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Abstract
-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.
We randomized 24 adult cardiac troponin T (cTnT-Q(92)) 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-Q(92) 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 1alpha (I) and transforming growth factor-beta1, a mediator of angiotensin
II profibrotic effect, were also reduced by 50%. Losartan had no effect on myocyte
disarray.
Treatment with losartan reversed interstitial fibrosis and the expression of collagen
1alpha (I) and transforming growth factor-beta1 in the hearts of cTnT-Q(92) 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.
[1
]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.