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Almost four decades since its initial discovery in brain (Schulman and Greengard, 1978), the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) has now emerged as a key signaling molecule in the heart. The isoform that predominates in heart, CaMKIId, directly regulates expression and function of several of the main cardiac ion channels and Ca2+ handling proteins (Bers and Grandi, 2009). CaMKII-dependent effects are thought to orchestrate many of the electrophysiologic and contractile adaptations to common cardiac stressors, such as rapid pacing, adrenergic stimulation, and oxidative challenge. In the context of disease, CaMKII has been shown to contribute to a remarkably wide variety of cardiac pathologies, including myocardial hypertrophy, ischemia, heart failure (HF), and arrhythmia. CaMKII expression is increased in patients with HF (Hoch et al., 1999), and elevated CaMKII expression and activity have been implicated in the transition to HF (Zhang et al., 2003). Indeed, inhibiting CaMKII appears to reduce arrhythmias and pathological signaling, which makes this kinase a promising new therapeutic target (Anderson et al., 2011). © 2014 Grandi, Edwards, Herren and Bers.

Calcium/calmodulin-dependent protein kinase II (CaMKII) activity has been shown to contribute to arrhythmogenesis in a remarkably broad range of cardiac pathologies. Several of these involve significant structural and electrophysiologic remodeling, whereas others are due to specific channelopathies, and are not typically associated with arrhythmogenic changes to protein expression or cellular and tissue structure. The ability of CaMKII to contribute to arrhythmia across such a broad range of phenotypes suggests one of two interpretations regarding the role of CaMKII in cardiac arrhythmia: (1) some CaMKII-dependent mechanism is a common driver of arrhythmia irrespective of the specific etiology of the disease, or (2) these different etiologies expose different mechanisms by which CaMKII is capable of promoting arrhythmia. In this review, we dissect the available mechanistic evidence to explore these two possibilities and discuss how the various molecular actions of CaMKII promote arrhythmia in different pathophysiologic contexts.