CaMKII-Dependent Diastolic SR Ca2+ Leak and Elevated Diastolic Ca2+ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation
2010 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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CaMKII-Dependent Diastolic SR Ca2+ Leak and Elevated Diastolic Ca2+ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation
Neef, S.; Dybkova, N.; Sossalla, S. ; Ort, K. R.; Fluschnik, N.; Neumann, K. & Seipelt, R. et al. (2010)
Circulation Research, 106(6) pp. 1134-1144. DOI: https://doi.org/10.1161/CIRCRESAHA.109.203836
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- Authors
- Neef, Stefan; Dybkova, Nataliya; Sossalla, Samuel ; Ort, Katharina R.; Fluschnik, Nina; Neumann, Kay; Seipelt, Ralf; Schoendube, Friedrich A. ; Hasenfuß, Gerd ; Maier, Lars S.
- Abstract
- Rationale: Although research suggests that diastolic Ca2+ levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca2+ levels and play a role in triggering or maintaining AF by transient inward currents through Na+/Ca2+ exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca2+/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca2+ leak. Objective: We tested the hypothesis that CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels occurs in atrial myocardium of patients with AF. Methods and Results: We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40 +/- 14% (P<0.05), as well as CaMKII phosphorylation by 33 +/- 12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110 +/- 53%. Furthermore, cytosolic Ca2+ levels were elevated during diastole (229 +/- 20 versus 164 +/- 8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca2+ leak in AF (P<0.05), which was not attributable to higher SR Ca2+ load. Tetracaine experiments confirmed that SR Ca2+ leak through RyR2 leads to the elevated diastolic Ca2+ level. CaMKII inhibition normalized SR Ca2+ leak and cytosolic Ca2+ levels without changes in L-type Ca2+ current. Conclusion: Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca2+ leak in human AF, causing elevated cytosolic Ca2+ levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF. ( Circ Res. 2010; 106: 1134-1144.)
- Issue Date
- 2010
- Publisher
- Lippincott Williams & Wilkins
- Journal
- Circulation Research
- ISSN
- 0009-7330