Laboratory of Cell Electrophysiology, Harefield Heart Science Centre, Imperial College London, London, UK.
Eur J Heart Fail. 2012 Jun;14(6):571-80. doi: 10.1093/eurjhf/hfs038. Epub 2012 Apr 1.
Ca(2+)-induced Ca(2+) release (CICR) is critical for contraction in cardiomyocytes. The transverse (t)-tubule system guarantees the proximity of the triggers for Ca(2+) release [L-type Ca(2+) channel, dihydropyridine receptors (DHPRs)] and the sarcoplasmic reticulum Ca(2+) release channels [ryanodine receptors (RyRs)]. Transverse tubule disruption occurs early in heart failure (HF). Clinical studies of left ventricular assist devices in HF indicate that mechanical unloading induces reverse remodelling. We hypothesize that unloading of failing hearts normalizes t-tubule structure and improves CICR.
Heart failure was induced in Lewis rats by left coronary artery ligation for 12 weeks; sham-operated animals were used as controls. Failing hearts were mechanically unloaded for 4 weeks by heterotopic abdominal heart transplantation (HF-UN). HF reduced the t-tubule density measured by di-8-ANEPPS staining in isolated left ventricular myocytes, and this was reversed by unloading. The deterioration in the regularity of the t-tubule system in HF was also reversed in HF-UN. Scanning ion conductance microscopy showed the reappearance of normal surface striations in HF-UN. Electron microscopy revealed recovery of normal t-tubule microarchitecture in HF-UN. L-type Ca(2+) current density, measured using whole-cell patch clamping, was reduced in HF but unaffected by unloading. The variance of the time-to-peak of the Ca(2+) transient, an index of CICR dyssynchrony, was increased in HF and normalized by unloading. The increased Ca(2+) spark frequency observed in HF was reduced in HF-UN. These results could be explained by the recoupling of orphaned RyRs in HF, as indicated by immunofluorescence.
Our data show that mechanical unloading of the failing heart reverses the pathological remodelling of the t-tubule system and improves CICR.
钙离子诱导的钙离子释放（CICR）对于心肌收缩至关重要。横管系统保证了钙离子释放的触发因素（L 型钙离子通道、二氢吡啶受体（DHPRs））和肌浆网钙离子释放通道（ryanodine 受体（RyRs））的接近。横管系统的破坏在心力衰竭（HF）早期就会发生。HF 左心室辅助装置的临床研究表明，机械卸载会引起逆重构。我们假设衰竭心脏的卸载会使横管结构正常化并改善 CICR。
通过左冠状动脉结扎在 Lewis 大鼠中诱导心力衰竭 12 周；假手术动物作为对照。通过异位腹部心脏移植（HF-UN）对衰竭心脏进行机械卸载 4 周。HF 降低了分离的左心室肌细胞中二 -8-ANEPPS 染色测量的横管密度，而卸载则逆转了这一过程。HF 中横管系统规律性的恶化在 HF-UN 中也得到了逆转。扫描离子电导显微镜显示 HF-UN 中正常表面条纹的重现。电子显微镜显示 HF-UN 中恢复了正常的横管微结构。使用全细胞膜片钳测量 L 型钙离子电流密度，HF 降低，但卸载不受影响。钙瞬变时峰值时间的方差（CICR 不同步的指标）在 HF 中增加，并通过卸载正常化。HF 中观察到的增加的 Ca2+火花频率在 HF-UN 中降低。这些结果可以通过免疫荧光显示 HF 中孤儿 RyRs 的重新偶联来解释。
我们的数据表明，衰竭心脏的机械卸载逆转了横管系统的病理性重构，并改善了 CICR。
