Atrial Fibrillation Is Associated With Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes

Abstract

Background— Spontaneous Ca 2+ release from the sarcoplasmic reticulum (SR) can generate afterdepolarizations, and these have the potential to initiate arrhythmias. Therefore, an association may exist between spontaneous SR Ca 2+ release and initiation of atrial fibrillation (AF), but this has not yet been reported. Methods and Results— Spontaneous Ca 2+ release from the SR, manifested as Ca 2+ sparks and Ca 2+ waves, was recorded with confocal microscopy in atrial myocytes isolated from patients with and those without AF. In addition, the spontaneous inward current associated with Ca 2+ waves was measured with the use of the perforated patch-clamp technique. The Ca 2+ spark frequency was higher in 8 patients with AF than in 16 patients without (6.0±1.2 versus 2.8±0.8 sparks/mm per second, P <0.05). Similarly, the spontaneous Ca 2+ wave frequency was greater in patients with AF (2.8±0.5 versus 1.1±0.3 waves/mm per second, P <0.01). The spontaneous inward current frequency was also higher in 10 patients with AF than in 13 patients without this arrhythmia (0.101±0.028 versus 0.031±0.007 per second, P <0.05, at a clamped potential of −80 mV). In contrast, both the Ca 2+ released from the SR and the Na + -Ca 2+ exchange rate induced by a rapid caffeine application were comparable in patients with and without AF. Conclusions— The observed increase in spontaneous Ca 2+ release in patients with AF probably is due to an upregulation of the SR Ca 2+ release channel activity, which may contribute to the development of AF.

2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design

“…183 During AF, the exceedingly high frequency of atrial excitation is expected to lead to RyR2 refractoriness 184 and downregulation of Ca 2+ handling proteins, 158 acting to prevent triggered activity in the presence of persistent AF. RyR2 leakiness is therefore unlikely to contribute to persistent AF.…”

Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation

“…Strong evidence has emerged that abnormal intracellular Ca 2+ handling plays a central role in the pathogenesis of focal sources and triggered activity in AF 5,8,10 . Defects in sarcolemmal ion channels, in particular decreased I Ca,L current, underlie electrical remodeling in AF, but are not sufficient to explain the enhancement of spontaneous Ca 2+ -release events in myocytes from AF patients 6, 7 .…”

“…The increased frequency of potentially arrhythmogenic Ca 2+ sparks and Ca 2+ waves are most likely caused by defective RyR2 channels 5,8,10 . Consistent with these observations, we previously found defects in RyR2 in atrial biopsies of patients in chronic AF.…”

“…Alterations in the subunit composition and posttranslational regulation of Ca 2+ -handling proteins have been proposed as possible causes of abnormal Ca 2+ handling 4, 5 . Whereas the amplitude of the atrial L-type Ca 2+ channel (I Ca,L ), the major trigger of Ca 2+ -induced Ca 2+ release from sarcoplasmic reticulum (SR), is reduced by ~60-70% in human AF 6, 7 , there is substantial evidence for increased ryanodine receptor (SR Ca 2+ -release channels; RyR2) activity in patients with AF 5,8 . It was shown in patients with chronic AF that RyR2 channels exhibited increased serine 2808 phosphorylation and decreased binding levels of the inhibitory subunit FKBP12.6 (calstabin2) 5 . These RyR2 changes lead to an enhanced sensitivity to Ca 2+ -induced activation at low cytosolic Ca 2+ levels, which increases the propensity to spontaneous SR Ca 2+ release events during diastole 5, 9 .…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…81,85,86,98,99 Furthermore, in a mouse model of CaMKII d overexpression, inhibition of CaMKII was shown to suppress isoprenaline-induced increases in diastolic leak and arrhythmias. 91 Ryanodine receptor instability and increased SR Ca 2þ leak are also considered to play an important role in AF 50,87,100 with CaMKII, again implicated as a significant mediator. 35,87 It is becoming increasingly clear that upregulated I Na,late , intracellular Na þ overload, and increased activity of CaMKII are not acting alone, but rather in concert in cardiac disease.…”