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Combined Effects of Low-Dose Spironolactone and Captopril Therapy in a Rat Model of Genetic Hypertrophic Cardiomyopathy

Resende, Micheline Monteiro de PhD; Kriegel, Alison Jessica BS; Greene, Andrew Seth PhD

Journal of Cardiovascular Pharmacology: December 2006 - Volume 48 - Issue 6 - p 265-273
doi: 10.1097/01.fjc.0000248236.43760.86
Original Article
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For several years, the severe side effects associated with the use of high doses of the aldosterone antagonist, spironolactone, limited its clinical use. Studies have recently shown efficacy and minimal side effects of low-dose spironolactone combined with standard therapy in the treatment of heart failure and hypertensive patients. The authors evaluated the effects of low-dose spironolactone alone or in combination with angiotensin-converting enzyme (ACE) inhibitors on the progression of left ventricular dysfunction and remodeling in a congenic rat model of hypertrophic cardiomyopathy.

The congenic SS-16BN/Mcwi rats developed severe cardiac hypertrophy despite being normotensive even on high-salt diet. SS-16BN/Mcwi and SS/Mcwi rats were fed a low-salt (0.4% NaCl) diet and were treated with vehicle (CON), spironolactone (20 mg/kg/d subcutaneously), captopril (100 mg/kg/d drinking water), or both spironolactone and captopril for 4 weeks. Blood pressure, plasma peptides, cardiac fibrosis, and echocardiography measurements were evaluated.

Spironolactone at a low dose had no effect on blood pressure, cardiac hypertrophy, and fibrosis in either strain. However, in combination with captopril, spironolactone decreased the cardiac hypertrophy more than captopril treatment alone. In the SS-16BN/Mcwi rats, the combined therapy significantly preserved the cardiac index when compared with control.

These data indicate that the addition of low-dose spironolactone to captopril treatment was more effective in preventing the progression of heart hypertrophy and ventricular dysfunction in the SS-16BN/Mcwi than captopril alone. This study suggests that combined spironolactone and captopril therapy may be useful in the treatment of hypertrophic cardiomyopathy.

From the Biotechnology and Bioengineering Center, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.

Received for publication May 23, 2006; accepted September 18, 2006.

Supported by National Institutes of Health grant HL-29587.

The authors state that they have no proprietary interest in the products named in this article.

Reprints: Andrew S. Greene, PhD, Department of Physiology Medical College of Wisconsin 8701 Watertown Plank Rd, Milwaukee, Wisconsin 53226 (e-mail: agreene@mcw.edu).

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INTRODUCTION

The classical mineralocorticoid effect of aldosterone on sodium transport in the kidney was long thought to be the predominant effect of this hormone. Studies have indicated that aldosterone has additional extrarenal functions, especially in the cardiovascular system, indicating a potential pathophysiologic role in the development of cardiac diseases.1 The deleterious effects of aldosterone are numerous, including myocardial and vascular fibrosis,1,2 direct vascular damage,3 baroreceptor dysfunction,4 and interference with myocardial norepinephrine uptake.5,6 In light of these findings, blocking the actions of aldosterone is of therapeutic importance.

The use of aldosterone antagonists for the treatment of myocardial failure and selected cases of hypertension, in combination with the current therapy, has been tested in recent clinical trials. The Randomized Aldactone Evaluation Study (RALES) was designed to explore the efficacy of low doses of spironolactone (an aldosterone antagonist) in combination with conventional therapy [loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, and digoxin] in patients with New York Heart Association class III or IV heart failure.7 The study reported a 30% decrease in cardiac-related mortality and hospitalization in the spironolactone-treated group.7 In a later study, selective antagonism of aldosterone with eplerenone was shown to be useful as an add-on therapy in patients whose hypertension was inadequately controlled by an ACE inhibitor or an AT1 receptor blocker alone.8 The fact that chronic treatment with ACE inhibitors or AT1 blockers may only transiently suppress aldosterone production (the aldosterone escape phenomenon9) suggests that direct blockade of aldosterone may be necessary.

The favorable results of these clinical trials in heart failure and hypertensive patients renewed interest in the use of aldosterone antagonism in cardiaovascular disease. Recent studies10 have implicated aldosterone in the pathogenesis of cardiac hypertrophy, fibrosis, and disarray in human hypertrophic cardiomyopathy (HCM). HCM is a primary disorder of the myocardium characterized by hypertrophy, usually affecting the left ventricle, in the absence of other loading conditions such as hypertension, aortic valve stenosis, or thyroid disease.11 The prevalence of HCM can be as high as 0.2% (or 1 in 500) in the general population,12 and the most serious complication is sudden cardiac death; HCM is the most common cause of sudden cardiac death in individuals younger than 35 years of age, including competitive athletes.13-15 Historically, the treatment strategy for reduction of the risk of sudden death has been the use of drugs such as β-blockers, verapamil, and antiarrhythmic agents.16-19 However, the effect of an aldosterone antagonist alone or in combination with the standard therapy has never been investigated in HCM.

In an attempt to develop an animal model to study the effect of spironolactone and captopril treatment in HCM, our laboratory generated a consomic rat strain with the substitution of chromosome 16 from the BN/Mcwi rat into the salt-sensitive hypertensive SS/Mcwi genomic background. In contrast to the parental salt-sensitive hypertensive (SS/Mcwi) rats, the consomic SS-16BN/Mcw strain is a normotensive rat, even when fed a high-salt diet (http://pga.mcw.edu). However, this strain presents left ventricular (LV) interstitial fibrosis and severe cardiac hypertrophy with occasional myocyte disarray (Fig. 1). Due to these characteristics, the SS-16BN/Mcwi rat is a valuable animal model of HCM that has allowed us to evaluate the effects of spironolactone, ACE inhibition, and the combined therapy in the progression of the cardiovascular disease in this model.

FIGURE 1

FIGURE 1

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METHODS

Experimental Design

The Medical College of Wisconsin (MCW) Institutional Animal Care and Use Committee approved all animal protocols. Animals were housed and cared for in the MCW Animal Resource Center and were fed a low-salt diet (0.4%) and water ad libitum. SS/Mcwi and SS-16BN/Mcwi rats 7 weeks old were randomly assigned to the following 4 experimental groups: control (CON, mineral oil, subcutaneous injection), captopril (CAP, 100 mg/kg/d in the drinking water), spironolactone (SPIRO, 20 mg/kg/d via subcutaneous injection), and CAP plus SPIRO (CMB, captopril, 100 mg/kg/d in drinking water and spironolactone 20 mg/kg /day via subcutaneous injection). The spironolactone was dissolved in mineral oil (Sigma). Animals were weighed weekly, and drug dosage was adjusted if necessary. Mean arterial pressure was measured using the tail-cuff method; measurements were performed before treatment (baseline) and after 4 weeks of treatment. Echocardiography measurements were performed before treatment and once each week for the 4 weeks after treatment was begun.

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Serial Echocardiographic Measurements

Rats were anesthetized with an intramuscular injection of a mixture of ketamine (100 mg/kg), acepromazine (2 mg/kg), and xylazine (50 mg/kg), and high-resolution echocardiography was performed weekly for the 4 weeks of treatment. Transthoracic echocardiograms were obtained using a 13-MHz probe (Vivid 7; GE Medical Systems, Boston, MA), which was gently placed on the shaved left hemithorax. LV end-systolic and end-diastolic dimensions as well as systolic and diastolic wall thickness were measured from the M-mode tracings at midpapillary level by using the leading-edge convention of the American Society of Echocardiography. For each M-mode measurement, at least 4 consecutive cardiac cycles were sampled. LV fractional shortening (FS) and LV end-diastolic volume (ESV) and end-systolic volume (EDV) were calculated as described previously.20 Cardiac output (CO) was calculated as the heart rate (HR) times the difference between LV EDV and ESV. The cardiac index was derived from the normalization of the cardiac output by body weight.

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Histologic Measurements of LV Fibrosis and Hypertrophy

After 4 weeks, rats were euthanized with an overdose of sodium pentobarbital. The hearts were rapidly isolated and placed in 500 mM KCl solution to wash away excess blood and promote complete cardiac relaxation. The hearts were weighed and fixed in 10% buffered formaldehyde solution for 18 to 24 hours. After fixation, the left ventricles were cross-sectioned at the equatorial midline, dehydrated, and embedded in paraffin. Five-micrometer sections were subsequently rehydrated and stained with Masson's Trichrome stain for image analysis of LV wall thickness and regional fibrosis measurements. The total LV wall thickness was quantified by measuring the distance (mm) between the lumen and the outside border of the LV wall using the Metamorph software (v.4.6; Universal Imaging Inc., Downingtown, PA). The total LV wall thickness was derived from the average of the measurements sampled in different regions of the LV, including the anterior, inferior, posterior, septum, and lateral wall.

For microscopic analysis of interstitial fibrosis, cross-sectional images were captured using a 20× objective on an Olympus BX40 microscope with a Polaroid DMC digital camera. Approximately 18 images were captured from each heart. At least 6 images were obtained from each of the endocardial, mesocardial, and epicardial regions of the left ventricle, sampled at approximately 60° intervals about the LV cross-section. The locations investigated were consistent across treatment groups. The LV wall thickness and the cross-sectional areas of tissue (regions of the image stained red) and collagen (regions of the image stained blue) were quantified using Metamorph software.

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Surgical Catheter Implantation and Plasma Peptide Measurements

At the end of the treatment period, rats were anesthetized with an intramuscular injection of a mixture of ketamine (100 mg/kg), acepromazine (2 mg/kg), and xylazine (50 mg/kg). A polyvinyl catheter was placed in the femoral artery and after 2 days of recovery, blood was collected from conscious rats and then centrifuged at 2000 × g at 4°C to collect plasma samples to measure plasma renin activity (PRA), angiotensin II, aldosterone, and atrial natriuretic factor (ANF) as previously described.21-23 Plasma sodium and potassium levels were determined using a flame photometer (model IL943; Instrumentation Laboratories, Lexington, MA).

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Statistical Analyses

All reported values are given as means ± SEM. Comparison between groups was performed using 2-way analysis of variance (ANOVA) followed by Fisher's LSD post hoc tests. Differences were determined to be statistically significant if P < 0.05.

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RESULTS

Body Weight and Heart/Body Weight Ratio

The final body weight of the captopril and the combined treated groups were lower than those of the control groups (Table 1). The reduction in body weight after chronic captopril treatment has also been observed in other studies.24-26 The exact reason for the reduced gain in body weight after captopril treatment is still unclear, but it may be related to loss of body fluid due to reduced angiotensin II and aldosterone levels after ACE inhibition. The heart-weight to body-weight ratio (mg/g) was significantly lower in captopril and combined treated groups when compared with control groups for both SS/Mcwi and SS-16BN/Mcwi rats (Table 1). The heart hypertrophy in SS/Mcwi rats was associated with a significant increase in blood pressure at the end of experimental period. In SS-16BN/Mcwi rats, however, the cardiac hypertrophy was independent of the hemodynamic (pressure and volume load) alterations. Even with lower blood pressure, the heart/body weight ratio was significantly higher in the control SS-16BN/Mcwi when compared with the control SS/Mcwi rats (3.18 ± 0.06 vs. 2.98 ± 0.06; P < 0.05) (Tables 1 and 2). Although captopril and combined therapy reduced the blood pressure of SS-16BN/Mcwi rats to similar levels, the heart/body weight ratio was significantly lower in the CMB group as compared with the CAP group (Table 1).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Histologic and Serial Echocardiographic Measurements of the LV Wall Thickness

Prior to treatment, M-mode echocardiographic measurements of the dorsal and ventral LV wall thickness were similar in control and treated rats (Fig. 2). A significant and progressive increase in the wall thickness was observed in CON and SPIRO SS/Mcwi and SS-16BN/Mcwi rats as treatment progressed. Captopril and combined therapy significantly attenuated the increase in the LV ventral and dorsal wall thickness at the first and second weeks of treatment in SS/Mcwi and SS-16BN/Mcwi rats. This effect was maintained throughout the experimental period.

FIGURE 2

FIGURE 2

After 4 weeks, the total LV wall thickness measured by histology showed a significant decrease in the total LV wall thickness in SS-16BN/Mcwi CAP and CMB groups compared with CON group (Fig. 3). The combined therapy offered additional reduction in the wall thickness compared with the monotherapy with captopril (Fig. 3). In SS/Mcwi rats, the evaluation of the wall thickness by histology showed that all treatments promoted a significant reduction in LV wall thickness when compared with control (Fig. 3). The only contrast between histological and echocardiographic measurements is that histology indicated a reduction in wall thickness due to spironolactone treatment in SS/Mcwi rats, whereas the echocardiographic measurements showed no effect.

FIGURE 3

FIGURE 3

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Blood Pressure and LV Functional Echocardiographic Measurements

Mean arterial pressure (MAP) increased significantly after 4 weeks in CON and SPIRO SS/Mcwi rats (115.30 ± 1.91 vs. 125.68 ± 3.51 and 112.00 ± 2.51 vs. 123.09 ± 1.68 mm Hg, respectively). Captopril alone or in combination with spironolactone suppressed the increase in MAP in SS/Mcwi rats and also decreased the MAP of SS-16BN/Mcwi rats (Table 1).

The LV functional analyses performed by echocardiography revealed that LV EDV and ESV, heart rate, cardiac output, stroke volume, and the LV FS did not differ significantly between the control and treated groups in either SS/Mcwi or SS-16BN/Mcwi rats. However, in both control SS/Mcwi and SS-16BN/Mcwi groups, the cardiac index (cardiac output/body weight) decreased significantly at the end of experimental period when compared with pretreatment measurements, and captopril or combined treatment prevented this decrease (Fig. 4). Interestingly, in SS-16BN/Mcwi rats treated with captopril or combined therapy, the cardiac index tended to be greater than pretreatment levels. At the end of experimental period, the cardiac index of SS-16BN/Mcwi CMB group was significantly higher than the CON group (0.63 ± 0.06 control vs. 0.85 ± 0.06 CMB mL/min/g, P < 0.05).

FIGURE 4

FIGURE 4

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LV Fibrosis

Collagen deposition was distributed heterogeneously throughout the myocardium, and fibrosis was significantly greater in the inner layer (endocardial side) than in the middle and outer layers in all groups (Fig. 5). Subendocardial collagen density was 17% greater in SS-16BN/Mcwi rats when compared with SS/Mcwi rats. The percent of fibrosis did not differ among SS/Mcwi control and treated groups. In SS-16BN/Mcwi rats, however, the percentage of cardiac fibrosis in all treated groups tended to be less than from the control group, although these differences did not reach statistical significance.

FIGURE 5

FIGURE 5

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Plasma Measurements

Data from analysis of plasma are shown in Table 2. Plasma sodium and potassium levels did not change after any treatment in either SS/Mcwi or SS-16BN/Mcwi rats. As expected, PRA increased significantly after captopril or combined therapy in both SS/Mcwi and SS-16BN/Mcwi rats. Angiotensin II was attenuated after captopril treatment in both SS/Mcwi and SS-16BN/Mcwi rats. However, plasma angiotensin II levels were not affected after the combined treatment in either SS/Mcwi or SS-16BN/Mcwi rats. Plasma ANF and aldosterone were attenuated in captopril treated SS/Mcwi and SS-16BN/Mcwi rats as compared with the control groups. The level of these peptides did not change after the combined treatment in SS/Mcwi or SS-16BN/Mcwi groups when compared with the control groups. There was a significant elevation in plasma ANF and aldosterone levels in CMB groups compared with captopril-treated SS/Mcwi and SS-16BN/Mcwi groups.

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DISCUSSION

We evaluated the effects of an aldosterone antagonist (spironolactone), an ACE inhibitor (captopril), or combined therapy on the progression of LV dysfunction and remodeling in a congenic rat model of HCM. Captopril treatment, but not spironolactone treatment, promoted a significant decrease in cardiac hypertrophy and improved the cardiac function in both SS/Mcwi and SS-16BN/Mcwi rats. However, the combination of a low-dose spironolactone and captopril lead to a more substantial decrease in LV wall thickness and heart/body weight ratio in both SS/Mcwi an SS-16BN/Mcwi rats than captopril alone. These findings are in agreement with other studies that showed the addition of an aldosterone antagonist to standard therapy with ACE inhibitors or AT1 blockers substantially reduces the cardiac hypertrophy and improves the cardiac function in different animal models of hypertension and heart failure.27-29

Unlike other animal models, the cardiac hypertrophy in SS-16BN/Mcwi rats is not associated with hypertension. This strain was first reported by our group as part of the screening process in the PhysGen PGA (http://pga.mcw.edu). Overall assessment of cardiac function in isolated hearts from the SS-16BN/Mcwi rats revealed evidence of hypertrophy (increased heart/body weight ratio), elevated intrinsic heart rate, decreased LV developed pressure and sensitivity to ischemia compared to control strains (http://pga.mcw.edu).

Although gene expression was not assessed in this study, it is interesting that the transfer of chromosome 16 produced the hypertrophic phenotype; a number of important cardiac regulatory genes are found on rat chromosome 16, including VEGF-c,30 NPY1r,31 NPY5r,32 and perhaps most interestingly Hand2.33 The HAND basic Helix-Loop-Helix (bHLH) transcription factors are essential for normal cardiac and extra-embryonic development.33 Induction of cardiac hypertrophy shows modulation of HAND expression, corresponding with observations in human cardiomyopathy.34 The downregulation of HAND expression observed in rodent hypertrophy and human cardiomyopathy may reflect a permissive role allowing cardiomyocytes to reinitiate the fetal gene program, which is associated with pathological cardiovascular remodeling.

In this study, cardiac hypertrophy was assessed by echocardiographic and histological measurements of the LV wall thickness and by heart to body weight ratio. The echocardiographic analysis of LV dorsal and ventral wall thickness as well as the heart to body weight ratio were not modified by spironolactone monotherapy. In contrast to our study, Tsybouleva et al10 showed that spironolactone (50 mg/kg/d) treatment for 10 weeks was able to reduce heart/body weight ratio in cardiomyophatic mice. The differences between these studies may be due to differences in the animal model. In contrast to our model, the hallmark of the mouse cardiomyopathic model is an increase in fibrosis and myocyte disarray rather than the clear cardiac hypertrophy observed in humans and in our rat model. The dose and duration of the treatment may be another factor that influenced the different responses; however, measurements of the plasma potassium as well as the aldosterone levels were not evaluated in the Tsybouleva et al study.

In contrast with the spironolactone monotherapy, the echocardiographic analysis of LV dorsal and ventral wall thickness showed a progressive and significant reduction in SS/Mcwi and SS-16BN/Mcwi CAP and CMB groups as compared with the control group. This effect was observed at a very early stage of the treatment, during the first or second week. The analysis of the heart to body weight ratio showed a significant reduction in rats that received captopril or combined therapy as compared with the control group. SS-16BN/Mcwi rats treated with combined therapy had a significantly lower heart/body weight ratio than the captopril- treated group. It is important to note that this response was independent of the blood pressure effects since combined therapy did not promote additional decrease in blood pressure when compared with captopril treatment, and this was consistent in both strains. Other studies have shown that spironolactone facilitates the cardioprotective effects of AT1 receptor blockade independent of blood pressure effects.35 A subpressor dose of spironolactone combined with candesartan further decreased LV weight, expression of collagen mRNA, and cardiac interstitial and perivascular fibrosis in stroke-prone spontaneously hypertensive rats when compared with both, candesartan or spironolactone treatment alone.35 Several studies have indicated that the interaction between spironolactone and ACE inhibition or AT1 receptor blockade exerts numerous effects that may directly or indirectly contribute to the reduction of cardiovascular remodeling and improvement in cardiac function. These effects include volume-electrolyte regulation and renal protection, increasing natriuresis28,36 and decreasing protein excretion;37,38 improvement in endothelial function,39 stimulation of endothelial nitric oxide bioactivity40; and reduction in the serum collagen marker and myocardial collagen turnover.39,41

The measurements of the total LV wall thickness by histology at the end of the experimental period also offered a good assessment of the geometric changes in the left ventricle caused by the different treatments. The histological measurements of the LV wall thickness correlated well with the ventral and dorsal wall echocardiography measurements with one exception: The histological evaluation of the wall thickness in SS/Mcwi rats in different regions of the left ventricle showed that all treatments promoted a significant reduction in LV wall thickness when compared to control. Echocardiography did not show a benefit from spironolactone treatment. This indicates that in some cases ultrasound measurements may under estimate the global reduction in LV hypertrophy. This study illustrates the need for use of different methods of cardiac hypertrophy assessment to better evaluate the cardiac remodeling changes after drug treatment.

Associated with the significant reduction in the cardiac hypertrophy after captopril or the combined therapy, the echocardiographic LV functional analysis revealed that the cardiac index significantly deteriorated at the end of the experimental period in the control SS/Mcwi and SS-16BN/Mcwi groups as compared with the pretreatment measurements. Captopril or combined treatment preserved the cardiac index in SS-16BN/Mcwi rats. The most significant effect was observed in the CMB group; however, no changes were seen in the stroke volume, cardiac output, or FS between the SS/Mcwi and SS-16BN/Mcwi groups.

Studies indicate that the increase in perivascular and interstitial myocardial fibrosis by aldosterone is one of the principal mechanisms responsible for the impairment in the cardiac function.42,43 Studies have shown that aldosterone regulates tissue inflammatory responses and stimulates cytokine secretion, fibroblast growth, and collagen turnover.44 These phenomena in turn lead to myocardial fibrosis and adverse ventricular remodeling. The analysis of myocardial fibrosis in SS/Mcwi and SS-16BN/Mcwi rats by Masson's Trichrome staining showed that there was a slight decrease in the percentage of LV fibrosis in the SS-16BN/Mcwi rats that received captopril, spironolactone, or the combined therapy as compared with the control group; however, the decreases did not reach statistical significance. Perhaps a reduction in myocardial fibrosis in these animals might be demonstrable if higher doses of spironolactone were used or if captopril or combined therapy with spironolactone were continued for a longer period of time. Our studies, however, have not been extended to investigate the effects of high doses of spironolactone on cardiac hypertrophy or fibrosis. A wide range of doses of spironolactone as well as the duration of the treatment have been reported in the literature. In the bulk of the studies, spironolactone dose normally varied from 5 to 80 mg/kg/d, although some studies have reported the use of a very high dose of 200 mg/kg/d.45 Although the high doses of spironolactone have been proved to be efficient in reducing heart fibrosis and hypertrophy in experimental studies,46,47 it is not applicable to the clinical settings due to the severe side effects, including hyperkalemia and sexual-hormone related disorders, which are difficult to assess in animals. In our study, we administered a 20 mg/kg/d dose of spironolactone for 4 weeks, which has been considered safe and efficacious in reducing heart fibrosis and hypertrophy in different animal models of heart hypertrophy48,49 and tested the combined effect with ACE inhibitors to evaluate the efficacy in reducing heart fibrosis and hypertrophy in the SSBN-16 rats.

Recently, 2 major clinical trials, the Randomized Aldactone Evaluation Study (RALES)7 and the Eplerenone Neurohormonal Efficacy and Survival Study (EPHESUS),50 have strongly supported the efficacy of low doses of aldosterone antagonists in combination with the current therapy (ACE inhibitors, β-blocker, and diuretics) for the treatment of myocardial failure and selected cases of hypertension. Our findings provide new insights into the pathophysiology of HCM and reveal how early intervention with aldosterone antagonist and ACE inhibitors could attenuate changes in cardiac remodeling in a consomic rat model of HCM.

The neuroendocrine activation, involving specifically the renin-angiotensin system, has been extensively implicated in the progression of cardiac fibrosis and LV remodeling.5,51,52 In this study, spironolactone alone did not promote significant changes in the neuroendocrine profile in either SS/Mcwi or SS-16BN/Mcwi rats. The aldosterone levels increased almost 2-fold in the spironolactone-treated SS-16BN/Mcwi rats (85.57 ± 20.08 vs. 44.52 ± 4.7; P < 0.09); however, due to the high variability found on this measurement, it did not reach the statistical significance established in our study (P < 0.05). Captopril treatment did decrease plasma levels of angiotensin II, aldosterone, and ANF in both SS/Mcwi and SS-16BN/Mcwi rats as compared with control. Other studies have also shown that ACE inhibitors improve LV loading conditions, remodeling, and neurohormonal activation and reduce heart hypertrophy.53Although we observed a significant reduction in heart hypertrophy after the combined therapy with spironolactone, the plasma levels of ANF, angiotensin II, and aldosterone did not change in either SS/Mcwi or SS-16BN/Mcwi rats. Plasma atrial natriuretic peptide level has been used as a reliable index of cardiac hypertrophy and decompensation in chronic heart failure.54-56 However, studies have shown that in some cases ANF levels do not correlate with symptoms or echocardiographically derived indices of LV structure and diastolic function.57-59 It is still not clear whether the interaction between spironolactone and captopril affects the neurohormonal system independently of the reduction in the cardiac hypertrophy. Additional experiments are necessary to investigate this effect.

In summary, we showed that a low dose of spironolactone was not sufficient to alter cardiac function and cardiac fibrosis; however, the combination of spironolactone with an ACE inhibitor decreased heart hypertrophy and improved cardiac function in a congenic rat model of HCM more than the ACE inhibitor alone. Although heart failure and hypertension are the main clinical indications for aldosterone antagonism, this study indicated that the combined therapy of spironolactone and captopril may be useful in the treatment of HCM.

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ACKNOWLEDGMENTS

This work was supported by National Institutes of Health Grant HL-29587. The authors thank Christine Puza for expert technical assistance, Jennifer Labecki for echocardiography assistance, and Dr. James Southern for histological examination.

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Keywords:

ACE inhibitor; spironolactone; hypertrophic cardiomyopathy

© 2006 Lippincott Williams & Wilkins, Inc.