© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Aldosterone receptor blockade improves left ventricular remodeling and increases ventricular fibrillation threshold in experimental heart failure
aDepartment of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy
bResearch Center for Endocrinology and Metabolism, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
cMedizinische Universitätsklinik Würzburg, Würzburg, Germany
dGiEnne Pharma, Milan, Italy
cittadin{at}unina.it
* Corresponding author. Medicina Interna, Via Pansini 5 (Ed. 18), University Federico II, 80131 Naples, Italy. Tel.: +39-081-746-4375; fax: +39-081-746-3199.
Received 15 August 2002; accepted 25 January 2003
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Abstract |
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Objectives: To investigate the effects of aldosterone receptor blockade in postinfarction heart failure. Methods: Eighty-seven rats with moderate myocardial infarction were randomized to receive either no drug or canrenone, the active metabolite of spironolactone, 20 mg/kg/day, or ramipril, 1 mg/kg/day, or a combination of the two drugs. Treatment was initiated 1 month after coronary ligation and lasted 4 weeks. Echocardiography was performed at baseline and after 4 weeks. LV catheterization, isolated heart studies, morphometric histology, myocardial norepinephrine and SERCA-2 mRNA were assessed at the end of the treatment period. Results: Infarct sizes were 33±3, 32±3, 34±3, and 34±4% in the placebo, canrenone, ramipril, and combination groups, respectively. Canrenone attenuated LV remodeling, improved LV systolic and diastolic function, and markedly reduced interstitial and perivascular fibrosis. These effects were increased by concomitant ramipril therapy. Moreover, myocardial norepinephrine content was decreased while ventricular fibrillation threshold significantly augmented by canrenone. SERCA-2 levels remained unchanged. Conclusions: Canrenone attenuated LV dilation and interstitial remodeling, and improved LV filling dynamics and systolic function in the rat model of postinfarction heart failure. Addition of ramipril conferred further cardioprotection. Canrenone also reduced myocardial norepinephrine content and increased ventricular fibrillation threshold. The data provide a potential explanation for the decreased sudden death observed in the RALES study.
The mechanisms of action of aldosterone inhibition are still poorly understood, despite its proven efficacy in heart failure. Rats with postinfarction heart failure were randomized to receive for 1 month either no drug or canrenone, or ramipril, or a combination of canrenone and ramipril. Canrenone treatment was associated with a significant attenuation of LV dilation, better LV diastolic and systolic dynamics, and a marked reduction of reactive fibrosis. These effects were enhanced by concomitant ramipril therapy. Moreover, canrenone increased ventricular fibrillation threshold and reduced myocardial norepinephrine content. The data may explain the reduced mortality demonstrated by the RALES.
KEYWORDS Antagonists; Connective tissue; Fibrosis; Heart failure; Ventricular arrhythmias
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The recent RALES study demonstrated that aldosterone receptor inhibition with spironolactone in chronic heart failure (CHF) increases survival by approximately 30% [1]. Particularly intriguing was the observation that spironolactone specifically reduced sudden death [1]. The mechanisms underlying these salutary actions of spironolactone are likely multiple. Indeed, aldosterone regulates not only renal electrolytes and body fluid, but also induces myocardial and vascular fibrosis, baroreceptor dysfunction, sympathetic activation, and parasympathetic inhibition [2].
Recent animal studies have provided novel insights into aldosterone role in heart failure progression. Chief among these was the demonstration of a functioning steroidogenic system in the heart, which is upregulated in postinfarction heart failure [3,4]. The enhanced local production of aldosterone, mediated by cardiac angiotensin II, is involved in the genesis of post-myocardial infarction (MI) reactive ventricular fibrosis and in the control of tissue norepinephrine content [4]. Interestingly, aldosterone receptor inhibition markedly reduces left ventricular (LV) reactive fibrosis, but does not affect reparative fibrosis and scar formation [5]. Moreover, spironolactone and converting enzyme inhibition (CEI) exhibited an unexpected synergistic action on natriuresis [6].
A number of questions still remain as to the effects of aldosterone inhibition (with and without concomitant treatment with CEI) on variables that are known to exert a profound impact on heart failure progression, including: (i) LV cavity geometry and wall stress in vivo; (ii) LV systolic function and intrinsic contractility in vitro; (iii) passive LV stiffness; (iv) ventricular arrhythmias, particularly ventricular fibrillation; (v) myocardial expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA-2). Because many of these issues have not been previously addressed, we undertook the present study to explore systematically the effects of canrenone conjugated with 
-cyclodextrin, either alone or associated with CEI on post-MI ventricular biology and function.
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2 Methods |
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All methods described conformed to the Guiding Principles for Research Involving Animals and Human Beings, and the protocol was approved by the Animal Care Committee of the University Federico II of Naples. Myocardial infarction was induced according to previously described methods [7]. Male Sprague–Dawley rats (Charles River Italy, Calco, Lodi, Italy) with a body weight ranging from 150 to 200 g, were anesthetized with a combination of ketamine HCl 20 mg/kg and xylazine 10 mg/kg i.p. (Sigma, Saint Louis, MO, USA) and orally intubated. After performing an anterior thoracotomy the heart was exteriorized and a 6-0 silk suture snugly placed around the proximal left anterior descending coronary artery. Sham animals underwent the same surgery, but did not receive the ligation of the coronary artery. Perioperative mortality rate in the infarcted groups was approximately 35%. One month after coronary ligation, rats were randomized to receive either canrenone-
-cyclodextrin (GiEnne Pharma, Italy), 20 mg/kg/day (18 rats), or the CEI ramipril (Astra Zeneca, Sweden) at the dose of 1 mg/kg/day (17 rats), or a combination of the two drugs (18 rats), or placebo (16 rats). The dose of canrenone was based on a previous dose-finding study [8].
2.1 Echocardiographic and hemodynamic studies
Transthoracic echocardiograms were performed in all animals at the randomization time and after 4 week of treatment, according to previously described methods [7], with an electronic system equipped with a 7 or 12 MHz probe (Agilent Technologies, MA, USA). All measurements, performed with an off-line analysis system by one observer who was blinded to prior results, were based on the average of three to six consecutive cardiac cycles.
Within 6 h from the final echocardiogram, rats underwent closed chest LV catheterization using a calibrated 2 French micromanometer-tipped catheter (Millar Instruments, Houston, TX, USA), as previously described [7].
2.2 Isolated, isovolumic, buffer-perfused rat preparation
To investigate systolic and diastolic function independent of loading conditions that are known to affect in vivo measurements, ex-vivo studies were performed using an isolated-isovolumic, buffer-perfused Langendorff preparation. Measurements of heart function were performed as previously described in detail [7,9]. Comparison between hearts of varying sizes was performed by obtaining a pressure–volume curve in each heart increasing the balloon volume in steps of 20–30 µl, as previously described [9]. The digital LV pressure tracing was analyzed to obtain peak systolic and diastolic pressure, time to peak systolic pressure, end-diastolic pressure, developed pressure, time from peak systolic pressure to 90% of relaxation. The diastolic pressure–volume (P–V) relations were found to best fit the exponential function: LV diastolic pressure=be(m·LV diastolic volume), which was linearized: ln LV diastolic pressure=ln b+m(LV diastolic volume) for statistical analysis. Statistical comparisons of LV diastolic P–V relations were made from the slopes of the linearized relations (LV chamber k) of this relation.
Ventricular fibrillation (VF) was induced by a.c. stimulation in isolated beating hearts according to previously reported methods [10], which were modified based on preliminary experiments in control and infarcted rats (n = 95). Briefly, a graded, 60-Hz a.c. stimulation was delivered to the heart via the punctate electrode located in the right ventricle, initially with a voltage level of 10 V (peak-to-peak) for 3 s. Regional electric potential were measure with pairs of electrodes sutured onto the right and LV surface. If the termination of current was not followed by sustained VF, the voltage level was increased by 5 V for the next delivery. The VF state was easily recognized by the irregular rapid electrical potentials following the end of stimulation. We considered continuation of VF state 
45 s as a successful induction.
2.3 Morphometric histology, collagen content and capillary density
Six hearts from each group were rapidly excised, gross examined, immersion fixed in formalin 4%, and embedded in paraffin [7,8]. The whole ventricles were cut serially into 10–14 transverse sections (varying according to the heart's size) 1 mm thick each, from apex to base. Six-µm thick transverse sections were subsequently stained with the following methods: (1) hematoxylin and eosin (H&E); (2) Mallory's trichrome; (3) Picrosirius red [8]. Parallel sections were immunostained with polyclonal anti-human collagen I and III (Monosan, Uden, The Netherlands), according to standard avidin–biotin–peroxidase technique. Normal rabbit serum was used for negative control [11]. Slides were observed with a Nikon Microphot FXA light microscope equipped with a polarized set and analysed with Zeiss KS300 software.
In each animal the following parameters were assessed from transverse sections taken at similar level, thus allowing intergroup comparisons of matching myocardial areas, by two observers blinded as to the treatment groups: (1) the percentage of infarcted areas [7]; (2) evaluation of cardiomyocyte diameter (staining H&E, 50 fields per animal) [7]; (3) collagen volume fraction (CVF) in myocardial areas remote from infarction (staining Picrosirius red and collagen I and III immuno, 40x magnification, 50 fields per animal); CVF was expressed as the mean percentage of connective tissue areas divided by total tissue area in the same field [11]; (4) capillary density taken as the number of capillaries per mm2 (staining GSLI) [12]; (4) perivascular collagen, quantified as previously described [13]. Collagen I and III isoforms were also detected by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE)–Western Blot according to standard methods [14]. Hydroxyproline content was determined as previously described [8].
2.4 SERCA-2 measures
We measured SERCA-2 mRNA insofar as its levels are considered an excellent marker of heart failure and for its central role in the control of myocardial relaxation. RNAse protection assay (RPA II kit Ambion) and the solution hybridization RNAse protection assay were performed according to the manufacturer's instructions with 20 µg of total RNA, prepared as previously described [15]. By use of the standard preparation in a standard curve, mRNA levels were expressed in absolute amounts and related to total RNA. Each RNA sample was analyzed in duplicate.
2.5 Myocardial norepinephrine content
Myocardial levels of norepinephrine were measured by high-performance liquid chromatography (HPLC) with electrochemical detection according to standard techniques [16].
2.6 Statistical analysis
All results are given as mean±S.E.M. Statistical analysis was performed using the SPSS statistical package. Between-group comparisons of echocardiographic indexes were performed with the two-way analysis of variance (ANOVA) with repeated measures in one factor (time). One-way ANOVA was used for the other comparisons. Where appropriate, comparisons to determine the significant changes within the same group over time and between groups at each time point were performed with the Neuman–Keuls test, after the samples were tested for normal distribution. Linear regression analysis was used as appropriate. A value of P<0.05 was considered significant.
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3 Results |
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No death was recorded over the treatment period. There were no significant differences in body weights among the study groups (Table 1). LV weight increased following experimental infarction by 30%, and was slightly reduced in all active treatment groups. Infarct size was similar in all groups, indicating that randomization resulted in a balanced distribution of infarct sizes. Heart rate did not change significantly over the treatment period. At 4 week, it was 295, 292, 301, 308, and 312 bpm in controls, MI, canrenone, combination, and ramipril group, respectively (P = NS).
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3.1 Echocardiographic and hemodynamic data
As expected, compared with shams, the untreated MI group showed LV dilation, reduction of relative wall thickness, and impaired systolic function (Table 2). Further accentuation of pathologic remodeling was observed over the treatment period, as manifested by progressive eccentric LV dilation, and reduction of fractional shortening. Canrenone alone prevented progressive LV dilation and dysfunction. In vivo catheterization showed a slight reduction of LV systolic pressure in the canrenone group as compared with the MI group (Table 2). Canrenone improved LV filling dynamics, as shown by
that was no longer different from sham controls. Due to the combined effect on LV pressure and architecture, LV posterior wall systolic and particularly diastolic load indexes were reduced in the canrenone group by 21 and 41%, respectively (Table 2).
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Combined CEI and canrenone treatment did not affect LV remodeling to a greater extent than canrenone alone, but had more relevant effects on LV function. Indeed, not only was LV fractional shortening prevented from deteriorating, but even improved in the combined treatment group (Table 2). LV systolic and end-diastolic pressures were further reduced by the combined treatment (P<0.05 for both systolic and end-diastolic pressure vs. all MI-groups). This resulted in a remarkable reduction of systolic and diastolic stress (–38 and –66% vs. MI rats, respectively), not only as compared with the MI but also with the canrenone and ramipril groups.
With ramipril alone, progressive LV dilation was not significantly attenuated, and LV fractional shortening did not improve (Table 2). LV systolic and end-diastolic pressure were reduced as compared with the MI group, to the same extent shown by canrenone alone. Systolic (–22%) and diastolic (–33%) posterior wall load indexes were significantly reduced as compared with untreated infarcted rats, although to a minor extent than in the combination group. As observed with the other treatments, was improved by CEI treatment. Fig. 1 displays representative echocardiographic tracings from all study groups.
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3.2 Langendorff data
As expected, the placebo-treated infarcted group exhibited a marked decrease of normalized developed pressure over the entire P–V loop when compared with sham-operated rats (–33% at 50% of Vmax) (Fig. 2, Table 3). Normalized diastolic pressure–volume loops were significantly shifted leftward and upward in infarcted rats. Passive LV stiffness, defined as k, the exponential slope of the pressure–volume relationship, was also increased by 47% in the infarcted rats. It must be stressed that we report data corrected for Vmax, otherwise a leftward shift of the P–V loop would have been observed in the rats with chronic myocardial infarction, as previously reported [5,14]. Langendorff experiments confirmed the beneficial effects of canrenone therapy on systolic and diastolic function, demonstrating that the improvement was not solely dependent upon better loading conditions, but was primarily due to enhanced chamber intrinsic contractility. Specifically, in vitro isovolumic developed pressure was higher in the canrenone group than in MI rats over a wide range of preloads, i.e., balloon volumes. As a prototype, at 50% of Vmax, normalized developed pressure was 30% higher than in the placebo infarcted group. Moreover, LV diastolic chamber distensibility was improved by canrenone treatment, with a significant shift of the P–V loop to the right (Fig. 2).
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), MI (
), MI-CAN (
), MI-CEI (
), MI-CAN-CEI (
). Top, The significant decrease of developed pressure observed in the MI group is attenuated by all treatments. Bottom, The diastolic component of the P–V loop is shifted markedly to the left in the MI group, indicating decreased LV distensibility. Treatment with canrenone and ramipril, particularly when used in combination, shifts the curve to the right. In both graphs, LV parameter of interest and the balloon volumes are normalized to Vmax. See text for experimental conditions. Of note, the statistical differences occurring at 50% of Vmax (see
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All active treatment groups attenuated the increase of passive LV stiffness, since k values did not show significant differences vs. the control group, particularly the combination group. Furthermore, normalized diastolic pressure at 50% of Vmax was significantly lower than in the MI, canrenone, and ramipril groups. Also in the ramipril group, the loss of contractile function following MI was significantly attenuated by treatment, as shown by the 30% increase of developed pressure compared with the MI group. Moreover, there was a slight shift to the left of the P–V loop, with significantly lower values of normalized diastolic pressure vs. the MI group.
3.3 Ventricular fibrillation threshold
Compared with sham controls, the infarcted rats exhibited a marked decrease (–69%) of electrically induced ventricular fibrillation threshold (Table 3). Canrenone alone and canrenone plus ramipril induced a significant rise of ventricular fibrillation threshold, which was no longer different from the control group. In the ramipril group, ventricular fibrillation threshold was not statistically different from that observed in the MI group.
3.4 Myocardial norepinephrine content and SERCA-2 expression
In the MI group, norepinephrine cardiac content was slightly higher but not significant different from controls (Fig. 3). Canrenone treatment and combination therapy were both associated with a marked decrease of myocardial norepinephrine content compared not only with the MI group, but also with the sham-operated animals. The ramipril group also exhibited a significant reduction of norepinephrine, but only compared with the MI group.
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The placebo infarcted group displayed a significant reduction of myocardial SERCA-2 mRNA expression (–26%), when compared with controls (Fig. 3). Only treatment with ramipril significantly attenuated SERCA-2 downregulation, while in the group treated with canrenone alone SERCA-2 transcript levels were significantly lower than in the sham animals.
3.5 Morphometric histology and immunohistochemistry
Morphometric histology showed no differences in myocyte area among the four study groups (Table 1). Sirius red staining showed a twofold increase of collagen volume fraction in infarcted vs. sham animals, which was confirmed by the hydroxyprolin assay. All treatments reduced significantly both collagen volume fraction and perivascular fibrosis. However, the treatment associated with the maximal antifibrotic effects was canrenone plus ramipril. In this case, hydroxyproline content was reduced by 57% vs. MI, and was significantly lower than in ramipril and canrenone groups. This synergistic action of canrenone and ramipril was particularly evident in the perivascular zones, where the reduction of perivascular collagen ratio averaged 76% in comparison with the MI group. Capillary density, which was decreased by 31% in the MI group compared with sham operated rats, was significantly increased in all active treatment groups. Western Blot analysis, immunohistochemistry, and picrosirius red observation under polarized light gave similar results regarding collagen I and collagen III. Collagen phenotype differed between the control and the MI group: the collagen I/III ratio was increased by 110% in the MI group (data obtained by Western blotting), compared with sham-operated animals. In all groups, there was a proportionate reduction of both collagen types, paralleling the reduction of collagen volume fraction, and thus the collagen I/III ratio was not significantly affected. Figs. 4 and 5
depict representative photographs from the study groups.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The present study demonstrates that aldosterone receptor inhibition with canrenone in experimental heart failure causes: (i) significant attenuation of LV dilation, and wall stress; (ii) improvement of LV contractility, relaxation, diastolic chamber distensibility, and passive LV stiffness; (iii) marked reduction of interstitial and perivascular fibrosis in the noninfarcted left ventricle; (iv) reduction of myocardial norepinephrine content and increase of LV ventricular fibrillation threshold. Moreover, (v) addition of a converting enzyme inhibitor confers additional cardioprotection as manifested by further reduction of interstitial remodeling, LV filling pressures, and wall stress, and improvements of LV distensibility and passive stiffness.
4.1 Current study
Attenuation of interstitial remodeling is, in all likelihood, the key mechanism of action of canrenone. Myocardial fibrosis is indeed a major prognostic determinant of cardiac remodeling [17]. It is associated with enhanced stiffness and electrical heterogeneity with attendant diastolic dysfunction and arrhythmias, both contributing to systolic impairment. Previous data by Capasso et al. [18] and Conrad et al. [19] demonstrated in animal models of heart failure that 2–3-fold increase of collagen volume fraction in the left ventricle is associated with diastolic dysfunction, while a further increase leads to combined diastolic and systolic dysfunction with clinical signs of congestive heart failure. On the other hand, inhibition of collagen synthesis by pharmacological means attenuates LV remodeling and improves function [14].
The reduction of perivascular fibrosis may lead to improved oxygen diffusion capacity in the non infarcted areas, while the reduced interstitial fibrosis may enhance filling dynamics and decrease stiffness [17]. In this regard, the finding of similar SERCA-2 mRNA levels in MI and canrenone-treated groups supports the concept that the observed enhancement of diastolic relaxation is more dependent upon fibrosis inhibition than on enhanced SERCA-2-mediated Ca+2 reuptake by the sarcoplasmic reticulum.
Notwithstanding the well accepted deleterious effects of increased collagen deposition in the setting of chronic heart failure, it is conceivable that not all of the reported findings may be explained simply by the antifibrotic properties of canrenone. First of all, it is possible that canrenone-induced reduction of LV systolic and diastolic wall stress blunted collagen deposition simply by attenuating the hemodynamic overload, independent of a direct antifibrotic action of aldosterone receptor inhibition. This is supported by the lower collagen deposition found in the combination group, which was associated with more marked reduction of both systolic and diastolic wall stress. The antifibrotic effect of canrenone is equally unlikely to have augmented the ventricular fibrillation threshold, because this effect was not present in the ramipril group, despite a significant antifibrotic action.
The mechanisms underlying the anthiarrhythmic effects of canrenone are unclear since also myocardial norepinephrine content did not play a major role, being reduced in all treatment groups. Possible explanations include a differential effect of canrenone and ramipril on electrical remodeling, the higher ventricular wall stress of the ramipril group in the in vitro experiments due to the higher LV volumes with the attendant contraction–excitation feedback, or the canrenone-induced decrease of Na+- and (via Na+/Ca2+-exchange) possibly of Ca2+-influx known to affect ventricular fibrillation threshold [20]. Future research is needed to test these hypotheses.
Our findings of higher ventricular fibrillation threshold may provide a mechanistic explanation for the decreased incidence of sudden death in the RALES study. Furthermore, considering that the cause of death in dilated cardiomyopathy is evenly divided between pump failure and sudden death, and that ventricular fibrillation causes more than 300,000 sudden deaths in the USA alone, it is worth testing further canrenone for its potential anthyarrhytmic properties [21,22].
Canrenone and ramipril acted synergistically to reverse LV pathologic remodeling. Not only did the combined treatment reduce fibrosis, as shown by the reduction of collagen volume fraction, hydroxyproline content, and perivascular collagen ratio, but also conferred further cardioprotection against diastolic and systolic dysfunction. Indeed, diastolic filling dynamics were more markedly improved in the combination group as compared with either treatment alone, as evidenced by the nearly normalized diastolic P–V loop and the remarkable reduction of LV end-diastolic pressures and load indexes. It is also noteworthy that only the combination group exhibited both reduced myocardial norepinephrine content and normal SERCA-2 levels. In this regard, recent investigations have shed new light on the complex interaction between the converting enzyme and the steroidogenic systems at cardiovascular level including: (i) the demonstration of aldosterone-induced increase of AT-1 receptor density and potentiation of Ang II stimulated hypertrophy in smooth muscle cells [23]; (ii) increased expression of CE by aldosterone in cultured neonatal cardiomyocytes [24]; (iii) Ang II induced increase of aldosterone cardiac production in normal and diseased states [3,4].
A final consideration relates to the comparison between the canrenone and the ramipril groups. The efficacy of either treatment alone appears comparable, considering the similar reduction of end-diastolic pressures, and systolic and diastolic load indexes. Canrenone appeared to yield a better protection against cavity dilation. In this regard, our data agree with those of Litwin et al. [25] who showed no significant changes in cavity diameters and systolic function in vivo after treatment with captopril in the same experimental setting. In the current study, ramipril alone did not show superior antifibrotic activity to canrenone, at variance with the previous work of Silvestre et al. [4] who showed that losartan totally prevented fibrosis in the non infarcted myocardium. However, it must be stressed that the drugs employed were different in the two studies (losartan vs. ramipril and spironolactone vs. canrenone) and that it is difficult to choose doses of different drugs producing similar biological effects in different experimental settings. Furthermore, Brilla et al. [26] reported differential effects on collagen metabolism of angiotensin II and aldosterone in cultured adult rat cardiac fibroblasts. On the other hand, the attenuation of SERCA-2 downregulation appears to be a peculiar property of ramipril, previously shown in different model systems [27] and potentially capable of slowing heart failure progression.
4.2 Clinical implications
Following the publication of the RALES study, a major increase in the use of spironolactone use has occurred. The current study contributes to unravel the mechanisms of action of aldosterone inhibition in postinfarction heart failure, providing information about its role in the modulation of cardiac structure and function. Moreover, our data open an entirely new perspective on the potential role of aldosterone receptor inhibition in the prevention of ventricular fibrillation, which may account for the significant decrease of sudden death observed in the RALES study. Finally, by reporting synergistic actions of CEI and aldosterone receptor inhibition therapy, our study stresses the importance of a combined treatment to maximize the beneficial effects on heart failure progression.
Time for primary review 26 days.
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Acknowledgements |
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This work was supported in part by a grant from MURST (L.S.). We thank Ms. Marion Walser for her excellent technical assistance. We also thank Professor F. Angelini and Professor E. Limatola from the Laboratory of Istologia ed Analisi di Immagine del Dipartimento di Biologia Evolutiva e Comparata of Naples, for their generous support.
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 M. F. Rossier, S. Lenglet, L. Vetterli, M. Python, and A. Maturana Corticosteroids and Redox Potential Modulate Spontaneous Contractions in Isolated Rat Ventricular Cardiomyocytes Hypertension, October 1, 2008; 52(4): 721 - 728. [Abstract] [Full Text] [PDF]
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 B. Pitt and G. S. Pitt Added Benefit of Mineralocorticoid Receptor Blockade in the Primary Prevention of Sudden Cardiac Death Circulation, June 12, 2007; 115(23): 2976 - 2982. [Full Text] [PDF]
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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]
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 K. Anand, A. N Mooss, and S. M Mohiuddin Review: Aldosterone Inhibition Reduces the Risk of Sudden Cardiac Death in Patients with Heart Failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2006; 7(1): 15 - 19. [Abstract] [PDF]
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N. Laleve, M. C. Rebsamen, S. Barrere-Lemaire, E. Perrier, J. Nargeot, J.-P. Benitah, and M. F. Rossier Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes Cardiovasc Res, August 1, 2005; 67(2): 216 - 224. [Abstract] [Full Text] [PDF]
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D. Fraccarollo, P. Galuppo, I. Schmidt, G. Ertl, and J. Bauersachs Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction Cardiovasc Res, July 1, 2005; 67(1): 97 - 105. [Abstract] [Full Text] [PDF]
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J. Katada, T. Meguro, H. Saito, A. Ohashi, T. Anzai, S. Ogawa, and T. Yoshikawa Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor-Knockout Mice After Myocardial Infarction Circulation, May 3, 2005; 111(17): 2157 - 2164. [Abstract] [Full Text] [PDF]
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A. Lal, J. P. Veinot, and F. H.H. Leenen Critical role of CNS effects of aldosterone in cardiac remodeling post-myocardial infarction in rats Cardiovasc Res, December 1, 2004; 64(3): 437 - 447. [Abstract] [Full Text] [PDF]
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 G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]
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