TNFalpha-antagonist neither improve cardiac remodelling or cardiac function at early stage of heart failure in diabetic rats.
OBJECTIVE
Despite tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in patients with heart failure and previous preclinical study with TNFalpha-antagonist has been demonstrated to improve cardiac function in acute heart failure, recent clinical trials using TNFalpha-antagonist in patients with chronic severe heart failure have been disappointing. The aim was to study why TNFalpha-antagonist may not work during long-term treatment in chronic heart failure (CHF) in experimental model.


METHODS
49 rats were used at the age of 26 weeks: healthy Whistar Kyoto rats (WKY, n = 26) and diabetic (WKY+D, n = 23). Rats in each group received either a 12-week treatment with TNFalpha-antagonist (Etanercept) or NaCl injections.


RESULTS
In diabetic rats, there were increased plasma glucose level and blood pressure. By use of echocardiography diabetic rats displayed not only enlarged and thinned left ventricles but also decreased both systolic and diastolic functions. Moreover, there are increased interleukin-6 (IL6) mRNA levels. However, TNFalpha-antagonist, etanercept, does not improve either cardiac remodelling or cardiac function. IL6 mRNA level remained unchanged after treatment of etanercept.


CONCLUSIONS
Chronic treatment of TNFalpha-antagonist has no favourable effect on either cardiac remodelling or cardiac function. It is therefore inappropriate to use TNFalpha-antagonist in CHF in diabetes as underlying cause.
Isic
Azra
A
Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Scharin Tang
Margareta
M
Haugen
Espen
E
Fu
Michael
M
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology; D000068800:Etanercept; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007074:Immunoglobulin G / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
D007074:Immunoglobulin G; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept