A single intravenous sTNFR-Fc administration at the time of reperfusion limits infarct size--implications in reperfusion strategies in man.
BACKGROUND
Reperfusion of the ischemic myocardium is associated with increased inflammatory processes that can exert deleterious effects and therefore contribute to cardiac dysfunction. The aim of the present study was to verify whether the administration of sTNFR-Fc, a scavenger of the pro-inflammatory cytokine TNF-alpha, at the time of reperfusion would protect against myocardial infarction and reduce the severity of early mechanical dysfunction.


METHODS
Male Wistar rats were subjected to 60 min coronary occlusion followed by reperfusion. A bolus of sTNFR-Fc (10 microg/kg, i.v.) (MI + sTNFR-Fc group) or a placebo (MI group) was injected prior to reperfusion. Cardiac geometry was assessed by echocardiography 1, 3 and 7 days after reperfusion. Eight days after reperfusion, left ventricular (LV) function was evaluated under basal conditions and during an experimental challenge of volume overload. Finally, infarct size was measured after euthanasia.


RESULTS
sTNFR-Fc administration markedly reduced infarct size (P < 0.01) and decreased LV dilation as assessed by the echocardiographic measurement of the LV end diastolic area, 7 days post-MI (P < 0.01). Moreover, LV end-diastolic pressure was significantly preserved by sTNFR-Fc 1 week after myocardial infarction, under basal conditions (P < 0.05) as well as during cardiac overload (P < 0.05).


CONCLUSIONS
A single administration of sTNFR-Fc at the time of reperfusion after myocardial infarction is able to limit infarct size and to reduce early LV diastolic dysfunction in rats. These findings suggest that intravenous neutralization of TNF-alpha during surgical cardiac reperfusion might improve the outcome of myocardial infarction in humans.
Toufektsian
Marie-Claire
MC
TIMC-PRETA CNRS (UMR 5525), Equipe Coeur & Nutrition, Université de Grenoble, Bât. Jean Roget, Domaine de la Merci, Grenoble 38000, France.
Robbez-Masson
Vanessa
V
Sanou
Drissa
D
Jouan
Marie-Gabrielle
MG
Ormezzano
Olivier
O
de Leiris
Joël
J
Boucher
François
F
D000818:Animals; D003627:Data Interpretation, Statistical; D004195:Disease Models, Animal; D004452:Echocardiography / Q000379:methods; D000068800:Etanercept; D005070:Evans Blue; D005544:Forecasting; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007275:Injections, Intravenous / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D005070:Evans Blue; D000068800:Etanercept