Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death.
BACKGROUND
Diastolic spontaneous Ca(2+) waves (DCWs) are recognized as important contributors to triggered arrhythmias. DCWs are thought to arise when [Ca(2+)] in sarcoplasmic reticulum ([Ca(2+)](SR)) reaches a certain threshold level, which might be reduced in cardiac disease as a consequence of sensitization of ryanodine receptors (RyR2s) to luminal Ca(2+).


OBJECTIVE
We investigated the mechanisms of DCW generation in myocytes from normal and diseased hearts, using a canine model of post-myocardial infarction ventricular fibrillation (VF).


RESULTS
The frequency of DCWs, recorded during periodic pacing in the presence of a β-adrenergic receptor agonist isoproterenol, was significantly higher in VF myocytes than in normal controls. Rather than occurring immediately on reaching a final [Ca(2+)](SR), DCWs arose with a distinct time delay after attaining steady [Ca(2+)](SR) in both experimental groups. Although the rate of [Ca(2+)](SR) recovery after the SR Ca(2+) release was similar between the groups, in VF myocytes the latency to DCWs was shorter, and the [Ca(2+)](SR) at DCW initiation was lower. The restitution of depolarization-induced Ca(2+) transients, assessed by a 2-pulse protocol, was significantly faster in VF myocytes than in controls. The VF-related alterations in myocyte Ca(2+) cycling were mimicked by the RyR2 agonist, caffeine. The reducing agent, mercaptopropionylglycine, or the CaMKII inhibitor, KN93, decreased DCW frequency and normalized restitution of Ca(2+) release in VF myocytes.


CONCLUSIONS
The attainment of a certain threshold [Ca(2+)](SR) is not sufficient for the generation of DCWs. Postrelease Ca(2+) signaling refractoriness critically influences the occurrence of DCWs. Shortened Ca(2+) signaling refractoriness due to RyR2 phosphorylation and oxidation is responsible for the increased rate of DCWs observed in VF myocytes and could provide a substrate for synchronization of arrhythmogenic events at the tissue level in hearts prone to VF.
Davis Heart and Lung Research Institute, The Ohio State University Medical Center, 473 W 12th Ave., Columbus, OH 43210, USA.. Andriy.Belevych@osumc.edu
Andriy E
AE
Belevych
Dmitry
D
Terentyev
Radmila
R
Terentyeva
Hsiang-Ting
HT
Ho
Inna
I
Gyorke
Ingrid M
IM
Bonilla
Cynthia A
CA
Carnes
George E
GE
Billman
Sandor
S
Györke
D000318:Adrenergic beta-Agonists; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004195:Disease Models, Animal; D004285:Dogs; D056966:Excitation Contraction Coupling; D005260:Female; D007545:Isoproterenol; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011930:Reaction Time; D019163:Reducing Agents / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D008625:Tiopronin / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000096926:Benzenesulfonamides
D000318:Adrenergic beta-Agonists; D001596:Benzylamines; D002110:Caffeine; D002120:Calcium Channel Agonists; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol; D047428:Protein Kinase Inhibitors; D019163:Reducing Agents; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; D008625:Tiopronin; C072105:KN 93; D000096926:Benzenesulfonamides