Abstract 2094: A Recombinant Human Neuregulin-1 Peptide Added to Celsior Solution Improves Preservation of the Rat Heart
Introduction: The neuregulin-1/ErbB receptor complex plays a critical role in normal heart function and in the adaptation of the heart to injury. In adult cardiomyocytes NRG-1 protects against myofibrillar disarray and promotes cell survival, via pro-survival pathways involving ERK1/2 and PI3-K/Akt via activation of ErbB2/4 receptors. We have shown previously that rhNRG-1, a 61-amino acid receptor-active recombinant human neuregulin-1 (beta2a isoform) peptide improves cardiac function and survival in various animal models of ischaemic, dilated and viral cardiomyopathy.
Hypothesis: That the addition of rhNRG-1 to a commercial preservation solution (Celsior; C) improves cardiac preservation after prolonged hypothermic storage.
Methods: Pre-arrest indices of cardiac function were measured in 22 isolated working rat hearts. Hearts were arrested and stored for 6 hours at 2–3°C in C ± rhNRG-1(14nM). A third group of isolated hearts were pre-treated with the PI3K inhibitor, Wortmannin, before storage in C plus rhNRG-1. After storage, hearts were remounted and functional measurements repeated. Total and phosho-Akt were assessed by Western Blotting.
Results: Recovery of cardiac function was significantly better in hearts stored in C plus rhNRG-1 vs C alone. Post-storage recovery of each parameter is expressed as a percentage of its pre-storage baseline (mean ± SEM). Cardiac output recovery increased from 1.4±0.62 to 21.2±7.9 (p=0.03). Coronary flow recovery increased from 1.7±1.1 to 39±11.5 (p<0.01). Heart rate recovery increased from 32.2±8.6 to 75.7±11.7 (p=0.01). Western blotting revealed increased expression of phospho-Akt in rhNRG-1 stored hearts (p<0.05), confirming upregulation of the PI3K/Akt pathway; an effect abrogated by Wortmannin (p<0.05).
Conclusions: rhNRG-1 improves transplanted heart function after hypothermic storage by activation of the pro-survival Akt pathway. rhNRG-1 shows promise for enhancing donor heart preservation.