Abstract 14053: The Sphingosine 1-phosphate Receptor Agonist Fingolimod Increases Myocardial Salvage and Decreases Adverse Post-infarction Left Ventricular Remodeling in a Porcine Model of Reperfused Myocardial Infarction
Background: Sphingosine-1 phosphate (S1P) is a biophospholipid with antiapoptotic properties. Previous experiments suggest protective effects of S1P receptor (S1P-R) agonism against ischemia-reperfusion (I-R) injury in several organs, and also in cardiomyocyte cell culture. Fingolimod (FIN) is the only S1P-R agonist FDA-approved for clinical use in multiple sclerosis. The objective of our study was to determine if S1P-R activation by FIN during ischemia 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 14 pigs by balloon occlusion of the proximal LAD for 60 min, followed by reperfusion. Animals randomly received FIN 15 minutes prior to reperfusion and then daily for the next 3 days, or saline for controls. Animals were evaluated with cardiac MRI and 3D-echo at 1 week and 1 month post MI. Histology and Western blot analysis were performed after 1 month.
Results: One week after MI, despite similar of myocardium at risk in both groups (41.9 ± 3.7% vs 41.6 ± 2.7%, p=NS), FIN significantly reduced MI size (32.8 ± 2.8% vs 39.7 ± 3.7% of LV, p < .01), resulting in 5-fold larger salvaged myocardium, and improved LV systolic function (MRI LVEF 39.6 ± 4.1% vs 33.6 ± 2.8%, p < .01). LV mechanics measured by 3D-strain were also improved in FIN pigs. Importantly, these cardioprotective effects of FIN were preserved one month post MI (MRI LVEF 43.7 ± 5.8% vs 33.3 ± 4.2%, p < .001). Additionally, FIN mitigated post-MI LV remodeling leading to lower LV mass (62.9 ± 3.9 vs 72.2 ± 5.5 g, p < .001) and less LV dilatation (LVESV 55.1 ± 13.5 vs 79.6 ± 19.2 mL, p < .05). Consistent with this, histology revealed less cardiomyocyte hypertrophy and lower interstitial fibrosis. Activation of Akt and ERK1/2 were significantly lower in FIN pigs supporting a reduction in compensatory hypertrophy.
Conclusions: Early S1P-R activation by fingolimod 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 S1P-R agonism during myocardial ischemia that has therapeutic potential and merits further investigation
- © 2013 by American Heart Association, Inc.