Ryanodine receptor dysfunction and triggered activity in the heart

被引:25
作者
Katra, Rodolphe P. [1 ]
Oya, Toshiyuki [1 ]
Hoeker, Gregory S. [1 ]
Laurita, Kenneth R. [1 ]
机构
[1] Case Western Reserve Univ, Heart & Vasc Res Ctr, Dept Biomed Engn, Cleveland, OH 44106 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2007年 / 292卷 / 05期
关键词
spontaneous calcium release; sudden death; arrhythmia mechanisms;
D O I
10.1152/ajpheart.00924.2006
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Arrhythmogenesis has been increasingly linked to cardiac ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that, under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed high-resolution optical mapping of intracellular calcium and transmembrane potential in the canine left ventricular wedge preparation (n = 28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6 dissociation and P-adrenergic stimulation (20-150 mu M rapamycin, 0.2 mu M isoproterenol). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, rapamycin, or isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythimas (monomorphic and polymorphic tachycardia) were commonly observed. After washout of rapamycin and isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium but not the endocardium (P < 0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, but rather by fast calcium reuptake kinetics. These data suggest that, under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of SCR may be a mechanism for multifocal arrhythmias associated with RyR dysfunction.
引用
收藏
页码:H2144 / H2151
页数:8
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