Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling, and impairs systolic function after myocardial infarction in the pig.
BACKGROUND
Cyclooxygenase (COX)-2 expression in the heart increases after myocardial infarction (MI). In murine models of MI, COX-2 inhibition preserves left ventricular dimensions and function. We studied the effect of selective COX-2 inhibition on left ventricular remodeling and function after MI in a pig model.


RESULTS
Twenty-two pigs were assigned to COX-2 inhibition with a COX-2 inhibitor (COX-2i; celecoxib 400 mg twice daily; n=14) or a control group (n=8). MI was induced by left circumflex coronary artery ligation, and the animals were euthanized 6 weeks later. Cardiac dimensions and function were assessed with echocardiography and conductance catheters. Infarct size and collagen density were analyzed with triphenyltetrazolium chloride staining and picrosirius red staining, respectively. COX-2 inhibition increased mortality compared with controls (50% versus 0%, P=0.022), whereas infarct size was similar (13.1+/-0.7% versus 14.1+/-0.1%, P=0.536). The decrease in thickness of the infarcted myocardial wall was more pronounced in the COX-2i group (60.6+/-9.6% versus 36.2+/-5.7%, P=0.001). End-diastolic volume was higher in the COX-2i group (133.9+/-33.5 versus 91.1+/-24.0 mL; P=0.021), as was the end-systolic volume at 100 mm Hg (81.7+/-27.8 versus 56.3+/-21.1 mL; P=0.037), which indicates that systolic function was more severely impaired. Infarct collagen density was lower after COX-2i treatment (25.3+/-3.9 versus 56.1+/-23.8 gray value/mm2; P=0.005).


CONCLUSIONS
In pigs, COX-2 inhibition after MI is associated with increased mortality, enhanced left ventricular remodeling, and impaired systolic function, probably due to decreased infarct collagen fiber density.
Timmers
Leo
L
Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Sluijter
Joost P G
JP
Verlaan
Cees W J
CW
Steendijk
Paul
P
Cramer
Maarten Jan
MJ
Emons
Maringa
M
Strijder
Chaylendra
C
Gründeman
Paul F
PF
Sze
Siu Kwan
SK
Hua
Lin
L
Piek
Jan J
JJ
Borst
Cornelius
C
Pasterkamp
Gerard
G
de Kleijn
Dominique P V
DP
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000473:pathology; D000068579:Celecoxib; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D009203:Myocardial Infarction / Q000201:enzymology* / Q000401:mortality; D011720:Pyrazoles / Q000009:adverse effects* / Q000494:pharmacology; D012307:Risk Factors; D013449:Sulfonamides / Q000009:adverse effects* / Q000494:pharmacology; D013552:Swine; D013599:Systole / Q000187:drug effects / Q000502:physiology*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D003094:Collagen; D051546:Cyclooxygenase 2; D000068579:Celecoxib