title: Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure.
abstract: BACKGROUND
  Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(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.
  
  
  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 microm(-1).s(-1), P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIdelta-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 CaMKIIdelta(C) 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.
authors.affiliation: Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Göttingen, Germany.
authors.forename: Can M
authors.initials: CM
authors.lastname: Sag
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Wadsack
authors.forename: Sepideh
authors.initials: S
authors.lastname: Khabbazzadeh
authors.forename: Marco
authors.initials: M
authors.lastname: Abesser
authors.forename: Clemens
authors.initials: C
authors.lastname: Grefe
authors.forename: Kay
authors.initials: K
authors.lastname: Neumann
authors.forename: Marie-Kristin
authors.initials: MK
authors.lastname: Opiela
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Sebastian K G
authors.initials: SK
authors.lastname: Maier
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D001596:Benzylamines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D007545:Isoproterenol; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D002118:Calcium; D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol; D047428:Protein Kinase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C517674:Camk2g protein, mouse