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CLINICAL RESEARCH: HEART FAILURE

Effects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction

Shu Kasama, MD^*,*, Takuji Toyama, MD^*, Hisao Kumakura, MD, Yoshiaki Takayama, MD, Shuichi Ichikawa, MD, Tadashi Suzuki, MD^* and Masahiko Kurabayashi, MD^*

^* Department of Cardiovascular Medicine, Gunma University School of Medicine, Maebashi, Japan
Cardiovascular Hospital of Central Japan, Gunma, Japan

Manuscript received July 21, 2004; revised manuscript received October 13, 2004, accepted November 11, 2004.

^* Reprint requests and correspondence: Dr. Shu Kasama, Department of Cardiovascular Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma 371-0034, Japan (Email: s-kasama{at}bay.wind.ne.jp).

	Abstract

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OBJECTIVES: We sought to evaluate the effects of angiotensin receptor blocker (ARB) on cardiac sympathetic nerve activity (CSNA) in patients with congestive heart failure (CHF) with a preserved left ventricular ejection fraction (LVEF).

BACKGROUND: Approximately 50% of patients with CHF have preserved LVEF. It is reported that ARB therapy improves CSNA in CHF patients and reduced LVEF. However, the effect of ARB therapy on CSNA evaluated by iodine-123 meta-iodobenzylguanidine (¹²³I-MIBG) scintigraphy has not been determined in CHF patients with preserved LVEF.

METHODS: We selected 50 patients with nonischemic CHF and LVEF >40% who were treated with standard therapy. Twenty-five patients were randomized to also receive candesartan, whereas the remaining 25 patients received placebo. The delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS), and washout rate (WR) were determined by ¹²³I-MIBG scintigraphy before and six months after treatment. The LV end-diastolic volume and LVEF were determined by echocardiography, and the plasma brain natriuretic peptide (BNP) concentration was also measured.

RESULTS: In patients receiving candesartan, ¹²³I-MIBG scintigraphic and echocardiographic parameters were significantly improved after treatment. In contrast, there were no significant changes in these parameters in patients receiving placebo. There was a significant correlation between the changes in ¹²³I-MIBG scintigraphic findings and the percent change in BNP from baseline to six months in patients receiving candesartan (TDS: r = 0.587, p < 0.005; H/M ratio: r = –0.509, p < 0.01; WR: r = 0.602, p < 0.005).

CONCLUSIONS: Adding candesartan to standard therapy can improve CSNA and LV performance in CHF patients with preserved LVEF.

Abbreviations and Acronyms   ARB = angiotensin receptor blocker   BNP = brain natriuretic peptide   CHF = congestive heart failure   H/M = heart/mediastinum count   LVEDV = left ventricular end-diastolic volume   LVEF = left ventricular ejection fraction   123I-MIBG = iodine-123 meta-iodobenzylguanidine   NYHA = New York Heart Association   TDS = total defect score   WR = washout rate

Cardiac imaging with iodine-123 meta-iodobenzylguanidine (¹²³I-MIBG), an analogue of norepinephrine, is a useful tool for detecting abnormalities of the myocardial adrenergic nervous system in patients with CHF (4–6). Furthermore, cardiac sympathetic nerve activity evaluated by ¹²³I-MIBG scintigraphy has useful prognostic value in patients with CHF (6). Several studies have suggested that treatment of heart failure in patients with CHF can improve cardiac sympathetic nerve activity, as demonstrated by cardiac ¹²³I-MIBG scintigraphy (7–14). In these studies, all of the patients evaluated by ¹²³I-MIBG had impaired LV function, and there have been no reports on the use of cardiac ¹²³I-MIBG scintigraphy to evaluate the effect of adding candesartan to standard therapy in CHF patients with preserved LVEF. Accordingly, this study was performed to determine whether candesartan could improve cardiac sympathetic nerve activity in patients with CHF and an LVEF >40%.

	Methods

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Patients.   From January 2002 to September 2003, 50 patients were admitted to our institution with their first episode of nonischemic heart failure and preserved LVEF. We confirmed that all patients had symptoms and signs of congestive heart failure in this study. A detailed history was taken, and physical examination was performed before inclusion in the study. Chest radiography, standard electrocardiography, echocardiography, cardiac catheterization (including coronary angiography and left ventriculography), and thallium-201 and ¹²³I-MIBG scintigraphy were also performed for all patients. The subjects included 33 men and 17 women (mean age 66.3 years [range 48 to 85 years]). They were in New York Heart Association (NYHA) functional class II or III at the time of enrollment, and all had an LVEF >40%. The cause of CHF was hypertensive heart disease (n = 31), valvular heart disease (n = 10), or idiopathic cardiomyopathy (n = 9). Patients were excluded if they had a history of myocardial infarction, coronary artery disease, congenital heart disease, primary hepatic failure, or active cancer.

Cardiac medications at baseline and follow-up included an angiotensin-converting enzyme (ACE) inhibitor in 47 patients and a loop diuretic in 45 patients, as well as a beta-blocker in 6 patients and spironolactone in 9 patients (Table 1). The management of the patients was decided by the attending physician. The study was approved by the ethics review board of our institution, and written, informed consent was obtained from all patients.

Cardiac ¹²³I-MIBG scintigraphy.   The method of ¹²³I-MIBG imaging has been described previously (10–14). The tracer was obtained from Daiichi Radioisotope Laboratories (Tokyo, Japan), and a dose of 111 MBq was injected intravenously while the patient was in a supine position. Anterior planar images and single-photon emission computed tomography (SPECT) images were acquired at 15 min after injection and again 4 h later. SPECT imaging was performed using a single-head gamma camera (Millennium MPR, GE Medical Systems, Waukesha, Wisconsin). The validation parameters of the gamma camera were within the specified limits. Images were acquired for 40 s in each of the 32 steps over a 180° orbit and recorded digitally at a resolution of 128 x 128 pixels from the anterior planar ¹²³I-MIBG image.

The heart/mediastinum count (H/M) ratio was determined from the delayed anterior planar ¹²³I-MIBG image. The washout rate (WR) was calculated using the following formula: ([(H)-(M)]early – [(H)-(M)delayed)/[(H)-(M)]early x 100 (%), where (H) = mean count per pixel in the left ventricle, and (M) = mean count per pixel in the upper mediastinum.

The delayed myocardial SPECT images of each patient were divided into 20 segments (i.e., short-axis images obtained at the basal, middle, and apical levels of the ventricle were divided into six segments each, and the apical part of the vertical long-axis image was divided into two segments). Regional tracer uptake was then assessed semiquantitatively using a 4-point scoring system (0 = normal uptake; 1 = mildly reduced uptake; 2 = moderately reduced uptake; 3 = severely reduced uptake). In addition, the total defect score (TDS) was calculated as the sum of all defect scores.

Assessment was performed in a blinded fashion by two independent observers with no knowledge of the clinical status or medical therapy of the patients. The level of interobserver agreement was highly significant (r = 0.90, p < 0.001). At our laboratory, the normal range for the delayed TDS is 6 to 10; the delayed H/M ratio is 2.00 to 2.80; and the normal WR range is 22% to 32%. We confirmed that the delayed TDS of normal subjects correlated with the normal WR (r = 0.766, p < 0.001). There was also a significant correlation between the normal delayed H/M ratio and normal WR (r = –0.718, p < 0.001).

Echocardiography.   Echocardiography was performed using standard methods in a blinded manner before and after six months of treatment. Two independent, experienced echocardiographers who had no knowledge of the study performed all of the measurements. Left ventricular end-diastolic volume (LVEDV) and LVEF were calculated using the modified method of Simpson (15).

Measurement of BNP.   Blood samples were collected into test tubes containing EDTA after the patient had rested in a supine position for at least 30 min. Plasma was separated by centrifugation and frozen at –84°C. The plasma concentration of brain natriuretic peptide (BNP) was then measured with a specific immunoradiometric assay for human BNP using a commercial kit (Shionogi, Osaka, Japan). The percent change in the BNP level from baseline to six months was calculated using the following formula: ([BNP after 6 months] – [BNP before treatment]/[BNP before treatment]) x 100 (%).

Statistical analysis.   Statistical analysis was performed using StatView software (Abacus Concepts, Berkeley, California) for Macintosh (Apple Computer, Inc., Cupertino, California). The numerical results are expressed as the mean value ± SD. Comparison of baseline categorical data between the two groups was conducted using the chi-square test, and differences between continuous variables were evaluated using the unpaired t test. Changes in NYHA functional class were assessed using the Wilcoxon matched pairs signed rank test. In patients who underwent repeat assessment, changes from baseline were evaluated within each treatment group using a paired t test and between the candesartan and placebo groups using two-way analysis of variance. Linear regression analysis was used to determine the relationship between continuous variables. In all analyses, p < 0.05 was considered statistically significant.

	Results

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Clinical characteristics.   There were no significant differences in hemodynamic characteristics or cardiac medications between the two groups on entry into the study. Before treatment, the TDS, H/M ratio, WR, LVEDV, LVEF, NYHA functional class, and plasma BNP concentration were similar in both groups (Table 1). None of the patients changed their baseline cardiac medication during the follow-up period. The mean dose of enalapril was 7.2 ± 3.0 mg/day in the candesartan group versus 7.3 ± 3.2 mg/day in the placebo group (p = NS). The mean dose of perindopril was 2.1 ± 0.9 mg/day in the candesartan group versus 2.0 ± 1.0 mg/day in the placebo group (p = NS). The mean dose of carvedilol was 13 ± 6 mg/day in the candesartan group versus 13 ± 6 mg/day in the placebo group (p = NS). The mean dose of furosemide was 30 ± 10 mg/day in the candesartan group versus 31 ± 12 mg/day in the placebo group (p = NS). Furthermore, the dose of spironolactone was only 25 mg/day in both groups. All patients were clinically stable, and no major events occurred during the follow-up period.

Comparison of changes in hemodynamics before and after treatment.   After six months, systolic and diastolic blood pressure tended to decrease in patients receiving candesartan (132 ± 18 vs. 129 ± 19 mm Hg, and 80 ± 13 vs. 78 ± 10 mm Hg, respectively). However, there were no significant differences in these parameters. In patients receiving placebo, there were no significant differences between baseline systolic and diastolic blood pressure and after six months (130 ± 20 vs. 129 ± 18 mm Hg and 78 ± 14 vs. 78 ± 13 mm Hg, respectively). In both groups, the heart rate did not change significantly after six months (in patients receiving candesartan, from 72 ± 12 beats/min to 72 ± 13 beats/min; in patients receiving placebo, from 74 ± 14 beats/min to 73 ± 14 beats/min).

Comparison of cardiac ¹²³I-MIBG scintigraphic findings before and after treatment.   The TDS, H/M ratio, and WR data are shown in Table 2. In the patients receiving candesartan, the TDS decreased significantly after six months (23 ± 8) compared with the baseline value (28 ± 8, p < 0.0005). In the patients receiving placebo, however, there was no significant difference between the baseline TDS and that after six months. Furthermore, the TDS of patients receiving candesartan was significantly lower than that of patients receiving placebo after six months (p < 0.05). Segmental analysis of the defect scores in both groups showed improvement in uptake by the inferior wall, although the change was not statistically significant. In the patients receiving candesartan, the H/M ratio increased significantly after six months (2.00 ± 0.22) compared with the baseline value (1.87 ± 0.24, p < 0.005). In the patients receiving placebo, however, there was no significant difference between the value at baseline and that after six months. Furthermore, the H/M ratio of patients receiving candesartan was significantly higher than that of patients receiving the placebo after six months (p < 0.005). Candesartan treatment caused the WR to decrease significantly after six months (32 ± 8%) compared with the baseline values (37 ± 11%, p < 0.005). In contrast, there were no significant differences between the values at baseline and six months in the patients treated with placebo. Furthermore, the WR of patients receiving candesartan was significantly lower than that of patients receiving the placebo after six months (p < 0.005). Representative ¹²³I-MIBG images for both groups before and after treatment are shown in Figures 1 and 2.

View larger version (69K): [in this window] [in a new window]   Figure 1 Representative anterior planar delayed 123I-meta-iodobenzylguandine images before and after treatment from the candesartan group. In this example, the delayed heart/mediastinum count ratios before and after treatment were 1.89 and 2.21, respectively. The washout rates before and after treatment were 45% and 27%, respectively.

View larger version (17K): [in this window] [in a new window]   Figure 3 Changes in the New York Heart Association (NYHA) functional class during treatment in the two groups.

Relationship between percent change in BNP and ¹²³I-MIBG scintigraphic findings before and after treatment.   There was a significant correlation between the changes in ¹²³I-MIBG scintigraphic findings and the percent change in BNP from baseline to six months (Fig. 4) in the patients receiving candesartan (TDS: r = 0.587, p < 0.005; H/M ratio: r = –0.509, p < 0.01; and WR: r = 0.602, p < 0.005). In contrast, there was no relationship between BNP and scintigraphic parameters in the patients receiving placebo.

View larger version (14K): [in this window] [in a new window]   Figure 4 Correlation between changes in the 123I-meta-iodobenzylguandine scintigraphic findings and the percent change in brain natriuretic peptide (BNP) from baseline to six months in patients receiving candesartan. Delta TDS = total defect score value after six months – pretreatment TDS value; delta H/M ratio = heart/mediastinum count ratio after six months – pretreatment H/M ratio; delta WR = washout rate after six months – pretreatment WR.

	Discussion

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The potential adverse effects of angiotensin on cardiovascular function make its inhibition an attractive therapeutic approach to heart failure. Although ACE inhibitors were designed to decrease the circulating and tissue concentrations of angiotensin II (A-II), recent evidence suggests that the current therapeutic regimens using ACE inhibitors do not adequately suppress A-II production (16). Several reports have suggested an important role of non–ACE-mediated enzymatic pathways in the conversion of angiotensin I to A-II (17,18). Therefore, the strategy of providing more comprehensive blockade of angiotensin with the ARB candesartan appears to be a rational treatment for heart failure. It has been reported that there are several subtypes of the A-II receptor (19), among which the AT₂ receptor is known to have an antagonistic action on the AT₁ receptor and thus has a beneficial effect on the myocardium (19). Therefore, because the ARB candesartan selectively inhibits the AT₁ receptor, this drug may have a superior cardioprotective effect compared with ACE inhibitor treatment alone.

Cohn et al. (20) reported that the addition of an ARB could significantly improve cardiac function and reduce both mortality and morbidity in patients with heart failure. In the present study, LV volume and cardiac function both significantly improved by adding candesartan to the standard therapy. When we evaluated other echocardiographic data, including mitral regurgitation and diastolic parameters (the E/A ratio and deceleration time), a marked improvement was observed in both groups, but there were no significant intergroup differences in the changes (data not shown). Moreover, the addition of candesartan also improved the symptoms of heart failure, as shown by changes in NYHA functional class.

Iodine-123 MIBG is an analogue of the adrenergic neuron-blocking agent guanethidine, which is thought to utilize the same myocardial uptake and release mechanisms as norepinephrine (21). The myocardial norepinephrine concentration and ¹²³I-MIBG uptake correlate in patients with CHF (5), so cardiac ¹²³I-MIBG imaging seems to be a useful tool for detecting abnormalities of the myocardial adrenergic nervous system in CHF patients (4–6). Furthermore, cardiac sympathetic nerve activity evaluated by ¹²³I-MIBG scintigraphic findings and LV function correlate (6), and ¹²³I-MIBG scintigraphy has useful prognostic value for patients with CHF (6). In patients with nonischemic cardiomyopathy, a large proportion of the reduced uptake of norepinephrine is probably due to a loss of neuronal norepinephrine from the failing myocardium. However, some of the reduction appears to be functional (i.e., reversible) and is mediated by hormonal factors, including angiotensin and aldosterone. Struthers (22) reported that once norepinephrine is taken up by cardiac myocytes, it is rapidly metabolized and inactivated, so that such uptake is equivalent to local removed by the myocardium.

Several reports have suggested that ACE inhibitors (7,8), beta-blockers (8–10), spironolactone (11,12), and ARBs (13) can improve cardiac sympathetic nerve activity in patients with CHF, based on cardiac ¹²³I-MIBG scintigraphic findings. However, all of the CHF patients in these studies had poor LV function, and there have been no reports on the use of cardiac ¹²³I-MIBG scintigraphy to evaluate the effect of heart failure therapy in CHF patients with preserved LVEF. Before treatment of the patients in this study, the TDS and WR were relatively lower and the H/M ratio was relatively higher than in our previous reports (10–13). Thus, these findings provide the first evidence indicating that cardiac sympathetic nerve activity is impaired less severely in CHF patients with preserved LVEF than in patients with poor LV function. In addition, these findings are consistent with the observation that the changes in ¹²³I-MIBG scintigraphic parameters after candesartan treatment are less remarkable compared with those in patients with reduced LV function.

In general, the decreased TDS and H/M ratio in the failing myocardium are related to impaired neuronal uptake, whereas increased WR reflects enhanced neurotransmitter release by the adrenergic nerves of the myocardium. Therefore, the TDS and H/M ratio are decreased and WR increased in patients with a failing myocardium, and the use of therapeutic agents improves these parameters (7–14). In this study, these parameters improved after the addition of candesartan to the standard therapy. There are several possible reasons for this beneficial effect. First, the addition of candesartan to an ACE inhibitor may result in stronger inhibition of the renin-angiotensin-aldosterone system, which ameliorates cardiac function. Second, candesartan by itself may exert favorable effects on cardiac function irrespective of concomitant use of an ACE inhibitor. Third, candesartan may play a cardioprotective role by increasing the myocardial uptake of norepinephrine and reducing norepinephrine release, given that the ARB inhibits beta-adrenergic receptor-mediated signaling as well as A-II receptor, as reported by Rockman et al. (23,24).

The plasma BNP level is a useful prognostic indicator in patients with CHF (25), because it is a ventricular hormone (26). Treatment of CHF guided by the plasma BNP level has been reported to reduce cardiovascular events (27), so a decrease in BNP may be associated with a better outcome, as is the case in the CHARM-Preserved study (2). Moreover, Latini et al. (28) reported that plasma BNP concentration is the most powerful indicator after ARB therapy in patients with CHF. In our study, plasma BNP concentrations significantly decreased due to the addition of candesartan to standard therapy in CHF patients with preserved LVEF. Furthermore, we detected a significant correlation between changes in the ¹²³I-MIBG scintigraphic findings and the percent change in BNP from baseline to six months of candesartan treatment in CHF patients with preserved LVEF.

In our study, almost all of the patients were treated with ACE inhibitors at baseline. The echocardiographic and ¹²³I-MIBG scintigraphic parameters and plasma BNP level tended to improve in patients receiving the placebo, but the changes were not statistically significant. Therefore, it may be important to further inhibit the renin-angiotensin-aldosterone system by adding candesartan to ACE inhibitors in CHF patients with preserved LVEF.

Study limitations.   The small number of patients included in this study was a major limitation. In addition, the dose of candesartan was relatively low. In the future, we need to study the long-term effects of candesartan on cardiac sympathetic nerve activity in a larger group of patients.

Recently, it has been reported that aldosterone is produced in the ventricles of patients with heart failure (29), and that the aldosterone synthase gene is expressed in cardiac tissue (30). Furthermore, it has been reported that aldosterone could induce the expression of ACE messenger ribonucleic acid in cultured neonatal cardiocytes (31). We did not measure plasma renin activity or the aldosterone concentration. However, the local renin-angiotensin-aldosterone system may be activated even if the plasma renin activity or aldosterone concentration is normal. Therefore, adding candesartan to standard therapy may be important to more completely inhibit the renin-angiotensin-aldosterone system in CHF patients with preserved LVEF.

In this study, hypertensive heart disease was a major cause of heart failure in both groups. In general, patients with high blood pressure had impaired cardiac sympathetic nerve activity, and the use of agents improved ¹²³I-MIBG scintigraphy (32). In patients receiving candesartan in our study, there were no significant differences in blood pressure after six months. Therefore, we believe that adding candesartan to standard therapy can improve cardiac sympathetic nerve activity in CHF patients with preserved LVEF even if blood pressure is not affected.

Conclusions.   The TDS, H/M, and WR determined by ¹²³I-MIBG scintigraphy were all significantly improved after six months of candesartan treatment. The LV volume and cardiac function were also improved due to candesartan therapy. Furthermore, the plasma BNP concentration was decreased significantly. There was a significant correlation between changes in the ¹²³I-MIBG scintigraphic findings and the percent change in BNP from baseline to six months in patients receiving candesartan. These findings suggest that adding candesartan to standard therapy can improve cardiac sympathetic nerve activity and LV performance in CHF patients with preserved LVEF.

View larger version (70K): [in this window] [in a new window]   Figure 2 Representative anterior planar delayed 123I-meta-iodobenzylguandine images before and after treatment from the placebo group. In this example, the delayed heart/mediastinum count ratios before and after treatment were 1.93 and 1.81, respectively. The washout rates before and after treatment were 42% and 46%, respectively.

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