Alpha Omega Alpha Honor Medical Society

2014 Research Abstract

The impact of Interleukin-18 (IL-18) blockade on inflammation in a model of heart failure with preserved ejection fraction (HFpEF)

Investigator: Jessica Regan, Virginia Commonwealth University School of Medicine

Mentor: Antonio Abbate, MD, PhD

Abstract

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents approximately 50% of patients with HF, the mechanisms of disease are poorly understood and therapies are generally ineffective in reducing HF progression. Inflammation is a key component of HF, therefore we hypothesized that the pro-inflammatory cytokine IL-18 is up regulated in HFpEF and that by targeting IL-18 we can improve diastolic dysfunction in HFpEF

Methods: Osmotic pumps were implanted subcutaneously in eight-week-old male CD1 wild-type mice and C57 IL-18KO mice assigned to the ATII (0.2 mg/Kg/day) or volume-matched vehicle (N=8/group) for 4 weeks. Recombinant murine IL-18 binding protein (IL-18bp) was dosed daily to CD1 mice randomly assigned to treatment groups of 0.1, 0.3 or 1.0mg•Kg-1•day-1. We measured LV dimensions and ejection fraction (LVEF) through echocardiography, LV relaxation with pulsed-wave Doppler, and LV end-diastolic pressures (LVEDP) through LV catheterization. Hearts were rapidly excised, snap frozen in liquid nitrogen and mRNA levels were quantified by RT-PCR.

Results: IL-18 mRNA levels are increased 7-fold following induction of HFpEF by 28 day infusion of low dose ATII . Both genetic and pharmacological IL-18 blockade ameliorated the increase (worsening) LV isovolumetric relaxation time (IVRT), myocardial performance index (MPI) and LVEDP without altering LV dimensions, mass or EF.

Conclusion: IL-18 levels are increased following induction of HFpEF by chronic infusion of low dose ATII in the mouse. Blockade of IL-18 improves the characteristic diastolic dysfunction of HFpEF, providing a novel therapeutic target for patients with HF.

Last modified: 6/11/2015

Updated on June 15, 2015.


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