Previous reports indicate that
IL18 is a novel candidate gene for diastolic dysfunction in
sickle cell disease (SCD)-related
cardiomyopathy. We hypothesize that
interleukin-18 (IL-18) mediates the development of
cardiomyopathy and
ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac
fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating
IL-18 levels, as well as reduced
voltage-gated potassium channel expression, which translates to reduced transient outward
potassium current (Ito) in isolated cardiomyocytes. Administering
IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained
IL-18 inhibition via IL-18-binding
protein resulted in decreased cardiac
fibrosis and NF-κB phosphorylation, improved diastolic function, normalized
electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial
fibrosis or increased QTc displayed greater
IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma
IL-18 levels. PBMC-derived
IL18 gene expression was increased in patients who did not survive compared with those who did.
IL-18 is a mediator of sickle cell
cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for
sudden death.