A new anti-fibrotic drug attenuates cardiac remodeling and systolic dysfunction following experimental myocardial infarction

Yuan Zhang, Maros Elsik, Amanda J Edgley, Alison J Cox, Andrew R Kompa, Bing Wang, Christina Yan Ru Tan, Fay L Khong, David I Stapleton, Steven Zammit, Spencer J Williams, Richard E Gilbert, Henry Krum, Darren J Kelly
International Journal of Cardiology 2013 September 30, 168 (2): 1174-85

BACKGROUND: Pathological deposition of extracellular matrix in the non-infarct zone (NIZ) of the ventricle post myocardial infarction (MI) is a key contributor to cardiac remodeling and heart failure. FT011, a novel antifibrotic compound, was evaluated for its efficacy in neonatal cardiac fibroblasts (NCF) and in an experimental MI model.

METHODS AND RESULTS: Collagen synthesis in NCF was determined by (3)H-proline incorporation following stimulation with TGF-β or angiotensin II (Ang II). FT011 inhibited collagen synthesis to both agents in a dose dependent manner. In vivo, Sprague Dawley rats underwent left anterior descending coronary artery ligation or sham surgery and were randomized one week later to receive either FT011 (200mg/kg/day) or vehicle for a further 4 weeks. Echocardiography and cardiac catheterization were performed, and tissues were collected for histological analysis of collagen, myocyte hypertrophy, interstitial macrophage accumulation and Smad2 phosphorylation. mRNA expression of collagens I and III and TGF-β was measured using in situ hybridization and RT-PCR, respectively. FT011 treatment was associated with improved cardiac function (increased ejection fraction, fraction shortening and preload recruitable stroke work) and myocardial remodeling (reduced left ventricular diameter and volume at both end diastolic and systolic) compared with vehicle treatment. FT011 significantly reduced collagen matrix deposition, myocyte hypertrophy and interstitial macrophage infiltration, and mRNA expression of collagens I and III in NIZ compared with vehicle treatment.

CONCLUSION: Anti-fibrotic therapy with FT011 in MI rats attenuated fibrosis and preserved systolic function.

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