FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy

Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti-fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren-2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans. Homozygous Ren-2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 1.28 vs, 2.42 0.43/area; type I collagen, 4.09 1.16 vs. 1.42 0.38/area; type III collagen, 1.52 0.33 vs. 0.71 0.14 /area; P 0.05), cardiomyocyte hypertrophy (882 38 vs. 659 28 m(2); P 0.05), and interstitial macrophage influx (66 5.3 vs, 44 7.9 number/section; P 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 0.016 vs. 0.577 0.024 cm), increased ejection fraction (75 1.1 vs. 83 1.2) and preload recruitable stroke work relationship (44 6.7 vs. 77 6.3 slope-mmHg; P 0.05), and reduced end-diastolic pressurevolume relationship (0.059 0.011 vs. 0.02 0.003 slope-mmHg/L; P 0.05). A direct anti-fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.