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(Circulation. 2008;117:2670-2683.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, Inhibits Apoptosis in Experimental Acute Myocardial Infarction

Antonio Abbate, MD^*; Fadi N. Salloum, PhD^*; Elena Vecile, PhD^*; Anindita Das, PhD; Nicholas N. Hoke, BS; Stefania Straino, BS; Giuseppe G.L. Biondi-Zoccai, MD; Jon-Erik Houser, MD; Ian Z. Qureshi, PhD; Evan D. Ownby, MD; Edoardo Gustini, PhD; Luigi M. Biasucci, MD; Anna Severino, PhD; Maurizio C. Capogrossi, MD; George W. Vetrovec, MD; Filippo Crea, MD; Alfonso Baldi, MD; Rakesh C. Kukreja, PhD; Aldo Dobrina, MD

From the Virginia Commonwealth University Pauley Heart Center, Richmond (A.A., F.N.S., A.D., N.N.H., S.S., J.-E.H., I.Z.Q., E.D.O., G.W.V., R.C.K.); Institute of Cardiology, Catholic University, Rome, Italy (A.A., L.M.B., A.S., F.C.); Department of Pathology and of Physiology, University of Trieste, Trieste, Italy (E.V., E.G., A.D.); Laboratorio di Patologia Vascolare, Istituto Dermopatico Immacolata–IRCCS, Rome, Italy (S.S., M.C.C.); Division of Cardiology, University of Turin, Turin, Italy (G.G.L.B.-Z.); and Department of Biochemistry and Biophysics "F. Cedrangolo," Section of Pathologic Anatomy, Second University of Naples, Naples, Italy (A.B.).

Correspondence to Dr Antonio Abbate, Assistant Professor of Medicine, Division of Cardiology/VCU Pauley Heart Center, Virginia Commonwealth University, 1200 E Broad St, West Hospital, 10th Floor, East Wing, Room 1041, PO Box 980281, Richmond, VA 23298–0281. E-mail aabbate{at}mcvh-vcu.com

Received September 17, 2007; accepted March 31, 2008.

Background— Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction.

Methods and Results— Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline (P=0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose (P=0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1±0.2% versus 0.5±0.3% [P<0.001] and 4.2±0.4% versus 1.1±0.2% [P<0.001], respectively). Compared with saline-treated animals, anakinra-treated mice and rats showed signs of more favorable ventricular remodeling. In vitro, anakinra significantly prevented apoptosis induced by simulated ischemia and inhibited caspase-1 and -9 activities.

Conclusions— Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.

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Clinical Summaries
Circulation 2008 117: 2567-2569. [Extract] [Full Text]