title: FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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 µm(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 pressure-volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope-mmHg/μL; P < 0.05).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, St Vincent's Hospital, University of Melbourne, Australia.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Edgley
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Cox
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Powell
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Kompa
authors.forename: David I
authors.initials: DI
authors.lastname: Stapleton
authors.forename: Steven C
authors.initials: SC
authors.lastname: Zammit
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D002109:Caffeic Acids / Q000627:therapeutic use*; D006328:Cardiac Catheterization; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy*; D005355:Fibrosis / Q000188:drug therapy; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D062367:ortho-Aminobenzoates / Q000627:therapeutic use*
chemical_list: D000933:Antifibrinolytic Agents; D002109:Caffeic Acids; C576235:FT011; D062367:ortho-Aminobenzoates; D013311:Streptozocin; D003094:Collagen