Published online before print July 31, 2009, doi: 10.1161/CIRCHEARTFAILURE.109.865279
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Original Articles |
Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Cardiac Arrhythmogenesis in Heart Failure
From the Department of Cardiology and Pneumology (C.M.S., D.P.W., S.K., C.G., K.N., M.-K.O., S.N., L.S.M.), Heart Center, Georg-August-University, Göttingen; the Medizinische Klinik und Poliklinik I (M.A., S.K.G.M.), Universitätsklinikum Würzburg, Würzburg; the Department of Internal Medicine III (J.B.), University of Heidelberg, Heidelberg, Germany; the Department of Molecular Biology (E.N.O.), University of Texas Southwestern Medical Center, Dallas, Tex; and the Department of Pharmacology (J.H.B.), University of California, San Diego, Calif.
Correspondence to Lars S. Maier, MD, Department of Cardiology and Pneumology, Heart Center, Georg-August-University Göttingen, Robert-Koch-Street 40, 37075 Göttingen, Germany. E-mail lmaier{at}med.uni-goettingen.de
Received March 13, 2009; accepted July 9, 2009.
Background— Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)
C mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo.
Methods and Results— Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10–8 M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca]i rose clearly on ISO in TG but not in wild-type cells (+20±5% versus +3±4% at 10–6 M ISO, P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9±0.5 versus 2.0±0.4 sparks per 100 µm–1·s–1, P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKII-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P<0.05) and late (86% versus 43%, P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05).
Conclusions— We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIC mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.
Key Words: arrhythmia • calcium • excitation-contraction coupling • heart failure • sarcoplasmic reticulum • calcium-calmodulin-dependent protein kinase type 2
CLINICAL PERSPECTIVE
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