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 14.2Ϯ5.3 mg · kg -1 · d -1 and 42Ϯ9.6 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 (9.9Ϯ6.8% versus 4.5Ϯ2.2%, Pϭ0.01, and 27.6Ϯ10.6% versus 3.9Ϯ2.3%, PϽ0.001, respectively). Treatment with losartan reduced collagen volume fraction by 49% to 4.9Ϯ2.9%. 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-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. Key Words: cardiomyopathy Ⅲ fibrosis Ⅲ collagen Ⅲ death, sudden H ypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death (SCD) in the young, 1 is caused by mutations in sarcomeric proteins. 2 It is clinically diagnosed by unexplained cardiac hypertrophy and pathologically by myocyte hypertrophy, disarray, and interstitial fibrosis. 3 Hypertrophy and fibrosis are the major determinants of mortality, morbidity, and SCD 4,5 in HCM and in all acquired forms of cardiac diseases.The genetic basis of HCM has been elucidated, and research efforts are being directed to decipher its molecular pathogenesis and to determine the reversibility of the phenotypes. We previously proposed that interstitial fibrosis, like cardiac hypertrophy, occurs "secondary" to the activation of trophic and mitotic factors in the heart 6 and, thus, is potentially reversible by blocking cardiotrophic factors such as angiotensin II (Ang II). However, despite the well-established role of Ang II blockers in the attenuation of cardiac hypertrophy and fibrosis in acquired cardiac diseases, they are not conventionally used in the treatment of patients with HCM, a genetic paradigm of cardiac hypertrophy and fibrosis. We determined the effects of blocking Ang II on the int...

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

“…Recent data demonstrate that angiotensin II promotes cardiac fibrosis in part by activating Tgf-β signals (32). Moreover, the angiotensin II type I receptor antagonist losartan has had salutary effects on animal models of human diseases, including CsA-induced nephropathy (33), Marfan syndrome (34), skeletal myopathies (35), and transgenic overexpression of a cardiac troponin T mutation (36). To assess the effects of losartan in HCM, we treated prehypertrophic α-MHC 719/+ mice for 2 weeks prior to and during CsA induction of HCM.…”

Genomics, heart failure and sudden cardiac death

“…In animal models, SCD in transgenic mice with HF is correlated to high myocardial fibrosis (collagen) content [35,36]. Furthermore, blockade of the angiotensin II receptor type 1 by losartan has been shown to reverse and attenuate myocardial fibrosis in a transgenic HF model [37]. Taken together, the clinical and animal studies indicate that activation of the RAAS plays a critical role not only in promoting myocardial fibrosis, but also confers increased risk for SCD in HF patients.…”

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

“…83 Previous studies have suggested that losartan reduces TGF-␤ expression in heart and kidney. 84,85 Mdx mice treated for 6 to 9 months with losartan demonstrated less fiber size heterogeneity, less fibrosis per area, and increased strength by grip strength and absolute force of explanted muscle. 83 Many older DMD patients are currently being treated with losartan for the presumptive cardiac benefits of angiotensin II-type 1 receptor blockers, as previously described.…”