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21st World Congress on Heart Disease



Samuel C. Dudley, M.D., Ph.D., Brown University, The Miriam and Rhode Island Hospitals, Providence, RI, USA


Background: Diabetes is associated with prolonged QT interval and high risk of sudden cardiac death. A recent publication shows that cardiac macrophage-derived IL-1 causes QTc prolongation and increases arrhythmic risk in diabetes. Nevertheless, how IL-1 signals arrhythmic risk is unclear.

Methods and results: C57BL/6J mice were fed with 60 kcal% high fat diet (HFD) for 20 weeks. In comparison to the control mice fed with low fat diet, APD (41115 ms vs. 615 ms, p<0.05) and QTc interval (50.6 1.8ms vs. 41.5 0.8 ms, p<0.05) were substantially prolonged, and the inducibility of ventricular arrhythmia was significantly higher, while the heart function was preserved. Underlying these electrophysiological changes were alterations in L-type calcium current and Ca2+ handling leading to spontaneous sarcoplasmic reticulum (SR) Ca2+ releases and early afterdepolarizations (EADs). Cardiac IL-1 was elevated accompanied with upregulated NOX4 and increased mitochondrial reactive oxygen species (mitoROS). Inhibiting IL-1 or mitoROS by treating HFD mice with an IL-1 receptor antagonist (IL-1RA) or mitoTEMPO, respectively, shortened QT interval and APD, reduced calcium sparks and EADs, demonstrating that these electrophysiological changes were mediated by IL-1 and mitoROS. Moreover, inhibiting IL-1 lowered NOX4 and mitoROS, suggesting IL-1 signaled arrhythmia through ROS modulation. Further study revealed increased oxidation of ryanodine receptor and phosphorylation of Calcium/calmodulin-dependent protein kinase II (CaMKII), which was reversed by IL-1RA treatment.

Conclusion: Diabetes associated electrophysiological changes and arrhythmic risk was mediated by IL-1. ROS, especially mitoROS, may provide a mechanistic link between IL-1 and DM associated arrhythmia.



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