Background: Children born with congenital heart disease (CHD) often require complex open-heart surgery with long cardiopulmonary bypass (CPB) and aortic cross-clamp times (XC). Despite continued refinement in cardioplegia strategy during XC, ventricular dysfunction due to inadequate myocardial protection remains a major clinical problem. Our team has developed a pediatric surgical model of long CPB/XC in juvenile pig simulating surgical times of repair for common and complex CHD. In this model, we demonstrated time-dependent cardiac dysfunction correlating with metabolic-stress, oxidative-stress and cardiomyocyte injury. We also previously showed that glucagon-like peptide-1 (GLP-1) and its bioactive metabolites have cardioprotective properties in different but related settings of cardiac ischemic injury. This study investigates the cardioprotective properties of GLP-1(28-36), a natural metabolite of GLP-1, in the long pediatric CPB/XC surgical model.
METHODS AND RESULTS: We developed a model of long CPB/XC in 4-5 wk-old Yorkshire pigs subjected to either 90-min XC (common CHD repair, e.g. Tetralogy of Fallot) or 180-min XC (complex CHD repair, e.g. corrected transposition). Del Nido cardioplegia was delivered to induce cardiac arrest during XC. In each experimental group, either GLP-1(28-36) or a negative control SCRAM(28-36) peptide was added to the del Nido preparation in a blinded manner. In 90-min XC, addition of GLP-1(28-36) but not SCRAM(28-36) to del Nido [30nM; n=8 pigs/group] led to a longer time to first heart beat following XC removal (165±21 vs. 59±7 sec; P< 0.001), with markedly reduced myeloperoxidase (MPO: 74±19 vs. 131±30 ng/mL; P< 0.01) and cardiac Troponin-I (cTnI: 1.9±0.4 vs. 5.1±0.7 ng/mL; P< 0.001) indicating reduced oxidative stress and cardiomyocyte injury, respectively. In 180-min XC, addition of GLP-1(28-36) but not SCRAM(28-36) to del Nido [30nM; n=12 pigs/group] led to significantly improved weaning from CPB (survival post-CPB: 75.0 vs. 33.3%; P< 0.05). Additionally, GLP-1(28-36) treated hearts required less inotropic support to wean from CPB (maximum vasoactive-inotropic score: 20.0 vs. 16.6±4.3; P< 0.05) with signs of systolic (ejection fraction: 24.1±4.9 vs. 18.0±3.6%; P< 0.05) and diastolic (dP/dt min: -709±141 mmHg/sec vs. -549±114 mmHg/sec; P< 0.05) cardiac recovery 2-h post-CPB. We observed concordant reductions in oxidative stress (MPO: 103±28 vs. 251±38 ng/mL; P< 0.001) and cardiomyocyte injury (cTnI: 3.4±1.1 vs. 13.1±2.0 ng/mL; P< 0.001) for GLP-1(28-36) treated hearts following 180-min XC.
Conclusion: Using our new pediatric pig model simulating long CPB/XC times, we demonstrate that treatment with GLP-1(28-36) during XC reduced cardiac injury after 90-min XC. Strikingly, treatment with GLP-1(28-36) improved survival and cardiac recovery after 180-min XC.
