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

• Published in: International journal of cardiology 2013-09, Vol.168 (2), p.1174-1185
• Main Authors: Zhang, Yuan, Elsik, Maros, Edgley, Amanda J, Cox, Alison J, Kompa, Andrew R, Wang, Bing, Tan, Christina Yan Ru, Khong, Fay L, Stapleton, David I, Zammit, Steven, Williams, Spencer J, Gilbert, Richard E, Krum, Henry, Kelly, Darren J
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Antifibrinolytic Agents - pharmacology; Antifibrinolytic Agents - therapeutic use; Biological and medical sciences; Blood Pressure - drug effects; Blood Pressure - physiology; Caffeic Acids - pharmacology; Caffeic Acids - therapeutic use; Cardiology. Vascular system; Cardiovascular; Collagen - antagonists & inhibitors; Collagen - biosynthesis; Coronary heart disease; Fibrosis; FT011; Heart; Hypertrophy; Male; Medical sciences; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - pathology; Myocarditis. Cardiomyopathies; ortho-Aminobenzoates - pharmacology; ortho-Aminobenzoates - therapeutic use; Random Allocation; Rats; Rats, Sprague-Dawley; Systolic dysfunction; Ventricular Remodeling - drug effects; Ventricular Remodeling - physiology
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2012.11.067

Abstract 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 by3 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 (200 mg/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.