Calmodulin Kinase II and Arrhythmias in a Mouse Model of Cardiac Hypertrophy

Abstract

Background-Calmodulin kinase (CaMK) II is linked to arrhythmia mechanisms in cellular models where repolarization is prolonged. CaMKII upregulation and prolonged repolarization are general features of cardiomyopathy, but the role of CaMKII in arrhythmias in cardiomyopathy is unknown. Methods and Results-We studied a mouse model of cardiac hypertrophy attributable to transgenic (TG) overexpression of a constitutively active form of CaMKIV that also has increased endogenous CaMKII activity. ECG-telemetered TG mice had significantly more arrhythmias than wild-type (WT) littermate controls at baseline, and arrhythmias were additionally increased by isoproterenol. Arrhythmias were significantly suppressed by an inhibitory agent targeting endogenous CaMKII. TG mice had longer QT intervals and action potential durations than WT mice, and TG cardiomyocytes had frequent early afterdepolarizations (EADs), a hypothesized mechanism for triggering arrhythmias. EADs were absent in WT cells before and after isoproterenol, whereas EAD frequency was unaffected by isoproterenol in TG mice. L-type Ca 2ϩ channels (LTTCs) can activate EADs, and LTCC opening probability (Po) was significantly higher in TG than WT cardiomyocytes before and after isoproterenol. A CaMKII inhibitory peptide equalized TG and WT LTCC Po and eliminated EADs, whereas a peptide antagonist of the Na ϩ /Ca 2ϩ exchanger current, also hypothesized to support EADs, was ineffective. Conclusions-These findings support the hypothesis that CaMKII is a proarrhythmic signaling molecule in cardiac hypertrophy in vivo. Cellular studies point to EADs as a triggering mechanism for arrhythmias but suggest that the increase in arrhythmias after ␤-adrenergic stimulation is independent of enhanced EAD frequency.

Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy

“…Nine animals (four RyR2 R176Q/ϩ and five WT) were studied with ECG telemetry according to published methods (22,23). Briefly, transmitters (Data Sciences International, St. Paul, MN) were implanted in the abdominal cavity with s.c. electrodes in a lead I configuration.…”

Return of calcium: Manipulating intracellular calcium to prevent cardiac pathologies

“…DADs may also be generated under conditions of abnormal diastolic calcium leak through hyperphosphorylated RyRs, such as may occur in the setting of heart failure (16) or in rare familial arrhythmias associated with RyR missense mutations (17). Early afterdepolarizations (EADs) are another source of arrhythmias, caused by prolonged action potentials (due to failure of inward Na ϩ currents to inactivate or failure of outward K ϩ currents to activate) caused by drugs or mutation-induced dysfunction of Na ϩ or K ϩ channels (18), thus allowing excessive calcium entry through L-type calcium channels (19,20). Finally, abnormal calcium cycling by the SR has been implicated in the pathogenesis of action potential alternans (21) and spiral wave break-up leading to the development of ventricular fibrillation (22).…”

Blunderbuss to Mickey Mouse

“…In this issue of Circulation, Wu et al 23 report studies of a mouse that overexpresses calmodulin kinase IV (CaMKIV) and develops ventricular hypertrophy. It also has increased endogenous CaMKII activity.…”

“…Critical to this activity may be its function to autophosphorylate and thereby to persist in its "downstream" effects, even after the "upstream" event that initially stimulated it has waned. One of the most potent stimuli for its activation is Ca 2ϩ , and Wu and colleagues 23 take advantage of this, using isoproterenol as an agonist to trigger Ca loading and potentiate the occurrence of arrhythmias. A critical and interesting part of the effect reported is that isoproterenol did not increase the frequency of early afterdepolarizations (EADs) in these mice, but did facilitate the occurrence of arrhythmia.…”

“…Nonetheless, the quality of thought going into work on these models and the clarity of understanding which results in many cases clearly augur well for the long-term upgrading of our therapeutic armamentarium, a point well-made in the current issue of the Circulation. 23 …”