Abstract 562: Improvement In Left Ventricular Function Due To A Reduction Of Myocardial Fibrosis Following Myocardial Infarction Using A Purpose Designed Novel Anti Fibrotic Drug FT-011
Introduction: Following myocardial infarction (MI), pathological deposition of excess collagen adversely effects cardiac function. We evaluated the role of a novel anti-fibrotic drug FT-011 (Fibrotech, Australia) in preventing fibrosis and preserving ventricular function.
Methods: To first test for anti-fibrotic effects, isolated rat neonatal cardiac fibroblasts were stimulated with angiotensin II (AII)(0.1 μmol/L) or TGF-ß(10ng/ml) and treated with FT-011 (30–200 μmol/L) alone or in combination with the angiotensin II antagonist irbesartan (Irb)(10−5-10−7mmol/l). Effects on collagen synthesis were assessed by 3H-proline incorporation. Subsequently, ten week old Sprague Dawley rats underwent LAD artery ligation to induce MI (or sham procedure), then treatment for 4 weeks with FT-011(200 mg/kg/d) or vehicle, starting 1 week post surgery. Left ventricular (LV) function was assessed by echocardiography (day 2 and 35 post-surgery) and cardiac catheterization (day 35). Total collagen (TC) deposition (by picrosirius red staining) and collagen subtypes I and III (C-I, C-III, by immunohistochemistry) were assessed.
Results: A dose dependent reduction of collagen synthesis with FT-011 in response to both AII or TGF-ß stimulation (p<0.01), and a further reduction with FT-011±Irb was observed in vitro. In vivo, MIs were of comparable size. Treatment with FT-011 significantly reduced TC, C-I and C-III (p<0.05) in the myocardium, resulting in improved LV systolic function, normalization of diastolic function parameters (Table⇓) and improvement in heart failure with a reduction in lung/body weight ratio with FT-011 (p<0.05).
Conclusion: Post MI treatment with FT-011 improved heart function by reducing pathological remodeling of the ventricle. This appears to be occurring at least in part via a direct anti-fibrotic effect of the drug.