Heart. 2001;86:656–660[Abstract/Free Full Text]
41. Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation. 2001;103:72–77[Abstract/Free Full Text]
42. Yoshimura M, Nakamura S, Ito T, et al. Expression of aldosterone synthase gene in failing human heart: quantitative analysis using modified real-time polymerase chain reaction. J Clin Endocrinol Metab. 2002;87:3936–3940[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
S. Kasama, M. Furuya, T. Toyama, S. Ichikawa, and M. Kurabayashi
Effect of atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction
Eur. Heart J.,
June 2, 2008;
29(12):
1485 - 1494.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, H. Sumino, M. Nakazawa, N. Matsumoto, Y. Sato, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, et al.
Prognostic Value of Serial Cardiac 123I-MIBG Imaging in Patients with Stabilized Chronic Heart Failure and Reduced Left Ventricular Ejection Fraction
J. Nucl. Med.,
June 1, 2008;
49(6):
907 - 914.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J. Verberne, L. M. Brewster, G. A. Somsen, and B. L.F. van Eck-Smit
Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review
Eur. Heart J.,
May 1, 2008;
29(9):
1147 - 1159.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Nagahara, T. Nakata, A. Hashimoto, T. Wakabayashi, M. Kyuma, R. Noda, S. Shimoshige, K. Uno, K. Tsuchihashi, and K. Shimamoto
Predicting the Need for an Implantable Cardioverter Defibrillator Using Cardiac Metaiodobenzylguanidine Activity Together with Plasma Natriuretic Peptide Concentration or Left Ventricular Function
J. Nucl. Med.,
February 1, 2008;
49(2):
225 - 233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, H. Sumino, N. Matsumoto, Y. Sato, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi
Additive Effects of Spironolactone and Candesartan on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients with Congestive Heart Failure
J. Nucl. Med.,
December 1, 2007;
48(12):
1993 - 2000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, H. Sumino, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi
Long-Term Nicorandil Therapy Improves Cardiac Sympathetic Nerve Activity After Reperfusion Therapy in Patients with First Acute Myocardial Infarction
J. Nucl. Med.,
October 1, 2007;
48(10):
1676 - 1682.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Henneman, J. J. Bax, and E. E. van der Wall
Monitoring of therapeutic effect in heart failure patients: a clinical application of 123I MIBG imaging?
Eur. Heart J.,
April 4, 2007;
(2007)
ehl325v1.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, T. Hatori, H. Sumino, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi
Evaluation of cardiac sympathetic nerve activity and left ventricular remodelling in patients with dilated cardiomyopathy on the treatment containing carvedilol
Eur. Heart J.,
April 4, 2007;
(2007)
ehm048v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, T. Hatori, H. Sumino, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi
Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients With First Anterior Acute Myocardial Infarction
J. Am. Coll. Cardiol.,
February 13, 2007;
49(6):
667 - 674.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S Kasama, T Toyama, T Hatori, H Sumino, H Kumakura, Y Takayama, S Ichikawa, T Suzuki, and M Kurabayashi
Effects of torasemide on cardiac sympathetic nerve activity and left ventricular remodelling in patients with congestive heart failure
Heart,
October 1, 2006;
92(10):
1434 - 1440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Pitt, M. Gheorghiade, F. Zannad, J. L. Anderson, D. J. van Veldhuisen, A. Parkhomenko, R. Corbalan, E. Q. Klug, R. Mukherjee, H. Solomon, et al.
Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction <=30%
Eur J Heart Fail,
May 1, 2006;
8(3):
295 - 301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Buss, J. Backs, M. M. Kreusser, S. E. Hardt, C. Maser-Gluth, H. A. Katus, and M. Haass
Spironolactone Preserves Cardiac Norepinephrine Reuptake in Salt-Sensitive Dahl Rats
Endocrinology,
May 1, 2006;
147(5):
2526 - 2534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S Kasama, T Toyama, T Hatori, H Sumino, H Kumakura, Y Takayama, S Ichikawa, T Suzuki, and M Kurabayashi
Comparative effects of valsartan and enalapril on cardiac sympathetic nerve activity and plasma brain natriuretic peptide in patients with congestive heart failure
Heart,
May 1, 2006;
92(5):
625 - 630.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. G.A. Veliotes, A. J. Woodiwiss, D. A.J. Deftereos, D. Gray, O. Osadchii, and G. R. Norton
Aldosterone Receptor Blockade Prevents the Transition to Cardiac Pump Dysfunction Induced by {beta}-Adrenoreceptor Activation
Hypertension,
May 1, 2005;
45(5):
914 - 920.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi
Effects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction
J. Am. Coll. Cardiol.,
March 1, 2005;
45(5):
661 - 667.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gibbs, D. G. A. Veliotes, C. Anamourlis, D. Badenhorst, O. Osadchii, G. R. Norton, and A. J. Woodiwiss
Chronic {beta}-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties
Am J Physiol Heart Circ Physiol,
December 1, 2004;
287(6):
H2762 - H2767.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, S. Tange, T. Suzuki, and M. Kurabayashi
Dobutamine Stress 99mTc-Tetrofosmin Quantitative Gated SPECT Predicts Improvement of Cardiac Function After Carvedilol Treatment in Patients with Dilated Cardiomyopathy
J. Nucl. Med.,
November 1, 2004;
45(11):
1878 - 1884.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, T. Ishikawa, S. Ichikawa, T. Suzuki, and M. Kurabayashi
Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity in Patients with Decompensated Congestive Heart Failure
J. Nucl. Med.,
July 1, 2004;
45(7):
1108 - 1113.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D Struthers
Aldosterone blockade in heart failure
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2004;
5(1_suppl):
S23 - S27.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. Pitt, C. T Stier Jr, and S. Rajagopalan
Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2003;
4(3):
164 - 168.
[Abstract]
[PDF]
|
|
|
|
Top
Abstract
Methods