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Cardiovascular Research 2005 67(1):97-105; doi:10.1016/j.cardiores.2005.03.001
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Copyright © 2005, European Society of Cardiology

Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction

Daniela Fraccarollo*,1, Paolo Galuppo1, Isabel Schmidt, Georg Ertl and Johann Bauersachs

Medizinische Klinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

* Corresponding author. Medizinische Klinik I, Universitätsklinikum, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. Tel.: +49 931 201 36301; telefax: +49 931 201 36302. Email address: fraccaroll_d{at}medizin.uni-wuerzburg.de

Received 30 November 2004; revised 22 February 2005; accepted 1 March 2005


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Objectives: The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood.

Methods: We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats.

Results: Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure–volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of {alpha}- and β-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed.

Conclusions: Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.

KEYWORDS Aldosterone; Angiotensin; Remodeling; Myocardial infarction; Heart failure


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
The RALES study showed that the mineralocorticoid receptor antagonist spironolactone added to an angiotensin-converting enzyme (ACE) inhibitor in patients with severe congestive heart failure (CHF) reduces overall mortality [1]. Post-hoc substudies of the RALES and subsequent smaller trials in postinfarction patients reported a decrease in serum markers for cardiac collagen synthesis and a reduction of left ventricular dilatation [2–5]. Recently, the EPHESUS study showed that eplerenone, a selective aldosterone receptor blocker, on top of ACE inhibitors or angiotensin II type 1 (AT1) receptor blockers reduced morbidity and mortality among patients with left ventricular dysfunction after myocardial infarction (MI) [6].

However, little is known about the mechanism underlying the clinical benefits of combined mineralocorticoid receptor antagonism and AT1 receptor blockade in patients with MI and heart failure. AT1 receptor blockade and ACE inhibition both target angiotensin effects and do not directly block aldosterone action. Moreover, even in the presence of combined AT1 receptor blockade and ACE inhibition, production of aldosterone in CHF patients is not suppressed [7]. Aldosterone plasma levels [8–10] as well as aldosterone production in the heart [11,12] are increased after MI and in CHF. Aldosterone may contribute to the progression of heart failure by promoting sodium and water retention, oxidative stress, endothelial dysfunction, vascular and myocardial fibrosis [13–15]. Mineralocorticoid receptor antagonism on top of ACE inhibition provides additive beneficial effects on cardiac remodeling [16,17], endothelial dysfunction [18] and platelet activation [19] in experimental heart failure. However, these mechanisms have not been addressed for the combination of an aldosterone receptor blocker and an AT1 receptor inhibitor.

Accordingly, we tested the hypothesis that aldosterone receptor blockade would provide a benefit additional to AT1 receptor inhibition on hemodynamics, LV dilation, and molecular alterations in the failing heart after extensive MI in rats. We focused mainly on changes in the expression of genes responsible for progressive contractile dysfunction (myosin heavy-chain isogenes, SERCA2 ATPase), stiffness and fibrosis (collagen), as well as genes associated with pathologic hypertrophy (β-MHC and ANF). Gene expression of AT1 receptor, ACE, and endothelin-1, which may contribute to aldosterone-mediated LV fibrosis postinfarction, was also studied.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
All procedures conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

2.1. Myocardial infarction and study protocols
Left coronary artery ligation was performed in adult male Wistar rats (200–250 g) [16]. Starting on the 10th postoperative day, sham-operated animals received placebo treatment, surviving MI rats were randomly allocated to one of the following four treatment groups: placebo, eplerenone (100 mg/kg/day), irbesartan (50 mg/kg/day), or a combination of eplerenone and irbesartan for 9 weeks. Eplerenone was given in food, irbesartan administered by gavage once daily. The dose of eplerenone was selected from previous studies in which eplerenone provided marked end-organ protective effects in the heart and kidney of hypertensive rats [20]. Irbesartan was given at a dose of 50 mg/kg/day, which is the most commonly used dose for this drug in rats with heart failure [21,22].

2.2. Hemodynamic and LV volume measurements
Left ventricular systolic (LVSP) and end-diastolic pressures (LVEDP), dP/dt and right atrial pressure (RAP) were measured 10 weeks after MI, under pentobarbital anesthesia (30 mg/kg body wt IP) [16]. In vivo LV pressure–volume relationship was analyzed using conductance catheter (SPR-774, Millar Instruments). PVAN software (Millar Instruments) was used to analyze all pressure–volume loop data. LV volume was calculated for each rat from conductance volume corrected by the relative parallel conductance volume (Vp) as previously described [16].

2.3. Sample collection, infarct size
The right (RV) and the left ventricle, which included the septum, were separated in ice-cold saline and weighed. Infarct size was quantified histologically by planimetry. The LV was cut into three transverse sections: apex, middle ring (~3 mm), and base. From the middle ring, 5-µm sections were cut at 100-µm intervals and stained with picrosirius red. Infarct size (fraction of the infarcted left ventricle) was calculated as the average of all slices and expressed as a percentage of length. Rats with extensive infarcts (>45%) were included in the study.

2.4. Cardiac gene expression
Total RNA was isolated from LV samples (remote noninfarcted LV myocardium) using TRIzol reagent (Invitrogen) according to the manufacturer's instructions. One-microgram of total RNA samples was reversed-transcribed with oligo(dT) primers by using Superscript II (Invitrogen). Quantification of cardiac gene expression was determined by real time polymerase chain reaction (PCR) with iCycler iQ system (Bio-Rad). Published primer and probe sequences were employed to amplify and detect ACE [23], atrial natriuretic factor (ANF) [23], AT1 receptor [23], collagen type I [24] and type III [25], {alpha}-myosin heavy chain (MHC) [26], β-MHC [26], endothelin-1 (ET1) [23] and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) [24]. For each gene, standard was constructed by cloning the specific cDNA amplified fragment into pCR2.1-TOPO vector (Invitrogen). Serial 10-fold dilutions of the generated plasmid were used as standard curve. A given mRNA level was expressed as a ratio with respect to the level of mRNA for GAPDH.

2.5. Collagen content
Quantitative myocardial collagen assessment was performed as previously described [27] with minor modifications. Briefly, 7-µm picrosirius red sections of the interventricular septum were examined under either blue-filtered brightfield or polarized light. Images were analyzed using Scion Image Beta 4.02 program (Scion Corporation, USA).

2.6. Western blot analysis
LV samples (remote noninfarcted LV myocardium) were homogenized in ice-cold RIPA buffer. Proteins were determined by Bradford assay. Myocardial extracts (30 µg protein per lane) were mixed with sample loading buffer and under reducing conditions separated on 10% SDS–polyacrylamide gel [16]. Proteins were electrotransferred onto PVDF membrane (Immun-Blot®, Bio-Rad). The bands were detected using chemiluminescence assay (ECL Plus, Amersham). Primary antibody used recognizes: sarcoplasmic-reticulum calcium ATPase (SERCA2 ATPase; MA3-919, Affinity BioReagents).

2.7. Statistical analysis
Data are expressed as mean ± S.E.M. Statistical analysis was performed by one-way ANOVA followed by multiple comparisons using Fisher's protected least-significant difference test. Statistical analysis was performed using StatView 5.0 statistic program (Abacus Concepts, Berkley, CA, USA). Statistical significance was assumed at p<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
3.1. Global parameters
Infarct size and body weight (BW) were similar among the experimental groups (Table 1). LV weight was reduced in the eplerenone/irbesartan-treated CHF group compared to placebo. RV weight was markedly higher in placebo-treated CHF rats compared to sham-operated controls and significantly reduced by both monotherapies. Combination therapy led to a significant further decrease in RV weight compared to monotherapy with either eplerenone or irbesartan (Table 1).


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  		Table 1 Global parameters of sham-operated rats (Sham) and rats with heart failure (CHF) 10 weeks after MI: Effects of selective aldosterone receptor antagonism, AT1 receptor antagonism, or combined aldosterone and AT1 receptor antagonism

 
3.2. Hemodynamics and left ventricular dilation
LVSP was reduced in all CHF groups irrespective of treatment (Table 1). CHF rats on placebo developed elevated LVEDP and markedly lower LV dP/dtmax and dP/dtmin. Monotherapy with eplerenone or irbesartan significantly attenuated LVEDP and tended to enhance dP/dtmax and dP/dtmin, whereas combined treatment further prevented the rise in LVEDP and significantly improved dP/dt (Table 1). RAP was elevated in untreated CHF rats and reduced more significantly by combination therapy than monotherapies (Table 1). CHF resulted in a rightward shift of the LV pressure–volume loops to high volumes (Fig. 1). Eplerenone and irbesartan significantly decreased LV end-diastolic volume (LVEDV) compared to placebo. Combination therapy led to a further decrease in LVEDV compared to monotherapies (Fig. 1). LV end-systolic volume was increased in placebo CHF rats compared to controls (760 ± 88 vs. 192 ± 24 µl, p<0.01), significantly reduced by eplerenone (553 ± 99 µl, p<0.05) and by irbesartan (541 ± 60 µl, p<0.05) and further reduced by combination therapy (392 ± 33 µl, p<0.001).


Figure 1
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  		Fig. 1 Representative left ventricular pressure–volume loops (left) and left ventricular end-diastolic volume (right) measured in vivo with conductance catheter in sham-operated rats (Sham, n=8) and in rats with heart failure (P CHF, n=12) 10 weeks after MI: Effects of selective aldosterone receptor antagonism (E, n=8), AT1 receptor antagonism (I, n=7), or combined aldosterone and AT1 receptor antagonism (E+I, n=10). Mean ± S.E.M. *p<0.01 vs. Sham; {ddagger}p<0.05, {dagger}{dagger}p<0.001 vs. P CHF.

 
3.3. Left ventricular fibrosis
Interstitial fibrosis, collagen type I and type III gene expression in the noninfarcted LV myocardium were increased in placebo CHF rats, similarly attenuated by eplerenone and irbesartan, and slightly further reduced by combined aldosterone and AT1 receptor inhibition (Fig. 2).


Figure 2
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  		Fig. 2 Examples of Sirius red stained ventricular sections under brightfield or polarized light (right), and statistical analysis (left) of collagen type I and type III mRNA expression and collagen content in the left ventricle of sham-operated rats (Sham) and rats with heart failure (P CHF) 10 weeks after MI: Effects of selective aldosterone receptor antagonism (E), AT1 receptor antagonism (I), or combined aldosterone and AT1 receptor antagonism (E+I). Birefringence of sections under illumination with polarized light identifies collagen, including types I (collagen fibers appear orange or red) and type III (thinner collagen fibers appear green or yellow). Mean ± S.E.M. (n=7–10). *p<0.05 vs. Sham; {ddagger}p<0.05, {dagger}p<0.01 vs. P CHF.

 
3.4. Left ventricular expression of {alpha}-MHC, β-MHC, ANF and SERCA2 ATPase
{alpha}-MHC mRNA expression was reduced, β-MHC and ANF mRNA levels were substantially increased in CHF rats (Fig. 3). Eplerenone tended to attenuate but irbesartan and eplerenone/irbesartan almost completely prevented the reduction of {alpha}-MHC. Irbesartan and, to a lesser degree, eplerenone monotherapy tended to decrease cardiac β-MHC and ANF mRNAs and the combination augmented this effect of the individual drugs (Fig. 3). SERCA2 ATPase downregulation in placebo CHF rats was attenuated by irbesartan, and completely prevented by eplerenone/irbesartan (Fig. 3).


Figure 3
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  		Fig. 3 mRNA expression of {alpha}-MHC, β-MHC, ANF to GAPDH and SERCA2 ATPase protein expression in the left ventricle of sham-operated rats (Sham) and rats with heart failure (P CHF) 10 weeks after MI: Effects of selective aldosterone receptor antagonism (E), AT1 receptor antagonism (I), or combined aldosterone and AT1 receptor antagonism (E+I). Mean ± S.E.M. (n=7–10). *p<0.05 vs. Sham; {ddagger}p<0.05, {dagger}p<0.01, {dagger}{dagger}p<0.005 vs. P CHF.

 
3.5. Left ventricular expression of AT1 receptor, ACE and endothelin-1
The increase in AT1 receptor mRNA levels in the surviving LV myocardium from placebo CHF rats tended to be attenuated by AT1 receptor blockade, however, was significantly prevented only by aldosterone receptor blockade (Fig. 4). ACE gene expression was higher in CHF rats than in sham-operated rats. Treatment with eplerenone and irbesartan alone or in combination was associated with a significant reduction in ACE mRNA levels (Fig. 4). Endothelin-1 gene expression was increased in placebo CHF rats and significantly attenuated by eplerenone, irbesartan and eplerenone/irbesartan (Fig. 4).


Figure 4
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  		Fig. 4 Expression of AT1, ACE and endothelin-1 mRNA in the left ventricle of sham-operated rats (Sham) and rats with heart failure (P CHF) 10 weeks after MI: Effects of selective aldosterone receptor antagonism (E), AT1 receptor antagonism (I), or combined aldosterone and AT1 receptor antagonism (E+I). Mean ± S.E.M. (n=7–10). *p<0.05 vs. Sham; {ddagger}p<0.05, {dagger}p<0.01, {dagger}{dagger}p<0.005 vs. P CHF.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
In the present study we show that aldosterone receptor antagonism with eplerenone provides additional benefit to AT1 receptor blockade on postinfarction LV function and dilation by altering the expression of genes that regulate myocardial fibrosis and contractility. These data provide further insights into the mechanisms underlying the striking improvement in morbidity and mortality produced by aldosterone antagonism in addition to optimal standard therapy among patients with heart failure [1,6].

Coronary artery ligation in the rat produces a broad spectrum of cardiac dysfunction, ranging from minor impairment to overt heart failure, depending on MI size [28]. Only rats with extensive myocardial infarction were included in this study. Untreated MI animals developed severe CHF, evidenced by an augmented LV filling pressure and volume, as well as a marked deterioration of LV function. Irbesartan and eplerenone limited left ventricular dilation and attenuated CHF, as already reported with AT1 receptor antagonists [22,29,30] and aldosterone receptor blockers postinfarction [16,17,31]. Notably, AT1 inhibition combined with aldosterone antagonism provided additional beneficial effects on loading conditions and LV performance with an overall reduction in LV remodeling.

More effective improvement of heart failure by the combination therapy may be mediated in part by the greater effect on reactive fibrosis in the remote noninfarcted LV myocardium, a major determinant of ventricular remodeling in ischemic cardiomyopathy [32,33]. Alterations in the collagen matrix raise cardiac muscle stiffness and impair myocyte relengthening leading to progressive dysfunction and heart failure [32]. In this regard, the reduction of LV fibrosis together with the restoration of SERCA2 ATPase by eplerenone/irbesartan may have synergistically improved cardiac relaxation and systolic function. During cardiac relaxation, cytoplasmic calcium levels are predominantly regulated by SERCA2 ATPase and its downregulation in hypertrophied and/or failing myocardium is linked to diastolic dysfunction [34]. Additionally, downregulation of SERCA2 ATPase contributes to contractile dysfunction [34]. In CHF patients, the favorable functional effects of beta-blockers are related to prevention of SERCA ATPase downregulation [35].

Downregulation of {alpha}-MHC coupled with an upregulation of β-MHC has been demonstrated in failing human myocardium and may play a critical role in the impairment of cardiac function as well as in the pathophysiology of heart failure [35,36]. Lowes et al. [35] reported that functional improvement in dilated cardiomyopathy by beta-blocking agents was associated with an increase in {alpha}-MHC and a decrease in β-MHC myocardial gene expression. Accordingly, the additive improvement of MHC isoforms alterations by combined aldosterone and AT1 receptor inhibition may have provided greater benefits on LV hemodynamics and remodeling.

Several recent clinical data reported that aldosterone receptor antagonism on top of ACE inhibition provides additive benefits on cardiac remodeling in ischemic heart failure [3,5,37]. Although ACE inhibitors remain the essential drugs, our data suggest that combined aldosterone and AT1 receptor blockade may constitute the appropriate therapeutic approach to the amelioration of postinfarction ventricular remodeling and heart failure in patients who cannot tolerate ACE inhibitors.

We have previously shown that in rats with extensive MI, addition of eplerenone to ACE inhibition improved cardiac function and remodeling more effectively than ACE inhibition alone, with complementary effects on LV fibrosis and hypertrophy [16]. While eplerenone was superior to ACE inhibition in reducing LV collagen expression and accumulation, ACE inhibition had a greater effect on fetal gene expression and SERCA2 ATPase protein levels [16]. Of note, combined aldosterone and AT1 receptor antagonism led to comparable additive improvement of LV hemodynamics and remodeling as the combination of eplerenone and ACE inhibition [16]. In the present study, AT1 receptor blockade, like ACE inhibition [16], reversed the alterations in MHC isoforms, ANF and SERCA2 ATPase expression more effectively than aldosterone antagonism. Instead, LV collagen expression and accumulation were comparably reduced by AT1 receptor blockade and aldosterone antagonism, suggesting that aldosterone-induced fibrosis in postinfarction heart failure might arise via AT1-mediated mechanisms. Conceivably, the reduction of myocardial AT1 receptor expression by aldosterone antagonism may have contributed to decreased cardiac fibrosis. Indeed, independently of cardiac load, locally produced or circulating aldosterone stimulates cardiac fibrosis, either via a direct effect on the mineralocorticoid receptor, or indirectly by interfering with AT1 receptors, possibly leading to increased responsiveness of AT1 receptors to angiotensin II [38,39]. In aldosterone–salt-treated rats, spironolactone was as effective as the AT1 receptor antagonist losartan in preventing the upregulation of cardiac AT1 receptor and collagen accumulation [40]. The mechanisms responsible for the less pronounced reduction of myocardial AT1 receptor expression by AT1 receptor inhibition alone and on top of aldosterone antagonism remain to be investigated. Kijima et al. reported that upregulation of AT1 receptor mRNA was further increased by AT1 receptor antagonism in stretched cardiomyocytes, suggesting that AT1 receptor-mediated signals have inhibitory effects on AT1 receptor itself [41].

In the present study we provide additional mechanisms whereby aldosterone antagonism may exert beneficial effects in postinfarction heart failure. Eplerenone prevented ACE upregulation in the failing heart. Harada et al. reported that aldosterone, via mineralocorticoid receptors, upregulates ACE mRNA expression in neonatal rat cardiomyocytes, suggesting the existence of a positive feedback pathway from aldosterone to ACE, within the cardiac renin–angiotensin–aldosterone system [42]. Inhibition of this pathway, resulting in reduced angiotensin II and aldosterone production, may be an important mechanism contributing to the beneficial effects of eplerenone on cardiac fibrosis and failure postinfarction. Interestingly, angiotensin II did not increase the expression of ACE mRNA at the same molar level as aldosterone in neonatal cardiomyocytes [42]. This may explain the more pronounced effect of aldosterone receptor inhibition on ACE mRNA levels than AT1 antagonism. Moreover, no additional effect on ACE expression in the failing heart was observed by concomitant aldosterone and AT1 receptor antagonism. Consequently, more effective improvement of heart failure by the combination therapy unlikely was mediated by the reduction of ACE mRNA levels. In addition, long-term eplerenone treatment reduced myocardial endothelin-1 expression, which may also have contributed to benefit of aldosterone antagonism, by preventing the deleterious effects of endothelin-1 on the failing heart [43]. The mechanisms for reduced myocardial endothelin gene expression by aldosterone antagonism postinfarction remains unclear. Several studies described an interaction between aldosterone and endothelin-1. Aldosterone infusion enhances vascular endothelin-1 mRNA levels in salt-loaded rats [44]. On the other hand, endothelin-1 even in the presence of ACE inhibition stimulates aldosterone secretion, having a direct secretagogue effect on the adrenal cortex [45,46]. Endothelin-1 overexpression postinfarction correlated with the degree of cardiac dysfunction and failure [43]. However, we suppose that not only the improvement of LV hemodynamics accounted for myocardial endothelin-1 mRNA reduction by eplerenone. In fact, although combined aldosterone and AT1 receptor antagonism more effectively improved LV function and cardiac failure, we did not observe an additive effect on endothelin-1 mRNA expression. Therefore, the mechanisms by which aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade are unlikely related to the prevention of endothelin upregulation.

The doses of eplerenone and irbesartan used in this study were high, however drug dosages given in rat models of experimental CHF are usually much higher than that used in CHF patients due to different drug metabolism and efficacy [15,16,21,22]. Furthermore, the body weight in the combination therapy group was slightly lower than in the placebo CHF group. Although we cannot definitively exclude potential adverse effects of the drugs, more effective reduction of right atrial pressure and RV weight suggests that combined treatment led to less fluid retention.

In summary, additive improvement of LV remodeling associated with prevention of molecular changes responsible for progressive LV contractile dysfunction contributes to the beneficial effects of combined aldosterone and AT1 receptor blockade postinfarction.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
The authors thank Anna Dembny, Christian Cheng, Christian May and Michael Hoffmann for technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft (SFB355, B9, B10).


   Notes
 
1 Both authors contributed equally to the present study. Back

Time for primary review 34 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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