Original Article
Effects of mineralocorticoid receptor antagonist eplerenone on cardiac sympathetic nerve activity and left ventricular remodeling after reperfusion therapy in patients with first ST-segment elevation myocardial infarction

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Abstract

Purpose

The activation of the renin-angiotensin-aldosterone system prevents the uptake of norepinephrine and promotes structural remodeling of the heart. The mineralocorticoid receptor antagonist (MRA) eplerenone prevents left ventricular (LV) remodeling in patients with acute myocardial infarction, but its influence on cardiac sympathetic nerve activity (CSNA) has not been determined.

Methods

We retrospectively evaluated the first ST-segment elevation myocardial infarction (STEMI) patients in our database who underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy 3 weeks after admission. Eighty-four STEMI patients after primary coronary angioplasty were selected, and used propensity score matching to compare patients who treated with MRA (N = 42), and those who did not (N = 42). The LV end-diastolic volume, end-systolic volume, and ejection fraction were determined by echocardiography, and plasma procollagen type III amino terminal peptide (PIIINP) was measured before and 3 weeks after treatment. The delayed total defect score (TDS), delayed heart/mediastinum count (H/M) ratio, and washout rate (WR) were determined using 123I-MIBG scintigraphy after 3 weeks.

Results

Following primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine phosphokinase concentration, and recanalization time were similar in the two groups. However, the MRA group showed significantly lower TDS and WR values (TDS: 22.8 ± 8.1 vs 32.2 ± 11.5, P < 0.005; WR: 31.1 ± 9.0% vs 42.7 ± 9.9%, P < 0.001) and a significantly higher H/M ratio (2.23 ± 0.41 vs 2.03 ± 0.36, P < 0.05) than the non-MRA group. The degree of change in LV parameters, and PIIINP were more favorable in the MRA group than in the non-MRA group. Moreover, multiple linear regression analyses revealed that both WR and not MRA treatment were significant predictor for LV remodeling, along with PIIINP concentrations.

Conclusion

Administration of eplerenone improves CSNA and prevents LV remodeling in patients with a first STEMI.

Introduction

Since the Epleronone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS)1 reported the effectiveness of mineralocorticoid receptor antagonist (MRA) eplerenone in the treatment of acute myocardial infarction with left ventricular (LV) dysfunction, this agent has often been used in these patients. Aldosterone is well known to bind to mineralocorticoid receptors to regulate sodium and water reabsorption.2 Moreover, aldosterone displays both myocardial and renal effects that can have profound implications for LV remodeling,3 or abnormal cardiac sympathetic nerve activity (CSNA).4 In the EPHESUS trial, the eplerenone was demonstrated to reduce mortality in patients with acute myocardial infarction,1 and the beneficial outcome in the EPHESUS was shown to be associated with the suppression of cardiac collagen synthesis, and prevention of LV remodeling by this agent.5

Myocardial imaging with 123I-metaiodobenzylguanidine (MIBG), an analog of norepinephrine, is useful for detecting abnormalities in the myocardial adrenergic nervous system in patients with acute myocardial infarction.6 The myocardial ischemic area and cardiac 123I-MIBG defect size are correlated in patients undergoing reperfusion therapy for these patients.7 This imaging modality has been reported to be useful for predicting the adverse cardiac events in patients with ST-segment elevation myocardial infarction (STEMI).8 Furthermore, previous studies reported that aldosterone inhibition normalizes autonomic neural control in failing human heart,9 and attenuates enhanced CSNA in animal models of heart failure.10 These favorable effects were associated with the increased myocardial uptake of norepinephrine mediated by aldosterone blockade.4 Therefore, adding MRA to the standard therapy may normalize CSNA, i.e., improve 123I-MIBG uptake in failing human heart. However, to our knowledge, no studies have examined the effects of eplerenone on CSNA evaluated by 123I-MIBG scintigraphy in patients with STEMI.

Accordingly, we performed using our previously reported data,8 to evaluate the hypothesis that mineralocorticoid receptor antagonist eplerenone improves CSNA in patients undergoing primary percutaneous coronary intervention (PCI) following their first STEMI.

Section snippets

Patient Population

The consecutive patients admitted to our institution for STEMI were considered the study population. This study was sub-analysis using our previous database.8 The diagnosis of STEMI was made on the basis of chest pain > 30 minutes in duration, ST-segment elevation > 2 mm in two electrocardiographic leads, and more than threefold increase in serum creatine phosphokinase activity. In the acute phase, all patients were treated in standard fashion, including primary PCI. Patients were excluded from

Clinical Characteristics

No significant differences were observed in the clinical characteristics or cardiac medications were found between the two groups. Age, gender, culprit coronary artery, risk factors, recanalization time, and peak creatine phosphokinase concentrations in the acute phase were similar for both groups (Table 1). No differences were observed in the in-hospital medications (except eplerenone) and clinical follow-up of the two study groups. There were no differences in medication dose (all, P = NS),

Discussion

The findings of this study demonstrate for the first time that the addition of eplerenone to standard therapy can improve CSNA and prevent LV remodeling in patients with a first STEMI, as compared to standard conventional therapy alone. This agent can also suppress cardiac collagen synthesis during the acute to subacute phase of STEMI, following primary PCI.

Aldosterone promotes retention of sodium, loss of magnesium and potassium, myocardial and vascular fibrosis,3 baroreceptor dysfunction,20

New Knowledge Gained

While it is known that the cardioprotective treatments can improve CSNA evaluated by 123I-MIBG scintigraphy in patients with STEMI, we have shown that MRA have similar effects. Therefore, MRA treatment may be effective for reducing the incidence of cardiac events for these patients.

Conclusion

The TDS, H/M ratio, and WR determined by cardiac 123I-MIBG scintigraphy were better by use of eplerenone, as compared with the standard conventional therapy. Three weeks after treatment, LV parameters in the eplerenone group more favorable than those in the conventional therapy group. These findings indicate that administration of eplerenone can improve CSNA and prevent LV remodeling in patients with a first STEMI.

Funding

The authors have indicated they have no financial conflicts of interest.

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