Calcium/Calmodulin-Dependent Protein Kinase II Contributes to Cardiac Arrhythmogenesis in Heart Failure

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 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 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.

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation

“…Arrhythmogenic effects of ISO were found to be antagonized by CaMKII inhibitors in rabbit ventricle (26). Increased Ca 2+ leaking and DADs have been reported in myocytes from mice overexpressing CaMKII and ISO elicited ventricular arrhythmias that were prevented by KN-93 (27). Particularly relevant to AF, KN-93 prevented ISOevoked arrhythmic activity in rabbit pulmonary veins (28).…”

Cyclophilin D controls mitochondrial pore–dependent Ca2+ exchange, metabolic flexibility, and propensity for heart failure in mice

“…To further characterize this maladaptive phenotype due to hypertrophic stimulation, we crossed Ppif -/-mice with Ca 2+ /calmodulin-dependent protein kinase IIδc-transgenic mice (CaMKII-Tg). CaMKIIδc overexpression results in heart failure characterized by a loss of LV function and significant mortality, but more importantly these mice show alterations in intracellular Ca 2+ handling and a predisposition to increased mitochondrial Ca 2+ (17)(18)(19). As will be presented in figures below, this predisposition to elevated mitochondrial Ca 2+ with CaMKIIδc overexpression is similar to alterations observed in Ppif -/-hearts, making the cross mechanistically germane.…”

Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload

“…Cellular arrhythmias were induced upon addition of H 2 O 2 (200 μmol/L). It is generally accepted that after-contractions and after-transients were defined as cellular proarrhythmogenic events, in which early after-transients/contractions (EATs/ EACs) may correspond to EADs and delayed after-transients/ contractions (DATs/DACs) may correspond to DADs [7,[20][21][22][23] . Therefore, EATs/EACs and DATs/DACs can be used as proximal direct indices of EADs-like and DADs-like arrhythmias, respectively.…”