Objective To evaluate the effects of spironolactone on cardiac sympathetic nerve activity (CSNA) and left ventricular (LV) remodelling in patients with ST-segment elevation myocardial infarction (STEMI).
Design Single-centre, prospective, randomised evaluation study.
Setting Patients with a first STEMI and single-vessel disease undergoing primary coronary angioplasty.
Patients Sixty patients randomly assigned to two groups before angioplasty.
Interventions Patients were randomly assigned to receive or not the spironolactone before primary coronary angioplasty.
Main outcome The extent score (ES) was determined by use of 99mTc-pyrophosphate scintigraphy to evaluate the area of initial myocardial damage 3–5 days after primary angioplasty. The LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LV ejection fraction were determined by echocardiography, and plasma procollagen type III aminoterminal peptide (PIIINP) was measured before and 3 weeks after treatments. The delayed heart/mediastinum count (H/M) ratio, delayed total defect score (TDS) and washout rate (WR) were determined from 123I-meta-iodobenzylguanidine scintigraphy after 3 weeks.
Results After primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine kinase concentration, recanalisation time and ES were similar in the two groups. However, in the spironolactone group, the TDS and WR were significantly lower (TDS: mean (SD) 22.5 (8.0) vs 29.5 (10.1), p<0.005, WR: 30.5 (8.7)% vs 40.0 (10.9)%, p<0.001) and the H/M ratio was significantly higher (2.18 (0.37) vs 1.96 (0.30), p<0.05) than in the non-spironolactone group. Moreover, significant correlations were found between the degree of change in PIIINP concentration and change in LVEDV (r=0.559, p=0.001), or LVESV (r=0.546, p=0.002) in the spironolactone group.
Conclusion Administration of spironolactone improves CSNA and prevents LV remodelling in patients with a first STEMI.
- Myocardial infarction
- sympathetic nervous system
- nuclear cardiology
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Advances in percutaneous coronary interventions, such as the development of antithrombotic and stents therapies, have dramatically decreased the mortality and morbidity in patients with acute myocardial infarction (MI).1 2 However, the development of heart failure following acute MI, which is often accompanied by left ventricular (LV) remodelling, occurs in the chronic phase and often remains refractory to conventional drug treatment. Moreover, activation of cardiac sympathetic nerve activity (CSNA) is one of the pathophysiological abnormalities associated with heart failure.3
Aldosterone displays both myocardial and renal effects that can have profound implications for LV remodelling,4 or abnormal CSNA.5 In the Randomised ALdactone Evaluation Study (RALES), the aldosterone receptor antagonist spironolactone was shown to reduce mortality in patients with congestive heart failure,6 and the beneficial outcome in RALES was shown to be associated with the suppression of cardiac collagen synthesis by spironolactone.7 This agent has been also reported to have cardioprotective effects based on increasing the uptake of norepinephrine in both experimental animal models5 and failing human hearts.8 The efficacy of immediate administration of spironolactone in patients with acute MI has been reported previously.9 In that report, spironolactone treatment prevented LV dilatation and remodelling after primary coronary angioplasty in patients with acute MI.
Myocardial imaging with 123I-meta-iodobenzylguanidine (MIBG), an analogue of norepinephrine, is useful for detecting abnormalities in the myocardial adrenergic nervous system in patients with acute MI.10 Myocardial ischaemic area and cardiac 123I-MIBG defect size are correlated in patients undergoing reperfusion therapy for acute coronary syndromes.11 Many reports have suggested that inhibition of the renin–angiotensin–aldosterone system can improve CSNA, based on cardiac 123I-MIBG scintigraphic studies, in patients with heart disease.8 12–15 However, no studies have examined the changes in cardiac 123I-MIBG scintigraphic findings in response to spironolactone administration in patients with acute MI, especially ST-segment elevation MI (STEMI), although we previously reported improved CSNA in patients with non-ischaemic chronic heart failure.8
Accordingly, this study was performed to evaluate the hypothesis that the spironolactone improves CSNA in patients with a first STEMI undergoing primary coronary angioplasty.
Patients and methods
We prospectively studied 97 patients who were admitted to the coronary care unit of our institution with a first STEMI and presented with Thrombolysis In Myocardial Infarction (TIMI) grade 0 or 1 flow at initial coronary angiography. Admission criteria included prolonged chest pain (>30 min), electrocardiographic ST-segment elevations >2 mV in two or more leads, successful reperfusion therapy within 6 h of the onset and a greater than threefold increase in the serum creatine kinase concentration. Patients were excluded for the following reasons: age >85 years (two patients were excluded); cardiogenic shock or hypotension (systolic blood pressure <80 mm Hg) (three patients); hyperkalaemia (serum potassium >5.0 mEq/dl) or renal failure (serum creatine >2.0 mg/dl) (five patients); prior MI (five patients); multivessel disease (six patients); need for mechanical support (intra-aortic balloon pumping, mechanical ventilation, or both) (five patients); treatment with an oral angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or spironolactone within the previous 2 weeks (five patients). Therefore, this report is based on the remaining 66 patients. The study was approved by the ethics review board of our institution and informed written consent was obtained from all patients.
This is a prospective randomised study (double blind, 1:1 ratio). After establishing a diagnosis of STEMI, 66 patients were randomly allocated to the spironolactone (n=33) or non-spironolactone (n=33) groups before primary coronary angioplasty. In the spironolactone group, oral spironolactone (25 mg) was administered before angioplasty and this agent was then continued; placebo was started in the non-spironolactone group. All patients received oral aspirin and ticlopidine or clopidogrel before angioplasty.
All patients underwent cardiac catheterisation using the femoral approach after an injection of 100 U/kg of heparin. The infarct-related artery was visualised with contrast injections. Patients with persistent occlusion of the infarct-related vessel underwent percutaneous coronary intervention by standard techniques. Patients unable to achieve more than 50% patency and/or TIMI grade 3 flow were excluded from this study. With the patient's haemodynamic stability assured after angioplasty, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were started as soon as possible and β-adrenergic blocking agents were also administered within 5 days and then continued.
We measured plasma procollagen type III aminoterminal peptide (PIIINP) concentration and performed echocardiography before primary coronary angioplasty (ie, soon after the patients were admitted to the coronary care unit). We also performed resting 201-thallium (201Tl) and 99mTc-pyrophosphate (PYP) dual single-photon emission computed tomography (SPECT) imaging to evaluate the area of initial myocardial damage 3–5 days after primary angioplasty.
A follow-up series of examinations (measurement of PIIINP concentrations and echocardiography) were performed 3 weeks after angioplasty. We also performed 123I-MIBG scintigraphy at the same time.
Echocardiography was carried out by standard methods in a blinded manner before and 3 weeks after angioplasty. The LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV) and LV ejection fraction (LVEF) were calculated using the modified method of Simpson, as previously reported.8
The method of 123I-MIBG imaging has been described previously.16 17 Briefly, the 123I-MIBG was obtained from a commercial source (FUJIFILM RI Pharma Co Ltd, Tokyo, Japan). At 15 min and 4 h after injection, anterior planar and SPECT images were obtained with a single-head gamma camera (Millennium MPR, GE Medical Systems, Waukesha, Wisconsin, USA).
The heart/mediastinum count (H/M) ratio was determined from the anterior planar delayed 123I-MIBG image. The washout rate (WR) was calculated from early and delayed planar images. Regional tracer uptake was assessed semiquantitatively using a five-point scoring system (0=normal to 4=no uptake) in 17 segments on the delayed SPECT image as recommended by the American Heart Association. The total defect score (TDS) was calculated as the sum of all defect scores.
201Tl and 99mTc-PYP dual SPECT imaging
The method of 201Tl and 99mTc-PYP dual SPECT has been described previously.16 In brief, each patient received 740 MBq of 99mTc-PYP intravenously and then 74 MBq of 201Tl 2 h later. Fifteen minutes after the 201Tl injection, all patients underwent myocardial imaging with dual SPECT with the same system. For each patient, these images were divided into 17 segments by the same method as was used for 123I-MIBG imaging. We evaluated the 201Tl myocardial perfusion SPECT abnormalities using the TDS calculated by the same method. Furthermore, the extent score (ES) was determined from 99mTc-PYP as the sum of the area of abnormal uptake for all 17 segments.
Plasma PIIINP concentrations
Blood samples were collected from an antecubital vein. The PIIINP plasma levels were measured by a specific immunoradiometric assay using a commercial kit (CIS Bio International, Nagoya, Japan) as previously reported.17
Statistical analysis was performed by using SPSS 16.0 for Windows (SPSS Inc). Numerical results are expressed as the mean±SD. Variables were tested for skewness. For skewed variables, non-parametric tests were used for comparisons between groups (Mann–Whitney U test), whereas an unpaired t test was used for normally distributed variables. Categorical data were compared using two-sided χ2 tests. In patients who underwent repeat assessment, changes from baseline were evaluated within each treatment group using a paired t test and between the two groups using two-way analysis of variance. Linear regression analysis was used to determine the relationship between continuous variables. A value of p<0.05 was considered statistically significant.
In the spironolactone group, one patient experienced a cerebral infarction and two patients were excluded because the follow-up examinations after 3 weeks were not completely obtained. In the non-spironolactone group, three patients were excluded because the follow-up examinations were not completely obtained. Thus, 60/66 patients enrolled in the trial completed the entire protocol (spironolactone group, n=30; non-spironolactone group, n=30). No significant differences were seen in clinical characteristics between the subjects in the two groups on entry into the study. Age, gender, culprit coronary artery, risk factors, recanalisation time and peak creatine kinase concentrations in the acute phase were similar for both groups (table 1). There were also no differences in the in-hospital drugs and clinical follow-up between the two groups.
Comparison of cardiac 201Tl and 99mTc-PYP dual SPECT
Table 1 summarises the ES and TDS data for both groups as evaluated by cardiac 201Tl and 99mTc-PYP dual SPECT. Based on this dual SPECT evaluation, we confirmed that all patients had a first MI and there were no patients with previous MI. Both ES and TDS were similar between the spironolactone and non-spironolactone groups.
Comparison of left ventricular parameters 3 weeks after treatment
The LVEF, LVEDV and LVESV are shown in figure 1. In the spironolactone group, the LVEF increased significantly after 3 weeks compared with the baseline values. In contrast, in the non-spironolactone group the LVEDV and LVESV increased significantly after 3 weeks. Moreover, the degree of change in LVEF, LVEDV and LVESV in the spironolactone group was more favourable than in the non-spironolactone group.
Comparison of cardiac 123I-MIBG scintigraphic findings 3 weeks after treatment
The TDS, H/M ratio and WR are shown in figure 2. The TDS in the spironolactone group was significantly lower than in the non-spironolactone group (22.5 (8.0) vs 29.5 (10.1), p<0.005). The H/M ratio in the spironolactone group was significantly higher than in the non-spironolactone group (2.18 (0.37) vs 1.96 (0.30), p<0.05). Finally, the WR in the spironolactone group was significantly lower than in the non-spironolactone group (WR: 30.5 (8.7)% vs 40.0 (10.9)%, p<0.001).
Comparison of PIIINP concentrations
The plasma PIIINP concentrations at baseline and 3 weeks after treatment are shown in figure 3. In both groups, the plasma PIIINP concentrations were significantly increased after 3 weeks of treatment (in the spironolactone group, p<0.05; in the non-spironolactone group, p<0.001). However, the degree of change in PIIINP in the spironolactone group was significantly lower than in the non-spironolactone group (p<0.05) (figure 3).
Relationship between degree of changes in PIIINP and left ventricular volume baseline at 3 weeks after treatment
We found significant correlations between the degree of change in PIIINP concentration and that in LVEDV (r=0.559, p=0.001), or LVESV (r=0.546, p=0.002) in the spironolactone group. In contrast, there were no relationships between these parameters in the non-spironolactone group (LVEDV; r=0.346, p=0.160, LVESV; r=0.352, p=0.156) (figure 4).
Our findings in this study demonstrate for the first time that adding spironolactone to standard treatment can improve CSNA and prevent LV remodelling in patients with a first STEMI compared with standard conventional treatment alone. This agent can also suppress cardiac collagen synthesis during the acute to subacute phase of STEMI after primary coronary angioplasty.
The aldosterone promotes retention of sodium, loss of magnesium and potassium, myocardial and vascular fibrosis, baroreceptor dysfunction, vascular damage and arterial non-compliance, structural remodelling, sympathetic activation and parasympathetic inhibition.6–9 Moreover, Yoshimura et al18 reported that the aldosterone synthase gene is expressed in cardiac tissue and in another report they concluded that aldosterone is produced in the ventricles of the failing human heart.19 Therefore, spironolactone may have cardioprotective effects by directly suppressing aldosterone production in the cardiac tissue of failing heart.
123I-MIBG, an analogue of the adrenergic-neuron-blocking agent, guanethidine, is thought to use the same mechanism of myocardial uptake and release as norepinephrine.20 21 An association between myocardial norepinephrine concentrations and 123I-MIBG uptake in patients has been reported previously.22 Therefore, cardiac 123I-MIBG imaging may be a useful tool for detecting abnormalities of the myocardial adrenergic nervous system in patients with acute MI.10 We previously reported that addition of spironolactone to standard treatment improves CSNA evaluated by 123I-MIBG imaging in patients with non-ischaemic cardiomyopathy.8 However, there are no reports on the changes in cardiac 123I-MIBG scintigraphic findings in response to spironolactone administration in patients with STEMI. In this study, the TDS, H/M ratio and WR determined by cardiac 123I-MIBG scintigraphy were better in the spironolactone group than in the conventional treatment group.
It is well known that the aldosterone receptor antagonist spironolactone reduces mortality in patients with congestive heart failure, as shown in the RALES trial,6 and also that eplerenone reduces morbidity and mortality among patients with acute MI complicated by LV dysfunction, as shown in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial.23 In this study, we included only the patients with successful reperfusion therapy within 6 h of the onset and excluded the patients with severe heart failure. Furthermore, the patients in the non-spironolactone group were also given standard treatment for acute MI. Therefore, the population of previous reports—RALES7 or EPHESUS23—differed from that of our study. We suggested that immediate administration of spironolactone may be at least effective for CSNA in our stabilised patients with acute MI. In the future, we need to evaluate the effects of spironolactone on CSNA and prognosis in a larger group of patients, including those with severe heart failure owing to extensive infarction.
On the other hand, we have recently reported that 123I-MIBG scintigraphic parameters 3 weeks after the onset of STEMI are a significant predictor of cardiac events in patients with STEMI.24 For these reasons, increasing effort has been directed towards pharmacological improvement in CSNA. This study found that adding spironolactone to standard treatment had beneficial effects on 123I-MIBG scintigraphic findings compared with standard treatment alone. Therefore, our findings demonstrate for the first time that aldosterone blocking agents had beneficial effects for CSNA in patients with STEMI, so our result may be associated with a better outcome as was the case in the previous studies.7 23
Currently, nuclear imaging with 99mTc-PYP scintigraphy is used to measure the area of initial myocardial damage after acute MI.16 A significant correlation has been reported between myocardial 99mTc-PYP scintigraphic uptake and the area at risk in patients with myocardial infarction.25 In our study, the ES evaluated by 99mTc-PYP was similar in both groups. Thus, the initial area at risk in both groups in this study was similar. However, in the subacute phase (3 weeks after primary angioplasty), 123I-MIBG scintigraphic parameters in the spironolactone group were more favourable than in the non-spironolactone group. Based on this, we concluded that administration of spironolactone during the acute to subacute phase of STEMI may have a beneficial effect on CSNA after reperfusion therapy.
Plasma PIIINP concentrations may constitute a biochemical marker for myocardial fibrosis or LV remodelling in patients with acute MI.26 Tsutamoto et al27 reported that administration of spironolactone together with standard treatment reduced both plasma PIIINP concentrations and LV mass index in the failing human heart. The increase in aldosterone extraction by the failing heart stimulates myocardial collagen turnover and induces LV remodelling, as occurs in vitro.28 Because spironolactone inhibits the aldosterone extraction through the heart, this agent prevents LV remodelling by antiproliferative and anti-hypertrophic effects.27 In this study, the plasma PIIINP concentrations in the acute phase were significantly increased after 3 weeks in both groups. However, the degree of change in PIIINP in the spironolactone group was significantly lower than in the non-spironolactone group. Moreover, we found significant correlations between the changes in PIIINP and LV volume from baseline to the subacute phase in patients with STEMI. We suggest that adding spironolactone to standard treatment not only improves CSNA, but also attenuates myocardial fibrosis and prevents LV remodelling in comparison with standard conventional treatment after reperfusion therapy in patients with STEMI.
Although favourable effects of spironolactone treatment have been established, little is known about the time course and duration of these effects. We previously reported that spironolactone improve CSNA and prevent LV remodelling evaluated by 123I-MIBG scintigraphy, echocardiography and plasma PIIINP concentrations between the start of treatment and 6 months after treatment in patients with congestive cardiomyopathy including ischaemic heart disease.12 We now have follow-up data for those patients. 123I-MIBG scintigraphic and echocardiographic parameters were improved and plasma PIIINP concentrations were decreased 1 year later and reached a plateau afterwards (data not shown). Therefore, we believe that the spironolactone is strongly effective for at least 1 year and the effect continues after this. However, further studies will be required to confirm this hypothesis.
It is known that LV remodelling after acute MI occurs in phases. The early phase of infarct expansion is complete in about 2 weeks,29 and the later process takes several months.30 This LV remodelling after MI has been shown to portend a poor prognosis.29 30 In this study, we could not perform echocardiography at the chronic phase. Therefore, in the future, we need to examine the effects of spironolactone on LV parameters of the chronic phase using larger numbers of patients and evaluate the prognosis in patients with and without spironolactone treatment.
Another limitation is that we did not measure elaborately other parameters of CSNA. In this study, we evaluated heart rate variability for about half of the patients in each group. This parameter tended to be more favourable for the group receiving spironolactone than for the standard treatment group, but not statistically significant. Moreover, we did not evaluate β-receptor function. Because no reports have evaluated the effects of spironolactone treatment on β-receptor function in the failing human heart, we need to examine such effects in the future.
The TDS, H/M ratio and WR, as determined by cardiac 123I-MIBG scintigraphy were better in the group receiving spironolactone than in the group receiving standard conventional treatment. The ES determined by 99mTc pyrophosphate was similar in the two groups. Three weeks after treatment, LV parameters were better in the spironolactone group than in the conventional treatment group. These findings indicate that administration of spironolactone can improve cardiac sympathetic nerve activity and LV remodelling in patients with a first STEMI.
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the ethics committee at the Cardiovascular Hospital of Central Japan.
Provenance and peer review Not commissioned; externally peer reviewed.
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