Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Medical Center, 473 W. 12th Avenue Columbus, OH 43210, USA.
Cardiovasc Res. 2011 Jun 1;90(3):493-502. doi: 10.1093/cvr/cvr025. Epub 2011 Jan 27.
In heart failure (HF), abnormal myocyte Ca(2+) handling has been implicated in cardiac arrhythmias and contractile dysfunction. In the present study, we investigated the relationships between Ca(2+) handling, reduced myocyte contractility, and enhanced arrhythmogenesis during HF progression in a canine model of non-ischaemic HF.
Key Ca(2+) handling parameters were determined by measuring cytosolic and intra-sarcoplasmic reticulum (SR) [Ca(2+)] in isolated ventricular myocytes at different stages of HF. The progression of HF was associated with an early and continuous increase in ryanodine receptor (RyR2)-mediated SR Ca(2+) leak. The increase in RyR2 activity was paralleled by an increase in the frequency of diastolic spontaneous Ca(2+) waves (SCWs) in HF myocytes under conditions of β-adrenergic stimulation. In addition to causing arrhythmogenic-delayed afterdepolarizations, SCWs decreased the amplitude of subsequent electrically evoked Ca(2+) transients by depleting SR Ca(2+). At late stages of HF, Ca(2+) release oscillated essentially independent of electrical pacing. The increased propensity for the generation of SCWs in HF myocytes was attributable to reduced ability of the RyR2 channels to become refractory following Ca(2+) release. The progressive alterations in RyR2 function and Ca(2+) cycling in HF myocytes were associated with sequential modifications of RyR2 by CaMKII-dependent phosphorylation and thiol oxidation.
These findings suggest that destabilized RyR2 activity due to excessive CaMKII phopshorylation and oxidation resulting in impaired post-release refractoriness is a common mechanism involved in arrhythmogenesis and contractile dysfunction in the failing heart.
在心力衰竭（HF）中，肌细胞 Ca(2+) 处理的异常与心律失常和收缩功能障碍有关。本研究在非缺血性 HF 的犬模型中，研究了 HF 进展过程中 Ca(2+) 处理、心肌细胞收缩力降低和心律失常易发性增强之间的关系。
通过在不同 HF 阶段测量分离的心室肌细胞胞质和肌浆网（SR）[Ca(2+)]来确定关键的 Ca(2+) 处理参数。HF 的进展与 RyR2 介导的 SR Ca(2+) 泄漏的早期和持续增加有关。HF 心肌细胞在β-肾上腺素能刺激下，RyR2 活性的增加与舒张自发性 Ca(2+) 波（SCWs）的频率增加平行。除了引起心律失常性延迟后除极外，SCWs 通过耗尽 SR Ca(2+) 来降低随后电诱发 Ca(2+) 瞬变的幅度。在 HF 的晚期，Ca(2+) 释放基本上独立于电起搏而发生振荡。HF 心肌细胞中 SCWs 产生的倾向性增加归因于 RyR2 通道在 Ca(2+) 释放后变得不应期的能力降低。HF 心肌细胞中 RyR2 功能和 Ca(2+) 循环的进行性改变与 RyR2 被 CaMKII 依赖性磷酸化和巯基氧化的顺序修饰有关。
这些发现表明，由于过度的 CaMKII 磷酸化和氧化导致的 RyR2 活性不稳定，从而导致释放后不应期受损，这是心力衰竭中心律失常和收缩功能障碍的共同机制。
