Abstract 19734: Gdf-5 Deficiency Prevents Cardiac Rupture Following Acute Myocardial Infarction in Mice
Background: Despite considerable advances in the treatment of myocardial infarction (MI), cardiac rupture remains a devastating complication. We previously showed that growth and differentiation factor-5 (Gdf5) is involved in chronic ventricular remodeling post-MI, however the role of Gdf5 in the acute phase of injury responses post-MI was not known.
Methods & Results: Wild-type (WT) and Gdf5 knock-out (KO) mice underwent permanent ligation of the LAD artery to induce experimental MI. KO mice had decreased incidence of cardiac rupture as compared to WT mice (4/25 vs. 17/25; P<0.05), with improved survival over 28d (80% vs. 28%, N=25/group; P<0.0001). Infarct sizes as determined by TTC staining before the onset of cardiac rupture events at 3d post-MI did not differ between KO and WT mice (43±2% vs. 43±2% of LV; N=10/group; P=NS). Decreased post-MI heart:body weight ratios of KO mice (6.5±0.2 vs. 8.1±0.4 mg/g; N=10/group; P<0.0001) suggest decreased myocardial edema and preserved tissue integrity in KO hearts. Higher collagen1a1 (2-fold increase; P<0.05) and collagen 3a1 mRNA (14-fold increase; P<0.01) and collagen1a1 protein levels (2-fold increase; P<0.05) were also observed in infarct areas of KO as compared to WT hearts at 3d post-MI. mRNA expression of inflammatory markers were also altered in infarcted areas of KO mice. Invasive hemodynamics revealed KO mice had decreased pre- and post-MI blood pressures. Together, these results suggest that loss of Gdf5 reduced the incidence of cardiac rupture by decreased inflammation, increased matrix deposition, and reduced mechanical forces on infarcted myocardium. To determine if cardiac or leukocyte-derived Gdf5 promote cardiac rupture, reciprocal bone marrow transplants were performed. Leukocyte Gdf5 did not regulate cardiac rupture phenotype of KO mice, suggesting that cardiac-derived Gdf5 moderates rupture post-MI.
Conclusion: Cardiac Gdf5 promotes rupture and mortality post-MI through the suppression of collagen synthesis, enhanced cardiac inflammation, and maintenance of normal blood pressure, together contributing to reduced integrity of cardiac tissue post-MI. These results suggest suppression of tissue Gdf5 as a potential therapeutic intervention to prevent cardiac rupture post-MI.
Author Disclosures: C.G. White-Dzuro: None. E. Shikatani: None. A. Momen: None. M. Husain: None.
- © 2016 by American Heart Association, Inc.