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

Do Sun Lim, Silvia Lutucuta, Pavan Bachireddy, Keith Youker, Alida Evans, Mark Entman, Robert Roberts, Ali J. Marian

Research output: Contribution to journalArticlepeer-review

336 Citations (Scopus)


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 1α (I) and transforming growth factor-β1, 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 1α (I) and transforming growth factor-β1 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.

Original languageEnglish
Pages (from-to)789-791
Number of pages3
Issue number6
Publication statusPublished - 2001 Feb 13
Externally publishedYes


  • Cardiomyopathy
  • Collagen
  • Death, sudden
  • Fibrosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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