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(Circulation. 2001;103:789.)
© 2001 American Heart Association, Inc.
Brief Rapid Communication |
Angiotensin II Blockade Reverses Myocardial Fibrosis in a Transgenic Mouse Model of Human Hypertrophic Cardiomyopathy
From the Section of Cardiology, Department of Medicine (D.-S.L., S.L., P.B., R.R., A.J.M.), and the Section of Cardiovascular Sciences and DeBakey Heart Center (K.Y., A.E., M.E.), Baylor College of Medicine, Houston, Tex.
Correspondence to A.J. Marian, MD, Associate Professor of Medicine, Section of Cardiology, One Baylor Plaza, 543E, Houston, TX 77030. E-mail amarian{at}bcm.tmc.edu
Background—Hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis. We propose that hypertrophy and fibrosis are secondary to the activation of trophic and mitotic factors and, thus, potentially reversible. We determined whether the blockade of angiotensin II, a known cardiotrophic factor, could reverse or attenuate interstitial fibrosis in a transgenic mouse model of human HCM.
Methods and Results—We
randomized 24 adult cardiac troponin T
(cTnT-Q92) mice, which exhibit myocyte
disarray and interstitial fibrosis, to treatment with losartan or
placebo and included 12 nontransgenic mice as controls. The mean dose
of losartan and the mean duration of therapy were 14.2±5.3 mg ·
kg–1 · d–1
and 42±9.6 days, respectively. Mean age, number of males and females,
and heart/body weight ratio were similar in the groups. Collagen volume
fraction and extent of myocyte disarray were increased in the
cTnT-Q92 mice (placebo group) compared with
nontransgenic mice (9.9±6.8% versus 4.5±2.2%,
P=0.01, and 27.6±10.6% versus
3.9±2.3%, P<0.001,
respectively). Treatment with losartan reduced collagen volume fraction
by 49% to 4.9±2.9%. The expression of collagen 1
(I) and
transforming growth factor-
1, a mediator of angiotensin II
profibrotic effect, were also reduced by 50%. Losartan had no effect
on myocyte disarray.
Conclusions—Treatment
with losartan reversed interstitial fibrosis and the expression of
collagen 1 (I) and transforming growth factor-1 in the hearts of
cTnT-Q92 mice. These findings suggest that
losartan has the potential to reverse or attenuate interstitial
fibrosis, a major predictor of sudden cardiac death, in human patients
with HCM.
Key Words: cardiomyopathy • fibrosis • collagen • death, sudden
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|
|
|
|
|
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|
|
|
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|
|
|
|
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|
|
|
|
|
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|
|
|
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|
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|
|
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|
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