Preventing post-infarction remodeling by inhibiting interleukin-1 with anakinra

Project: Research

Investigators

  • Antonio Abbate (PI)

Description

Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality. Many patients die early during the course, and those who survive are at risk for dying late from adverse cardiac remodelling and heart failure secondary to unfavorable ventricular remodeling. Interventions that limit the extent of infarction and/or inhibit apoptosis have the potential to prevent adverse remodelling and heart failure-related deaths. Interleukin-1 receptor antagonist (IL-1Ra) is part of the IL-1 family and competes with IL-1beta for its receptor acting as an anti-inflammatory protein. We hypothesize that IL-1Ra promotes cell survival by counteracting IL-1beta activity and through an intrinsic anti-apoptotic activity. We also propose that enhancement of this pathway by administration of exogenous IL-1Ra, anakinra, may prevent adverse cardiac remodelling and heart failure (HF) by limiting infarct size and inhibiting apoptosis. We propose to evaluate the role of endogenous IL-1Ra in AMI and post-infarction cardiac remodeling by studying wild-type and mice with targeted disruption of the gene coding for IL-1Ra (IL-1RN knock out) undergoing surgical coronary artery ligation and serial assessment of left ventricular dimension and function by transthoracic echocardiography, and assessment of heart failure signs at pathology.Specific aims: 1) To evaluate the role of endogenous IL-1Ra in AMI and post-infarction cardiac remodeling by studying wild-type and mice with targeted disruption of the gene coding for IL-1Ra (IL-1RN knock out); 2) To determine whether exogenous recombinant human (rh) IL-1Ra (anakinra) may prevent post-infarction remodeling and heart failure.Endpoints of interest: a) Infarct size at 24 hours; b) Cardiomyocyte apoptosis at 24 hours and 7 days; c) Left ventricular dimension and function at 14 and 28 days; d) Pulmonary congestion and cardiomegaly at 28 days.
Award amount$132,000.00
Award date07/01/2008
Program typeBeginning Grant-in-Aid
Award ID0865022E
Effective start/end date07/01/200806/30/2010
StatusFinished