PMC:6019327 / 45555-49127 JSONTXT

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Ca2+ release promoting triggered activity is likely to be an important mechanism of AF initiation.183 During AF, the exceedingly high frequency of atrial excitation is expected to lead to RyR2 refractoriness184 and downregulation of Ca2+ handling proteins,158 acting to prevent triggered activity in the presence of persistent AF. RyR2 leakiness is therefore unlikely to contribute to persistent AF.185 However, such considerations do not apply in PAF, in which ectopic activity likely related to Ca2+-dependent ectopy could play an important role. There is evidence that Ca2+ released from the leaky RyR2 receptors in the sarcoplasmic reticulum (SR) is exchanged by the Na+-Ca2+ exchanger (NCX), which produces an arrhythmogenic depolarizing current that induces atrial ectopic activity.186,187 In a mouse model characterized by progressive AF, SR Ca2+ leak is enhanced in association with Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent hyperphosphorylation of the ryanodine receptor.188 Genetic inhibition of the Ca2+ leak reduced structural remodeling and prevented the development of persistent AF.188 However, in isolated remodeled rabbit and human atrial myocytes, Ca2+ signaling was silenced through a variety of mechanisms.185 The authors suggested that Ca2+ silencing might be a protective mechanism against the Ca2+ overload that occurs during chronic AF, and challenged the notion that aberrant Ca2+ release contributes to the pathophysiology of persistent AF. However, during AF, the exceedingly high frequency of atrial excitation is expected to lead to RyR2 refractoriness and downregulation of Ca2+-handling proteins, acting to prevent triggered activity. Therefore, whether RyR2 leakiness contributes to persistent AF is now being disputed.158,184,185 A popular concept that had been promoted by some investigators over the last several years was that both initiation and maintenance of AF could be related to increased activity of protein kinase A (PKA) and/or Ca2+/CaMKII, with subsequent uncontrolled diastolic Ca2+ release from the SR.186 The idea is that Ca2+ released from the “leaky” RyR2 receptors in the SR would overactivate the NCX to extrude Ca2+ and produce an arrhythmogenic depolarizing current, thereby explaining both the contractile dysfunction and the high recurrence rate of the arrhythmia.186,187 In a recent study in mice with a mutation causing progressive AF, SR Ca2+ leak was reported to be enhanced in association with Ca2+/CaMKII–dependent hyperphosphorylation of the ryanodine receptor.188 Genetic inhibition of Ca2+/CaMKII-mediated RyR2-S2814 suppressed the Ca2+ leak, reduced structural remodeling, and prevented the development of persistent AF.188 However, recent studies in large animals and in humans have challenged the idea that Ca2+ dysfunction underlies AF maintenance and perpetuation. In isolated rabbit atrial myocytes, remodeling in response to sustained tachycardia for up to 5 days was shown to silence Ca2+ signaling through a failure of subcellular propagated Ca2+ release.185 The authors suggested that Ca2+ silencing might be a protective mechanism against the massive Ca2+ overload that occurs during chronic AF. In another study in human atrial myocytes, although CaMKII appeared to facilitate catecholamine-evoked arrhythmias in the atrial myocardium of patients with sinus rhythm, the same agonists failed to elicit arrhythmias in the atrial myocardium of patients with chronic AF, likely related to atrial remodeling, which included decreases in CaMKII-mediated processes.189"}