Abstract 14309: A Novel Fibroblast Activation Inhibitor, NM922, Attenuates Maladaptive Fibrotic Remodeling to Preserve Cardiac Function Following the Onset of Heart Failure
BackgroundCardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart. These maladaptive structural changes can worsen cardiac function accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor of the conversion of n...
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| Published in: | Circulation (New York, N.Y.) Vol. 132; no. Suppl_3 Suppl 3; p. A14309 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
by the American College of Cardiology Foundation and the American Heart Association, Inc
10-11-2015
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| Online Access: | Get full text |
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| Summary: | BackgroundCardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart. These maladaptive structural changes can worsen cardiac function accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor of the conversion of normal fibroblast to the myofibroblast phenotype in the setting of pressure overload induced HF.MethodsMale C57BL/6J mice (10 wks) were subjected to transverse aortic constriction (TAC; 27 g needle) and NM922 (NovoMedix, LLC50 mg/kg/d i.p.) or VEH (DMSO + HS-15) was administered daily starting at 6 wks post TAC. Echocardiography was assessed at baseline and for 16 wks post TAC. At the 16 wk endpoint, mice were sacrificed and hearts were collected for biochemical and molecular assessment.ResultsNM922 significantly attenuated TAC-induced left ventricular (LV) dilation at 16 wks post TAC (LVEDD3.5 ± 0.1 vs. 4.5 ± 0.2 mm, p < 0.01; LVESD2.5 ± 0.2 vs. 3.8 ± 0.3 mm, p < 0.01) compared to VEH. NM922 treated mice displayed reduced wall thickening (LVPWd1.0 ± 0.03 vs. 1.2 ± 0.05 mm; p < 0.05) at 10 wks post TAC compared to VEH. LV ejection fraction (LVEF) was preserved in NM922 treated mice at 8-16 wks post TAC compared to VEH (*p < 0.05; **p < 0.001) compared to VEH. Treatment with NM922 resulted in reductions in heart (8.5 ± 0.5 vs. 12.0 ± 0.9 mg/mm; p < 0.01) and lung (8.2 ± 0.3 vs. 11.5 ± 0.6 mg/mm; p < 0.0001) weights compared to VEH. Picrosirius Red staining revealed that NM922 reduced cardiac interstitial collagen volume fraction by 50% (p < 0.05 vs. VEH). Circulating BNP levels trended toward lower (p = 0.08) in the NM922 mice when compared to VEH.ConclusionChronic treatment with NM922 following the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of LVEF. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel agent protects the failing heart. |
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| ISSN: | 0009-7322 1524-4539 |
| DOI: | 10.1161/circ.132.suppl_3.14309 |