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      Ryanodine Receptor-Mediated Ca 2+ Events in Atrial Myocytes of Patients with Atrial Fibrillation

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          Background: Many alterations in sarcoplasmic reticulum Ca<sup>2+</sup> handling proteins in atrial myocytes have been associated with atrial fibrillation (AF) in clinical patients, whereas the functional consequences of these alterations mostly remain unclear. Methods and Results: To know whether or not ryanodine receptor (RyR)-mediated intracellular Ca<sup>2+</sup> events in AF atrial myocytes are affected by protein alterations, we investigated spontaneous Ca<sup>2+</sup> sparks and Ca<sup>2+</sup> waves in intact and permeabilized atrial myocytes of AF patients (n<sub>patients</sub> = 21) and normal sinus rhythm (NSR) patients (n<sub>patients</sub> = 22) by laser scanning confocal microscopy. It was found that the frequency, amplitude and rise time of Ca<sup>2+</sup> sparks were comparable between AF and NSR groups, while full width and full duration at half maximum intensity significantly increased in the AF group. Along with these changes, the frequency of small and global Ca<sup>2+</sup> waves increased in AF atrial myocytes. Conclusions: Our results clearly indicated that the spatiotemporal properties but not the frequency of Ca<sup>2+</sup> sparks were affected in AF atrial myocytes. In addition, the frequency of Ca<sup>2+</sup> waves increased. This profile of the alterations in RyR-mediated Ca<sup>2+</sup> events in AF atrial myocytes was different from previous studies. The underlying mechanisms, as well as possible reasons for this discrepancy, were discussed.

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          Most cited references 18

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          Electrical, contractile and structural remodeling during atrial fibrillation.

          The natural history of atrial fibrillation (AF) is characterized by a gradual worsening with time. The recent finding that AF itself produces changes in atrial function and structure has provided a possible explanation for the progressive nature of this arrhythmia. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to an increase in stability of AF. However, 'domestication of AF' must also depend on a 'second factor' since the persistence of AF continues to increase after electrical remodeling has been completed. Atrial contractile remodeling (loss of contractility) leads to a reduced atrial transport function after cardioversion of AF. An important clinical consequence is that during several days after restoration of sinus rhythm, the risk of atrial thrombus formation is still high. In addition, the reduction of atrial contractility during AF may enhance atrial dilatation which may add to the persistence of AF. Tachycardia-induced structural remodeling takes place in a different time domain (weeks to months). Myolysis probably contributes to the loss of atrial contractile force. Although it might explain the loss of efficacy of pharmacological cardioversion and the development of permanent AF, the role of structural remodeling in the progression of AF is still unclear. Atrial structural remodeling also occurs as a result of heart failure and other underlying cardiovascular diseases. The associated atrial fibrosis might explain intra-atrial conduction disturbances and the susceptibility for AF. Thus, both AF itself and the underlying heart disease are responsible for the development of the arrhythmogenic substrate. New strategies for prevention and termination of AF should be build on our knowledge of the mechanisms and time course of AF-induced atrial remodeling.
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            PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)

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              Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes.

              Spontaneous Ca2+ 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 Ca2+ release and initiation of atrial fibrillation (AF), but this has not yet been reported. Spontaneous Ca2+ release from the SR, manifested as Ca2+ sparks and Ca2+ 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 Ca2+ waves was measured with the use of the perforated patch-clamp technique. The Ca2+ 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 Ca2+ 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 Ca2+ released from the SR and the Na+-Ca2+ exchange rate induced by a rapid caffeine application were comparable in patients with and without AF. The observed increase in spontaneous Ca2+ release in patients with AF probably is due to an upregulation of the SR Ca2+ release channel activity, which may contribute to the development of AF.

                Author and article information

                S. Karger AG
                August 2008
                31 March 2008
                : 111
                : 2
                : 102-110
                aBio-X Life Science Research Center, College of Life Science and Biotechnology, Shanghai Jiao Tong University, bUnit of Cell Signal Transduction, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, cDepartment of Cardiac Surgery and Shanghai Institute of Cardiovascular Disease, Zhong Shan Hospital, Fu Dan University, and dShanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
                119697 Cardiology 2008;111:102–110
                © 2008 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 25, Pages: 9
                Original Research


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