IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias
| Autor: | Jared L. Christensen, Geetanjali Gupta, Sultan Ciftci-Yilmaz, Devang S. Parikh, Jason X.-J. Yuan, Rick A. Kittles, Yu Dong Fei, Yogendra Kanthi, Akash Gupta, Julio D. Duarte, Julia H. Indik, Ken Batai, Gideon Koren, Mayank Kansal, Haiyang Tang, Roberto Machado, Ankit A. Desai, Tong Zhou, Tae Yun Kim, Peter Bronk, I.D. Greener, Cheryl A. Hillery, Bum-Rak Choi, Joe G.N. Garcia, Guanbin Shi, Samuel C. Dudley, An Xie, Elizabeth Juneman |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Cardiac fibrosis Immunology Cardiomyopathy Diastole Anemia Sickle Cell 030204 cardiovascular system & hematology Biochemistry Sudden death 03 medical and health sciences Mice Young Adult 0302 clinical medicine Red Cells Iron and Erythropoiesis Fibrosis Internal medicine medicine Animals Humans business.industry Interleukin-18 Arrhythmias Cardiac Cell Biology Hematology medicine.disease Potassium channel 030104 developmental biology Endocrinology medicine.anatomical_structure Ventricle Tachycardia Ventricular Myocardial fibrosis business Cardiomyopathies |
| Zdroj: | Blood |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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