Previous reports indicate IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that IL-18 mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared to control (CTR) mice, a "humanized" mouse model of SCD exhibited increased cardiac fibrosis, prolonged action potential duration (APD), higher VT inducibility in vivo, higher cardiac NFκB phosphorylation and circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, translating to reduced outward potassium current (Ito) in isolated cardiomyocytes. IL-18 administration to isolated mice hearts resulted in VTs, originating from the right ventricle, and further reduced Ito in SCD mice cardiomyocytes. Sustained IL-18 inhibition via IL-18 binding protein resulted in decreased cardiac fibrosis and NFκB 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 (PBMC), with QTc strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in non-surviving over surviving subjects. 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.

Background: Hydrogen peroxide (H2O2)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. Methods: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H2O2 (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Gö 6983 (1 μM), was applied to test the involvement of PKC. Results: H2O2 perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H2O2-induced afterdepolarizations. Additional application of Gö 6983 with H2O2 effectively suppressed H2O2-induced afterdepolarizations. H2O2 increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H2O2 also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H2O2-induced enhancement of Ito. Conclusions: H2O2 induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.