On-pump coronary artery bypass surgery activates human myocardial NF-kappaB and increases TNF-alpha in the heart.
OBJECTIVE
Myocardial tumor necrosis factor alpha (TNF) production and nuclear factor kappa B (NF-kappaB) activation has been demonstrated in chronic heart failure and experimental models of acute ischemia-reperfusion injury. Further, a cause and effect relationship has been established between these events and cardiomyocyte apoptosis following such conditions. It remains unknown, however, whether the myocardial injury associated with coronary artery bypass surgery (CAB) results in myocardial NF-kappaB activation and TNF production. We hypothesized that CAB with cardiopulmonary bypass ("on-pump") activates human myocardial NF-kappaB and increases TNF in the heart.


METHODS
Patients, 18 to 65 years of age, scheduled for elective cardiac surgery but without other preexisting disease were considered eligible for the study. Biopsies of human myocardium were obtained before and after cardiopulmonary bypass and myocardial TNF levels were determined by ELISA and cytotoxicity assay, and NF-kappaB activation was determined by electrophoretic mobility shift assay (n = 6 patients). NF-kappaB activation was quantitated with gel densitometry.


RESULTS
The clinical characteristics of the study patients were as follows (means +/- SEM): mean age (y) 50.0 +/- 5.7, male 6 (100%), cardiopulmonary bypass time (min) 107 +/- 37.7, cross-clamp time (min) 68 +/- 17.6, number of CAB 3.0 +/- 1.1, and length of hospital stay (d) 4.8 +/- 0.9. Before CAB, myocardial TNF-alpha levels were 251 +/- 22 pg/g and 33 +/- 9 U/g, as determined by ELISA and cytotoxicity assay, respectively. Following CAB, human myocardial TNF-alpha levels increased to 892 +/- 71 pg/g (P = 0.0008) and 141 +/- 11 U/g (P = 0.0042), as determined by ELISA and cytotoxicity assay, respectively. Before CAB, the ratio of bound to unbound NF-kappaB DNA was 0.009 +/- 0.0007 and after CAB the ratio was 0.24 +/- 0.01 (P < 0.0001).


CONCLUSIONS
This study represents the initial demonstration that coronary artery bypass grafting results in an activation of NF-kappaB and an increase of TNF in the heart.
Meldrum
Daniel R
DR
Department of Surgery and Medicine, Indiana Center for Vascular Biology and Medicine, Indiana University Medical Center, Indianapolis, Indiana, USA. dmeldrum@iupui.edu
Partrick
David A
DA
Cleveland
Joseph C
JC
Shenkar
Robert
R
Meldrum
Kirstan K
KK
Raiesdana
Azad
A
Ayala
Alfred
A
Brown
John W
JW
Harken
Alden H
AH
D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D001026:Coronary Artery Bypass / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000209:etiology / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha