Background: Type 2 diabetes (T2D) increases arrhythmia risk through incompletely elucidated mechanisms. Ventricular arrhythmias could be initiated by delayed afterdepolarizations (DADs) resulting from elevated spontaneous sarcoplasmic reticulum (SR) Ca2+ release (SR Ca2+ leak). Objective: The purpose of this study was to test the role of DADs and SR Ca2+ leak in triggering arrhythmias in T2D hearts. Methods: We compared rats with late-onset T2D that display pancreatic and cardiac phenotypes similar to those in humans with T2D (HIP rats) and their nondiabetic littermates (wild type [WT]). Results: HIP rats showed higher propensity for premature ventricular complexes and ventricular tachyarrhythmias, whereas HIP myocytes displayed more frequent DADs and had lower SR Ca2+ content than WT. However, the threshold SR Ca2+ at which depolarizing transient inward currents (Itis) are generated was also significantly decreased in HIP myocytes and was below the actual SR Ca2+ load, which explains the increased DAD incidence despite reduced Ca2+ in SR. In agreement with these findings, Ca2+ spark frequency was augmented in myocytes from HIP vs WT rats, which suggests activation of ryanodine receptors (RyRs) in HIP hearts. Indeed, RyR phosphorylation (by CaMKII and protein kinase A) and oxidation are enhanced in HIP hearts, whereas there is no RyR O-GlcNAcylation in either HIP or control hearts. CaMKII inhibition dissipated the difference in Ca2+ spark frequency between HIP and WT myocytes. Conclusion: The threshold SR Ca2+ for generating depolarizing Itis is lower in T2D because of RyR activation after hyperphosphorylation and oxidation, which favors the occurrence of DADs despite low SR Ca2+ loads.
|Number of pages
|Published - May 2019
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grants HL135000 and HL109501 to Dr S. Despa and HL118474 to Dr F. Despa; and the Health Research Council of New Zealand Grant 15/331 to Dr Erickson.
© 2018 Heart Rhythm Society
- Ryanodine receptor
- Transient inward current
- Type 2 diabetes
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)