The promotion of arrhythmias in myocytes by mesenchymal stromal cells isolated from failing human hearts, which were found to produce high levels of Interleukin-6 (IL-6), was abated in the presence of anti-IL-6 monoclonal antibodies, according to study results intended to be presented at the annual meeting of the American College of Cardiology (ACC.20).
In a diseased state, cardiac mesenchymal stromal cells (cMSCs) remodel and secrete inflammatory cytokines, including IL-6. IL-6 has been shown to be a potent inducer of Ca2+-mediated arrhythmia substrates in human myocytes. While anti-IL-6 monoclonal antibodies have an established role in the treatment of autoimmune diseases and malignancies, their use in the treatment of cardiac disease has not been well studied.
Using extracted device leads and explanted hearts from patients with and without heart failure, investigators isolated cMSCs (“failing” and “non-failing” cMSCs, respectively), and quantified IL-6 using an enzyme-linked immunosorbent assay. Myocytes were derived from induced pluripotent stem cells (iPSCs) from individuals without heart failure and cultured in monolayers. Myocytes were treated with exogenous IL-6 or cocultured with failing cMSCs with and without anti-IL-6 monoclonal antibody. Fluorescent indicators were used to detect the presence of Ca2+ alternans during steady state pacing.
The secretion of IL-6 was found to be 5.6 times higher in failing vs nonfailing cMSCs (n=4; P <.005) and 66 times higher in cMSCs vs iPSC-derived human myocytes (n=5; P <.002). Myocytes that were cocultured with failing cMSCs or were exposed to exogenous IL-6 had large increases in Ca2+ alternans compared with myocytes cultured alone (343%, n=12, P <.001 and 300%, n=5, P <.002, respectively). These Ca2+ alternans were reduced to baseline levels in myocyte/cMSC cocultures treated vs not treated with IL-6 (reduction, 400%; n=18, P <.001).
“These results suggest a novel anti-arrhythmic therapeutic strategy in heart failure using anti-IL-6 drugs such as tocilizumab, sarilumab, or siltuximab,” concluded the researchers.
Vasireddi S, Sattayaprasert P, Moravec C, et al. Targeted anti-inflammatory treatment with anti-Il-6 monoclonal antibody for calcium-mediated arrhythmia substrates in heart failure. Intended to be presented at: American College of Cardiology’s 69th Annual Scientific Session; March 28-30, 2020; Chicago, IL. Presentation 915-09.