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Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy
D S Lim1, S Lutucuta, P Bachireddy
1Section of Cardiology, Department of Medicine, Section of Cardiovascular Sciences and DeBakey Heart Center, Baylor College of Medicine, Houston, Texas, USA.
Insights
Losartan treatment reversed interstitial fibrosis in a mouse model of hypertrophic cardiomyopathy (HCM). This suggests potential for treating fibrosis, a sudden cardiac death predictor, in human HCM patients.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young individuals.
- HCM is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis.
- Fibrosis in HCM may be secondary to trophic and mitotic factors, suggesting potential reversibility.
Purpose of the Study:
- To determine if blocking angiotensin II could reverse or attenuate interstitial fibrosis in a transgenic mouse model of human HCM.
- To investigate the therapeutic potential of angiotensin II blockade in mitigating HCM-related fibrosis.
Main Methods:
- Utilized a transgenic mouse model (cTnT-Q(92)) exhibiting myocyte disarray and interstitial fibrosis.
- Randomized 24 adult cTnT-Q(92) mice to treatment with losartan or placebo, with 12 non-transgenic mice as controls.
- Administered losartan at a mean dose of 14.2 mg/kg/day for approximately 42 days.
Main Results:
- cTnT-Q(92) mice showed increased collagen volume fraction and myocyte disarray compared to controls.
- Losartan treatment significantly reduced collagen volume fraction by 49%.
- Expression of collagen 1alpha(I) and transforming growth factor-beta1 were reduced by 50% with losartan therapy.
Conclusions:
- Losartan effectively reversed interstitial fibrosis and associated gene expression in the hearts of cTnT-Q(92) mice.
- These findings indicate losartan's potential to reverse or attenuate interstitial fibrosis in human HCM patients.
- Interstitial fibrosis is a critical predictor of sudden cardiac death in HCM, highlighting the therapeutic relevance of these findings.
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.
