Published Online
on July 31, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

CaMKII Contributes to Cardiac Arrhythmogenesis in Heart Failure

Can M. Sag¹; Daniel P. Wadsack¹; Sepideh Khabbazzadeh¹; Marco Abesser²; Clemens Grefe¹; Kay Neumann¹; Marie-Kristin Opiela¹; Johannes Backs³; Eric N. Olson⁴; Joan Heller Brown⁵; Stefan Neef¹; Sebastian K.G. Maier² and Lars S. Maier^1,6

¹ Georg-August-University Göttingen, Göttingen, Germany;
² Universitätsklinikum Würzburg, Würzburg, Germany;
³ University of Heidelberg, Heidelberg, Germany;
⁴ University of Texas Southwestern Medical Center, Dallas, TX;
⁵ University of California, San Diego, CA

^* Corresponding author; email: lmaier{at}med.uni-goettingen.de

Background—Transgenic CaMKII_C (TG) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and to 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 revealed an increased incidence of early afterdepolarizations (ADs) as compared to wild-type (WT) myocytes (P<0.05). CaMKII-inhibition (AIP) completely abolished these ADs in TG cells (P<0.05). Elevating intracellular Ca stores using ISO (10^-8 M) induced a larger amount of delayed ADs and spontaneous action potentials in TG as compared to WT (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak since diastolic [Ca] rose clearly upon ISO in TG but not in WT cells (+20±5% vs. +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 vs. 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% vs. 4%, P<0.05) and late (86% vs. 43%, P<0.05) non-stimulated events (NSEs) in TG vs. WT 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 CaMKII_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.

Key Words: arrhythmia • calcium • heart failure • sarcoplasmic reticulum • excitation-contraction coupling