Abstract 17897: Pharmacological Inhibition of PTEN Increases Myocardial Salvage, Reduces Infarct Size, and Decreases Adverse Post-infarction Left Ventricular Remodeling in a Porcine Model of Reperfused Myocardial Infarction
RISK pathway is the main cardioprotective pathway against ischemia-reperfusion (I-R) injury, and it starts with the phosphorylation (activation) of Akt. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a primary phosphatase that negatively regulates Akt phosphorylation. We hypothesized that the PTEN inhibitor, VO-OHpic, increases myocardial salvage, reduces myocardial infarction (MI) size, and mitigates left ventricular (LV) remodeling in a porcine model of I-R.
Methods: Acute MI was induced in 10 pigs by balloon occlusion of the proximal LAD for 60 min, followed by reperfusion. Animals randomly received VO-OHpic 15 minutes prior to reperfusion, or saline for controls. Animals were evaluated with cardiac MRI and 3D-echo at 1 week and 1 month post MI. Histology was performed after 1 month to assess LV remodeling.
Results: One week after MI, despite similar of myocardium at risk in both groups (40.9 ± 2.5% vs 40.9 ± 2.5%, p=NS), VO-OHpic significantly reduced MI size (28.3 ±1.7% vs 36.7 ± 3.1% of LV, p < .01), resulting in larger salvaged myocardium (30.8 ± 4.4% vs 5.5 ± 4.5% of AAR, p < .01), and improved LV systolic function (MRI LVEF 39.8 ± 4.1% vs 34.2 ± 2.4%, p < .01). LV mechanics measured by 3D-strain were also improved in VO-OHpic pigs. Importantly, these cardioprotective effects of PTEN inhibition were preserved one month post MI (MRI LVEF 43.5 ± 6.1% vs 34.6 ± 3.9%, p < .001). Additionally, VO-OHpic mitigated post-MI LV remodeling leading to lower LV mass (57.8 ± 3.3 vs 70.4 ± 4.6 g, p < .001) and more preserved LV architecture/shape (sphericity index 1.5 ± 0.1 vs 1.41 ± 0.1, p < .05). Consistent with this, histology revealed less cardiomyocyte hypertrophy and lower interstitial fibrosis in the pits treated with PTEN inhibition.
Conclusions: Early PTEN inhibition by VO-OHpic administration before reperfusion significantly increased myocardial salvage, reduced MI size, improved systolic LV function and LV mechanics, and reduced LV remodeling following acute MI. These data support a cardioprotective role for PTEN inhibition during myocardial ischemia that has therapeutic potential and merits further investigation
Author Disclosures: C.G. Santos-Gallego: None. B. Picatoste: None. I.U. Njerve: None. T.P. Vahl: None. K. Ishikawa: None. J. Sanz: None. R.J. Hajjar: None. V. Fuster: None. J. Badimon: None.
- © 2014 by American Heart Association, Inc.