QT interval prolongation and arrhythmia: an unbreakable connection?
QT interval prolongation is incontrovertibly linked to increased risk of arrhythmias but, paradoxically, QT interval prolongation can also be an effective antiarrhythmic strategy and is in fact the goal of class III antiarrhythmic drugs. This discussion examines the cellular effects of QT interval prolongation and proposes that calmodulin kinase II (CaMKII) is a specific cellular proarrhythmic signal that is activated downstream to QT interval prolongation. Inhibition of CaMKII can prevent cellular arrhythmia surrogates and in vivo arrhythmias linked to excessive action potential prolongation, suggesting that QT interval prolongation alone does not fully account for proarrhythmia. This reasoning points to the conclusion that QT interval modulation and prolongation not only grades cellular Ca2+ entry for cardiac contraction but also has the potential to recruit Ca2+-activated signalling molecules. CaMKII is one of these molecules and CaMKII activity is at least partially responsible for the proarrhythmic consequences of excessive QT interval prolongation.
Anderson
M E
ME
Department of Cardiovascular Medicine, Vanderbilt University Medical School, Nashville, TN, USA. mark.anderson@vanderbilt.edu
D000200:Action Potentials / Q000502:physiology; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008133:Long QT Syndrome / Q000503:physiopathology; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology
D015220:Calcium Channels; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium