Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure

Can M. Sag, Daniel P. Wadsack, Sepideh Khabbazzadeh, Marco Abesser, Clemens Grefe, Kay Neumann, Marie Kristin Opiela, Johannes Backs, Eric N. Olson, Joan Heller Brown, Stefan Neef, Sebastian K G Maier, Lars S. Maier

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116 Scopus citations

Abstract

Background-Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)δC 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 after depolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these after-depolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10-8 M) induced a larger amount of delayed after-depolarizations 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 CaMKIIδ-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 CaMKIIδC 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.

Original languageEnglish (US)
Pages (from-to)664-675
Number of pages12
JournalCirculation: Heart Failure
Volume2
Issue number6
DOIs
StatePublished - Nov 2009

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Keywords

  • Arrhythmia
  • Calcium
  • Calcium-calmodulin-dependent protein kinase type 2
  • Excitation-contraction coupling
  • Heart failure
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Sag, C. M., Wadsack, D. P., Khabbazzadeh, S., Abesser, M., Grefe, C., Neumann, K., Opiela, M. K., Backs, J., Olson, E. N., Brown, J. H., Neef, S., Maier, S. K. G., & Maier, L. S. (2009). Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure. Circulation: Heart Failure, 2(6), 664-675. https://doi.org/10.1161/CIRCHEARTFAILURE.109.865279