The relationship between arrhythmogenesis and impaired contractility in XXXX : role of altered @entity8452 receptor function.

@entity712 @entity235 @entity8452 @entity409 @entity40205 @entity1432 @entity141 @entity943
AIMS: In @entity712 ( @entity712 ), abnormal myocyte @entity141 handling has been implicated in @entity943 and @entity409 . In the present study, we investigated the relationships between @entity141 handling, reduced myocyte contractility, and enhanced arrhythmogenesis during @entity712 progression in a @entity235 model of non-ischaemic @entity712 . METHODS AND RESULTS: Key @entity141 handling parameters were determined by measuring cytosolic and intra-sarcoplasmic reticulum (SR) [ @entity141 ] in isolated ventricular myocytes at different stages of @entity712 . The progression of @entity712 was associated with an early and continuous increase in @entity8452 receptor ( @entity40205 )-mediated SR @entity141 leak. The increase in @entity40205 activity was paralleled by an increase in the frequency of diastolic spontaneous @entity141 waves (SCWs) in @entity712 myocytes under conditions of b-adrenergic stimulation. In addition to causing arrhythmogenic-delayed afterdepolarizations, SCWs decreased the amplitude of subsequent electrically evoked @entity141 transients by depleting SR @entity141 . At late stages of @entity712 , @entity141 release oscillated essentially independent of electrical pacing. The increased propensity for the generation of SCWs in @entity712 myocytes was attributable to reduced ability of the @entity40205 channels to become refractory following @entity141 release. The progressive alterations in @entity40205 function and @entity141 cycling in @entity712 myocytes were associated with sequential modifications of @entity40205 by CaMKII-dependent phosphorylation and @entity1432 oxidation. CONCLUSION: These findings suggest that destabilized @entity40205 activity due to excessive CaMKII phopshorylation and oxidation resulting in impaired post-release refractoriness is a common mechanism involved in arrhythmogenesis and @entity409 in the failing heart.
