Glucocorticoids reduce ischemia-reperfusion-induced myocardial apoptosis in immature hearts.
BACKGROUND
Transient myocardial dysfunction often occurs after ischemia-reperfusion with immature myocardium appearing particularly susceptible. Neutrophil adhesion and activation contribute to ischemia-reperfusion injury after cardiopulmonary bypass (CPB), possibly resulting in cell death. The hypothesis was that glucocorticoids could prevent reperfusion-induced myocardial dysfunction by blunting leukocyte-mediated injury.


METHODS
Neonatal piglets were cooled with CPB followed by 2 hours of circulatory arrest. Animals were rewarmed, removed from CPB, and allowed to recover for 2 hours. Methylprednisolone (60 mg/kg) was administered in the CPB priming solution to one group (intraoperative glucocorticoids). In another group (preoperative glucocorticoids), 30 mg/kg methylprednisolone was administered 6 hours before CPB in addition to the intraoperative dose (30 mg/kg). Control animals received no glucocorticoids.


RESULTS
Apoptotic myocardial cells measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and caspase-3 activity were reduced in animals administered glucocorticoids compared with controls (p < 0.05). Animals receiving either intraoperative or preoperative glucocorticoids had 0.10 +/- 0.07 and 0.13 +/- 0.05 apoptotic cells per high-power field, respectively, whereas 0.33 +/- 0.15 apoptotic cells were detected with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling in control animals. Glucocorticoid administration reduced myocardial intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 mRNA expression compared with control piglets. Maximum rate of increase of left ventricular pressure was 62% +/- 9% of baseline in control animals at 120 minutes of recovery compared with 96% +/- 6% and 95% +/- 10% of baseline in animals receiving intraoperative and preoperative glucocorticoids, respectively (p < 0.05).


CONCLUSIONS
The reduction of neutrophil adhesion and activation proteins in neonatal myocardium was associated with less apoptotic cell death after glucocorticoid administration. The blunting of apoptosis in glucocorticoid-treated animals was also associated with improved recovery of left ventricular systolic function in neonatal animals after CPB and circulatory arrest. Glucocorticoid attenuation of myocardial apoptosis might have important implications for maintaining long-term ventricular function after ischemia and reperfusion.
Pearl
Jeffrey M
JM
Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, Ohio 45229, USA. pearj0@chmcc.org
Nelson
David P
DP
Schwartz
Steven M
SM
Wagner
Connie J
CJ
Bauer
Steven M
SM
Setser
Elizabeth A
EA
Duffy
Jodie Y
JY
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002315:Cardiopulmonary Bypass; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005938:Glucocorticoids / Q000494:pharmacology*; D008775:Methylprednisolone / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology*; D011292:Premedication; D013552:Swine; D016277:Ventricular Function, Left / Q000187:drug effects
D005938:Glucocorticoids; D008775:Methylprednisolone