Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy

Abstract

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-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.

Conclusions: 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.

Figures

Figure 1

Interstitial fibrosis, expression of TGF-β1, and myocyte disarray in nontransgenic (non-tg) and cTnT-Q92 transgenic mice treated with placebo or losartan. A, B, and C show representative photomicrographs of thin myocardial sections stained with Sirius red F3BA, anti-TGF-β1 antibody, and hematoxylin and eosin, respectively, in experimental groups. Inset in B shows expression of TGF-β1 in nontransgenic group, which was localized to perivascular area.

Figure 2

A, Box-and-whisker plot showing median (bar), first and third quartiles (box), lowest and highest values, and individual data points for CVF. Mean CVF of myocardium was 4.5±2.2% (range, 1.5% to 8.7%) in nontransgenic mice (non-tg; n=12), 9.8±6.8% (range, 2.76% to 21.6%) in placebo group (n=12), and 4.9±2.9% (range, 1.05% to 9.90%) in losartan group (n=12) (P=0.011, 2 df). B represents a Northern blot showing expression of collagen 1α (I) and 28S and 18S bands in experimental groups.