Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure.
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.
Sag
Can M
CM
Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Göttingen, Germany.
Wadsack
Daniel P
DP
Khabbazzadeh
Sepideh
S
Abesser
Marco
M
Grefe
Clemens
C
Neumann
Kay
K
Opiela
Marie-Kristin
MK
Backs
Johannes
J
Olson
Eric N
EN
Brown
Joan Heller
JH
Neef
Stefan
S
Maier
Sebastian K G
SK
Maier
Lars S
LS
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
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