Abstract 20797: Sphingosine-1-Phosphate Receptor Agonist Fingolimod After Prolonged Circulatory Arrest Improves Cardiac and Neurological Outcomes in a Rat Model of Extracorporeal Life Support.
Introduction: Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for the treatment of multiple sclerosis and exerts anti-inflammatory and antiapoptotic properties.
Hypothesis: We hypothesized that sphingosine-1-phosphate receptor activation with fingolimod during circulatory arrest inhibits apoptosis and inflammation leading to increased myocardial and cerebral functions after reperfusion with extracorporeal life support (ECLS).
Methods and Results: Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, veno-arterial ECLS was instituted for 60 minutes. At the beginning of ECLS animals randomly received fingolimod or saline (control). Restoration of spontaneus circulation and 24 hours survival were higher in rats that received fingolimod (p = 0.03). Fingolimod treatment activated the cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways leading to decreased cardiomyocyte apoptosis and reduced myocardial oxidative stress. This resulted in improved recovery of left ventricle systolic and diastolic functions expressed by end-systolic pressure-volume relationship (Ees), preload recruitable stroke work (PRSW), diastolic pressure-volume relationship (EDPVR) and Tau. Neurological deficit scores were improved in fingolimod trated rats. Neuroprotection was determined by decreased inflammation, edema and apoptosis with significantly lower TNF-α expression, activated neutrophils, microglia/macrophages, and intercellular adhesion molecule-1 positive blood vessels.
Conclusions: Sphingosine-1-phosphate receptor activation with fingolimod increased survival, neurologic outcome and cardiac function after prolonged cardiac arrest treated with ECLS. Our data strongly support a cardioprotective and neuroprotective role for sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest.
Author Disclosures: A. Rungatscher: None. D. Linardi: None. L. San Biagio: None. M. Berton: None. N. Ahmed: None. M. Tessari: None. G. Luciani: None. G. Faggian: None.
- © 2016 by American Heart Association, Inc.