Calcium dysregulation in atrial fibrillation: the role of CaMKII

Abstract

Atrial fibrillation (AF) is the most frequently encountered clinical arrhythmia and is associated with increased morbidity and mortality. Ectopic activity and reentry are considered major arrhythmogenic mechanisms contributing to the initiation and maintenance of AF. In addition, AF is self-reinforcing through progressive electrical and structural remodeling which stabilize the arrhythmia and make it more difficult to treat. Recent research has suggested an important role for Ca(2+)-dysregulation in AF. Ca(2+)-handling abnormalities may promote ectopic activity, conduction abnormalities facilitating reentry, and AF-related remodeling. In this review article, we summarize the Ca(2+)-handling derangements occurring in AF and discuss their impact on fundamental arrhythmogenic mechanisms. We focus in particular on the role of the multifunctional Ca(2+)/calmodulin-dependent protein kinase type-II (CaMKII), which acts as a major link between Ca(2+)-dysregulation and arrhythmogenesis. CaMKII expression and activity are increased in AF and promote arrhythmogenesis through phosphorylation of various targets involved in cardiac electrophysiology and excitation-contraction coupling. We discuss the implications for potential novel therapeutic strategies for AF based on CaMKII and Ca(2+)-handling abnormalities.

Keywords: CaMKII; atrial fibrillation; calcium; ectopic activity; reentry.

Figure 1

Putative substrates for CaMKII-dependent phosphorylation in atrial cardiomyocytes and their consequences for atrial cellular electrophysiology and Ca²⁺-handling. CaMKII can phosphorylate the transient-outward K⁺-current (I_to), inward-rectifier K⁺-current (I_K1) and ultra-rapid delayed-rectifier K⁺-current (I_Kur), augmenting their functions and shortening action potential duration (APD). Phosphorylation of L-type Ca²⁺-current (I_Ca,L) and Na⁺-current (I_Na; resulting in an increased late component: I_Na,late) by CaMKII increases intracellular Ca²⁺ levels and prolongs APD. CaMKII-dependent phosphorylation of phospholamban (PLB) and sarcolipin (SLN) increases sarcoplasmic reticulum (SR) Ca²⁺-uptake, whereas phosphorylation of type-2 ryanodine-receptor channels (RyR2) promotes diastolic SR Ca²⁺-leak. CaMKII-dependent increases in expression of Na⁺/Ca²⁺-exchanger type-1 (NCX1) augment NCX-current (I_NCX), promoting the occurrence of delayed afterdepolarizations (DADs). In addition, Ca²⁺-handling abnormalities can activate small-conductance Ca²⁺-activated K⁺-currents (I_SK) and agonist-independent “constitutive” I_K,ACh, shortening APD, and promote altered gene expression via the Ca²⁺-dependent phosphatase calcineurin (Cn).

Figure 2

Atrial fibrillation (AF)-related mechanisms promoting CaMKII activation. AF-promoting conditions and/or AF itself can activate CaMKII via high atrial rates, oxidative stress, sympathetic hyperactivity, and hyperglycaemia, resulting in post-translational modifications (phosphorylation, oxidation, nitrosylation and glycosylation) of various residues in the regulatory domain of CaMKII. In addition, AF is associated with an increased total expression of the CaMKII holoenzyme. See text for details.

Figure 3

Proarrhythmic consequences of Ca²⁺/CaMKII dysregulation in atrial fibrillation (AF). CaMKII activation and CaMKII-dependent phosphorylation of type-2 ryanodine-receptor (RyR2) channels (RyR2-Ser2814-P) and phospholamban (PLB-Thr17-P), as well as other factors, promote spontaneous diastolic sarcoplasmic reticulum (SR) Ca²⁺-release events through RyR2 dysfunction and modulation of SR Ca²⁺-load in patients with paroxysmal AF (pAF; blue lines) and long-standing persistent, chronic AF (cAF; black lines). SR Ca²⁺-leak and diastolic SR Ca²⁺-release events can produce delayed afterdepolarizations (DADs) that contribute to ectopic activity. In addition, they can promote reentry through local repolarization abnormalities, as well as structural remodeling and conduction velocity (CV) slowing. Influences for which the proarrhythmic roles are more speculative have been indicated with dashed lines.