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
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.
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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 |
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