IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias

Akash Gupta, Yu Dong Fei, Tae Yun Kim, An Xie, Ken Batai, Ian Greener, Haiyang Tang, Sultan Ciftci-Yilmaz, Elizabeth Juneman, Julia H. Indik, Guanbin Shi, Jared Christensen, Geetanjali Gupta, Cheryl Hillery, Mayank M. Kansal, Devang S. Parikh, Tong Zhou, Jason X.J. Yuan, Yogendra Kanthi, Peter BronkGideon Koren, Rick Kittles, Julio D. Duarte, Joe G.N. Garcia, Roberto F. Machado, Samuel C. Dudley, Bum Rak Choi, Ankit A. Desai

Research output: Contribution to journalArticlepeer-review

Abstract

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. Key Points: • SCD mice exhibit a myocardium vulnerable to VT. • IL-18 is a novel therapeutic target for sickle cell cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1208-1218
Number of pages11
JournalBlood
Volume137
Issue number9
DOIs
StatePublished - Mar 4 2021

Bibliographical note

Funding Information:
This study was funded by grants from the National Center for Research Resources/National Center for Advancing Translational Sciences, National Institutes of Health (NIH) (UL1RR029879), the National Heart, Lung, and Blood Institute (R01 HL111656, R01 HL127342 [R.F.M.], and R01 136603 [A.A.D.]), the National Institute of General Medical Sciences (K23 GM112014) (J.D.D.), by the American Heart Association (14CRP18910051) (A.A.D.), and by the American Thoracic Society Foundation/Pulmonary Hypertension Association (A.A.D.).

Funding Information:
The authors thank Natalia Arana, Hector Quijada, Michelle Shi, Kyle Weigand, Josh Strom, Jon Groth, Vishal Mali, and Oluwaseun Kafisanwo for assistance with the mouse study. This study was funded by grants from the National Center for Research Resources/National Center for Advancing Translational Sciences, National Institutes of Health (NIH) (UL1RR029879), the National Heart, Lung, and Blood Institute (R01 HL111656, R01 HL127342 [R.F.M.], and R01 136603 [A.A.D.]), the National Institute of General Medical Sciences (K23 GM112014) (J.D.D.), by the American Heart Association (14CRP18910051) (A.A.D.), and by the American Thoracic Society Foundation/Pulmonary Hypertension Association (A.A.D.).

Publisher Copyright:
© 2021 American Society of Hematology

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