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EXPERIMENTAL STUDY

Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction

Cheuk-Man Yu, MD, FRACP^*, George L. Tipoe, MD, PhD, Kevin Wing-Hon Lai, Mphil^* and Chu-Pak Lau, MD, FACC^*

^* Division of Cardiology, Department of Medicine, Queen Mary Hospital, Hong Kong, China
Department of Anatomy, University of Hong Kong, Hong Kong, China

Manuscript received December 31, 2000; revised manuscript received June 1, 2001, accepted June 20, 2001.

Reprint requests and correspondence: Dr. Cheuk-Man Yu, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong, China
cmyua{at}hkucc.hku.hk

	Abstract

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OBJECTIVES

The goal of this study was to compare the relative efficacy of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) in suppressing the histopathologic changes that lead to ventricular remodeling after an acute myocardial infarction (AMI).

BACKGROUND

Myocardial interstitial fibrosis in the noninfarcted region is a major histologic landmark resulting in cardiac dysfunction after AMI. However, the relative potency of an ACE inhibitor and ARB on suppressing the histopathologic changes was unclear.

METHODS

Rats with AMI were randomized to fosinopril, valsartan or a combination of the two drugs for two or four weeks. The total, type I and type III collagen and activated fibroblasts and macrophages were quantified by histomorphometry. The expression of transforming growth factor-beta 1 (TGF-beta 1) messenger ribonucleic acid (mRNA) was determined by reverse transcription polymerase chain reaction.

RESULTS

Acute myocardial infarction resulted in significant elevation of total (p < 0.001) and type I (p < 0.001) collagen and a twofold increase in TGF-beta 1 mRNA expression (p < 0.001) in the septum at two and four weeks. Macrophages and activated myofibroblasts infiltrated extensively in the infarct zone. Treatment with valsartan or combination therapy normalized the total and type I collagen (p < 0.001) as well as TGF-beta 1 mRNA level (p < 0.01) in the septum and was associated with the suppression of macrophages and myofibroblasts in the infarct zone (p < 0.01). Fosinopril was less effective than valsartan or combination therapy.

CONCLUSIONS

The use of valsartan, especially combined with fosinopril, was more effective than fosinopril in the suppression of histopathologic changes resulting in cardiac remodeling after AMI. This study has important therapeutic implications in pharmacotherapy of clinical practice.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   alpha-SMA = alpha-smooth muscle actin   AMI = acute myocardial infarction   ANOVA = analysis of variance   ARB = angiotensin receptor blocker   AT1R = angiotensin II type 1 receptors   AT2R = angiotensin II type 2 receptors   cDNA = complementary deoxyribonucleic acid   LV = left ventricle/left ventricular   mRNA = messenger ribonucleic acid   RNA = ribonucleic acid   PCNA = proliferating cell nuclear antigen   PCR = polymerase chain reaction   RT-PCR = reverse transcription polymerase chain reaction   SDr = Sprague-Dawley rats   TGF-beta 1 = transforming growth factor-beta 1

To date, the pathogenic mechanisms that govern LV remodeling are not entirely clear. In animal models and patients with AMI, LV modeling is accompanied by the accumulation of myocardial interstitial collagen in the noninfarcted region of the heart (4,5). This was suppressed by either an ACE inhibitor or ARB (6,7). However, the stimuli that result in histopathologic changes are not fully understood. In pathologic fibrosis seen in LV hypertrophy, infiltration of activated myofibroblasts and possibly other inflammatory cells has been shown to play a pivotal role (8). In the infarct zone with fibrosis and scarring, an inflammatory process has been proposed that is characterized by numerous inflammatory cellular infiltration (9). The activation of interstitial or inflammatory cells and the subsequent deposition of interstitial collagen are likely mediated through transforming growth factor-beta 1 (TGF-beta 1), the fibrogenic cytokine (10). We hypothesized that, in the pathogenic process of myocardial interstitial fibrosis in the noninfarcted region, inflammatory cellular infiltration might play a role either to act locally or in a paracrine fashion through the production of TGF-beta 1. The aims of this study were to investigate whether: 1) local infiltration of macrophages and activated myofibroblasts played a role in the myocardial interstitial fibrosis in the noninfarcted region of the heart after AMI; 2) TGF-beta 1 was involved in interstitial fibrosis; 3) type I or type III collagen was involved in interstitial fibrosis; 4) the above changes were suppressed by an ACE inhibitor, ARB or a combination of the two drugs; and 5) ARB-based therapy was more effective than ACE inhibitor on the suppression of these pathogenic changes.

	Methods

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Animal preparation.   Ten-week-old male Sprague-Dawley rats (SDr) were used. They were housed at 23 to 25°C in a 12:12-h light-dark cycle with ad libitum food and water. Blood pressure and pulse were measured weekly by noninvasive tail occlusion cuff system (model 221, IITC Inc. Life Science Instruments, Woodland Hills, California) with computerized blood pressure monitor (model 31, IITC Inc. Life Science Instruments) (11). The measurement was performed in a slightly restrained, prewarmed room temperature. At least two measurements at steady-state were performed and the averaged value was taken. Acute myocardial infarction was induced by left coronary artery ligation as described previously (12). Briefly, SDr were anesthetized by intraperitoneal injection of katamine (50 mg/kg) and xylazine (10 mg/kg). They were intubated, ventilated and left thoracotomy was performed at the fifth and sixth ribs. The left coronary artery was ligated at approximately 3 mm from its origin by a 5.0 silk suture. Sham-operated rats underwent the same operation but, without coronary artery ligation, served as controls. The animal experiments were approved and performed according to the regulation of the Animal Ethics Committee of the University of Hong Kong.

Experimental protocol.   Twenty-four hours after AMI, the rats were randomized to one of the four groups: no treatment, ACE inhibitor by fosinopril (3 mg/l drinking water and the daily consumption per rat was 10 to 12 ml), valsartan (30 mg/day/kg by gavaging) and a combination of both drugs for two or four weeks (10 to 12 rats in each group). The dosage of these drugs was previously found to exert an antifibrotic effect in other organs in rats (13), and the timing of the commencement of the drugs will simulate a clinical situation after AMI. When the rats were sacrificed, half of the animals hearts were cut into four slices, fixed in ice cold 10% buffered formalin (pH 7.4), dehydrated through alcohol gradient and embedded in paraffin for sectioning. The other half of the hearts was snap frozen in liquid nitrogen for protein and RNA extraction.

Reverse transcription polymerase chain reaction (RT-PCR).   Frozen tissue samples were homogenized and ribonucleic acid (RNA) was extracted by acid-phenol-guanidinium-thiocyanate method (14). Gene expressions were detected by RT-PCR. The complementary deoxyribonucleic acid (cDNA) was synthesized by the superscript II first strand cDNA preamplification system (Gibco BRL, Rockville, Maryland) and subsequently used for polymerase chain reaction (PCR) amplification. Thirty cycles of PCR for TGF-beta 1 and beta-actin were preformed at 94°C for 1 min, 57°C for 1 min and 72°C for 1 min. The primers used were: TGF-beta 1, 5' GAA GCC ATC CGT GGC CAG AT 3' (forward) and 5'CCA GTG ACG TCA AAA GAC AG 3' (backward); beta-actin: 5'-CCT TCC TGG GTA TGG AAT CCT-3' (forward) and 5'GGA GCA ATG ATC TTG ATC TT 3' (backward). The levels of messenger RNA (mRNA) expression were quantified by the UV-gel documentation system (BioRad, Hercules, California).

Morphometric measurement.   Morphometric measurements were done by systematically scanning the regions using a Zeiss Axiophot microscope at a magnification of 200x by an investigator blinded to the groups. Every fifth field in the septum and every third field in the right ventricle were sampled for analysis. Fields containing vessels, artifacts or incomplete tissue were excluded. Each image was analyzed using hue, saturation and intensity detection mode of Leica Qwin Image Analyzer (Leica, United Kingdom) under standardized brightness and contrast according to the user manual of the software. Mean values of at least 15 fields were taken in each region of the heart for the following experiments.

Total collagen staining.   Total collagen was stained with sirius red (15). Five-µm paraffin sections from each slice were treated with 0.2% phosphomolydic acid for 5 min and then immersed in 0.1% sirius red solution for 90 min. After washing in 0.01N HCl for 2 min, the sections were dehydrated and mounted. Morphometric analysis for total collagen was calculated by dividing the sum area of the positively stained sirius red and the sum of the reference area multiplied by 100 (15).

Immunohistochemistry.   Detection of various tissue antigens was performed by the avidin-biotin-enzyme complex peroxidase method as previously described (11). The primary antibodies used were ED1 for macrophages (1:1000, Serotec, Oxford, United Kingdom) (16), alpha-smooth muscle actin (alpha-SMA) for fibroblasts (1:2500, DAKO, Carpinteria, California) (17) as well as type I and III collagen (1:2500 and 1:3000, Chemicon, Temecula, California). Positive signals were visualized by Vectastain Elite ABC Kit (Vector Lab, Burlingame, California) using 3,3'-diaminobenzidine tetra-hydrochloride (Sigma Immuno Chemicals, St. Louis, Missouri) as a chromogen. The number of macrophages and activated myofibroblasts were quantified by counting the total number of positively stained ED1 or alpha-SMA cells in 20 grid fields with a total area of 0.1 mm². The amount of collagen type I and III was quantified by Lica Qwin image analyzer and expressed in percents as described before.

Assessment of infarct size.   Each ventricle was cut into four horizontal slices and stained with sirius red for scar tissue. Using the same histomorphometric technique, the infarct size was calculated as mean percentage infarct area relative to the LV cross-sectional area at a magnification of 40x.

Statistical analysis.   The differences in mean value of the various treatment groups were analyzed by Scheffe’s multiple comparisons in one-way analysis of variance (ANOVA) (SPSS for Windows, version 7.5, SPSS Inc., Chicago, Illinois). The interaction of drug treatment and treatment period was analyzed by two-way ANOVA. The comparison of parametric variables between two and four weeks was performed by unpaired sample t test. A regression analysis was performed to correlate the amount of cellular infiltration and collagen. All the data were expressed as mean ± SD. A p value <0.05 was considered statistically significant.

	Results

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The mortality of the procedure was 40%. There was no late death in all groups during the study period. At baseline and at the end of the study, there was no difference in body weight or heart rate between AMI and sham-operated rats (Table 1). However, the blood pressure was significantly lower after fosinopril or valsartan therapy and was further reduced by combination therapy. There was no difference in infarct size between AMI and various treatment groups (Table 1).

Inflammatory cellular infiltration.   Macrophage or activated myofibroblast was not found in the myocardial interstitium of the noninfarcted septum and the right ventricle or the sham-operated rats (Table 3). In rats with AMI, there was significant infiltration of activated myofibroblasts and macrophages in the infarcted LV free wall, which were not seen in sham-operated rats. Two and four weeks after treatment with either fosinopril, valsartan or combination therapy there was a significantly decreased number of activated myofibroblasts in the infarct zone, though combination therapy was better than fosinopril alone (Fig. 1). On the other hand, only valsartan and combination therapy decreased the number of macrophages in the infarct zone (Table 3). After four weeks of therapy, the number of macrophages was significantly lower than it was at two weeks (p < 0.01), though the number of activated myofibroblasts remained comparable. There was a positive correlation between the amount of macrophages and type I collagen in the septum (r = 0.46, p = 0.001) but not the amount of activated myofibroblasts (r = 0.02, p = NS). The number of macrophages and activated myofibroblasts also modestly correlated with each other (r = 0.30, p = 0.002).

View larger version (117K): [in this window] [in a new window]   Figure 1 Immunolocalization of activated cardiac myofibroblasts (A to E) and macrophages (F to J) in the infarct region two weeks after acute myocardial infarction (AMI). The activated myofibroblasts and macrophages were stained dark brown by anti-alpha-smooth muscle actin and anti-ED-1 antibodies, respectively. There was significant infiltration of activated myofibroblasts (B) and macrophages (G) after AMI that were not seen in the sham-operated rats (A and F). Treatment with fosinopril (C) decreased the infiltration of activated myofibroblasts, but not the macrophages (H). On the other hand, valsartan (D and I) and combined therapy of fosinopril and valsartan (E and J) significantly reduced the number of activated myofibroblasts and macrophages in the infarct zone (magnification 400x).

View larger version (83K): [in this window] [in a new window]   Figure 2 Transforming growth factor-beta 1 (TGF-beta 1) messenger ribonucleic acid (mRNA) expression in different regions of the heart two weeks after acute myocardial infarction (AMI). Reverse transcription polymerase chain reaction was performed for RNA extracted from noninfarcted septum of the left ventricle and the right ventricle after AMI. In the noninfarcted septum, there was about twofold increase in TGF-beta 1 mRNA after AMI. Treatment with fosinopril (Fos) significantly decreased the amount of TGF-beta 1 mRNA expression in this region, while valsartan or a combination of fosinopril and valsartan (Fos + Val) normalized its expression. In the right ventricle, there was no significant change in TGF-beta 1 mRNA in any group. M = X174/HaeIII marker; Sham = sham-operated rats.

	Discussion

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Inflammatory cellular infiltration and interstitial fibrosis after AMI.   It was recently hypothesized that myocyte damage after AMI is mediated by an inflammation-like response. In one animal study, infiltration of inflammatory cells, such as macrophages and neutrophils, and phenotypic transformation of fibroblasts into activated myofibroblasts were observed in the infarct zone early after AMI (9). These cells play an active role in mediating cellular damage and synthesis of interstitial collagen in the infarct zone through the activation of fibrogenic cytokines (18). However, involvement of these cells in myocardial interstitial fibrosis has not been demonstrated in the noninfarcted regions in previous studies (4,19). A recent study using proliferating cell nuclear antigen (PCNA) as a marker found that it was expressed sporadically in the noninfarcted myocardium (7). Using specific monoclonal antibodies, we confirmed the absence of macrophages and activated myofibroblasts in the noninfarcted septum and the right ventricle. Therefore, the elevated PCNA observed in that study (7) without specific cellular finger-printing is likely representing the natural turnover of cardiac interstitial fibroblasts (nonactivated ones). Since activated cells with cytokine production are known to act in an autocrine and paracrine fashion, it is possible that cells infiltrated in the infarct zone acted as a source of fibrogenic cytokine production, which stimulated the extracellular matrix production in a local and paracrine manner. This hypothesis was also indirectly supported by the observation that reducing the inflammatory infiltrates in the infarct zone by an ACE inhibitor or ARB also normalized TGF-beta 1 gene expression and interstitial fibrosis in the septum and the right ventricle, and a positive correlation exists between the number of macrophages and the amount of interstitial fibrosis. The anti-inflammatory action of ACE inhibitors had been suggested in the rat model of renal tubulointerstitial fibrosis, in that reduction of interstitial cellular infiltrates as well as tubular immunoglobulin and complement reactivity was demonstrated after four weeks of treatment (20). This might work through suppression of inflammatory mediators such as the adhesion molecules, which has been suggested in human atherosclerosis (21). It is important to note that myocytes or cells other than those investigated in this study may contribute to the expression of fibrogenic cytokines (22).

Collagen deposition in the noninfarct zone after AMI.   Disproportional increase in type I collagen in the heart results in increased chamber stiffness and reduced ventricular compliance (23). Although a few studies had demonstrated the increase in total interstitial collagen in the noninfarcted region of the LV after AMI, the change in collagen composition was not entirely clear (4–7,19). Our study has shown that the type I, but not type III, collagen was increased in the septum and, to a lesser extent, in the right ventricle. This may represent an important structural basis in cardiac remodeling after AMI in which chamber dilation and myocardial dysfunction occur (1).

Effect of ACE inhibitors or ARBs on ultrastructural remodeling.   Activation of cardiac ACE has been demonstrated in the site of interstitial fibrosis after AMI (24). In addition, angiotensin II has been shown to induce fibroblast proliferation and increased collagen synthesis, while angiotensin II type 1 receptors (AT₁R) have been identified on cultured cardiac fibroblasts (25,26). These observations suggest that activation of the renin-angiotensin system play a key role in interstitial fibrosis. Previous studies using other ACE inhibitors or ARBs as treatment from four weeks to one year significantly reduced interstitial collagen (4,6,19,27). We confirmed and extended these observations by demonstrating that treatment with ARB-based regimens and, to a lesser extent, an ACE inhibitor, for as short as two weeks after AMI normalized myocardial interstitial fibrosis in the noninfarcted regions of the heart. In addition, we provide new data that the normalization of myocardial fibrosis was largely due to the decrease in type I collagen, but not type III. In accordance with the changes in collagen volume fraction, the expression of TGF-beta 1 mRNA was also reduced more effectively by ARB-based regimens. Therefore, valsartan is superior to fosinopril in the suppression of interstitial collagen deposition, while a combination of the two agents seems to confer the best benefit. In fact, there was a suggestion that the ACE inhibitor captopril only reduces myocardial hypertrophy but is unable to decrease myocardial collagen content after AMI (28). Two previous studies compared the effect of enalapril and losartan on the suppression of interstitial fibrosis in the noninfarcted LV and reported a similar efficacy between the two drugs (4,7). The difference between this study and others might be related to the difference in pharmacokinetics between agents of the same class, difference in the degree of tissue penetration and difference in route of administration.

In this study, the infarct size was not different in various treatment groups. This is expected, as therapy was only commenced 24 h after AMI. However, this model simulates our clinical practice, that an ACE inhibitor was only started after AMI. Unlike ischemic-reperfusion models in which infarct size was reduced by ACE inhibitors or ARBs that commenced before surgery (29), no reduction in infarct size was observed in the AMI models (30). The LV mass and function was not measured in this study and, therefore, the relationship between infarct size and extent of cardiac dysfunction was not known.

The additional benefit of combination therapy over fosinopril alone is likely to confirm the previous hypothesis that ACE inhibitors act mainly by enhancing the beneficial action of bradykinin rather than by suppressing angiotensin II production (31). From our results, it appeared that antagonizing the binding of angiotensin II to its AT₁R was a more promising cardioprotective mechanism after AMI. In the canine model of ischemic reperfusion, the cardioprotective effect of AT₁R antagonist was found to involve the upregulation of angiotensin II type 2 receptors (AT₂R) (32). In fact, a recent study has shown that the benefits of ACE inhibitors and ARBs on LV remodeling were blocked by a bradykinin receptor antagonist and AT₂R antagonist, respectively (33). The clinical benefit of ARBs might be particularly relevant in clinical practice as the expression level of AT₂R is much higher in human hearts than it is in rodent hearts so that the AT₂R-mediated actions are likely enhanced, such as the antiproliferative effect (34). Whether the observed advantage of valsartan on structural damages in animal models of AMI can be transformed into clinical benefit needs to be confirmed by the large, ongoing VALIANT trial (VALsartan In Acute myocardial iNfarction Trial).

In conclusion, AMI resulted in accumulation of type I myocardial interstitial collagen in the noninfarcted septum secondary to activation of TGF-beta 1 mRNA. Infiltration macrophages and activated myofibroblasts from the infarct zone are likely to play a paracrine role in these pathologic changes. Combination therapy with valsartan and fosinopril is more effective than fosinopril alone in the attenuation of these pathologic changes. The results might have therapeutic implication in the prevention of cardiac remodeling after AMI.

	Footnotes

 
Supported by the Committee for Research and Conference, Grant No. 44/1298 from the University of Hong Kong, China.

	References

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