Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure
Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure
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DOI：
10.1007/s10974-006-9089-y
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发表时间：
2006-05-01
影响因子：
2.7
通讯作者：
Soeller, C.
中科院分区：
文献类型：
--
作者：
Cannell, M. B.;Crossman, D. J.;Soeller, C.
利用L-型钙通道（DHPR）门控的蒙特-卡罗模型，我们研究了在人类心力衰竭中观察到的动作电位早期时程变化对兴奋收缩偶联的影响。将DHPR Ca ~（2+）内流的时间过程耦合成肌浆网Ca ~（2+）释放的简单模型。我们的模型表明，在人类心力衰竭的初始尖峰的损失应减少同步性的Ca 2+火花生产，并导致后期的Ca 2+火花和细胞内Ca 2+的更大的不均匀性的外观。在心脏二分体的交界空间内，DHPR与RyR的平均距离的小幅增加导致DHPR介导的局部[Ca 2 +]浓度增加激活RyR的能力显著降低。这表明，EC耦合的效率可能会降低，如果微结构的变化发展和这样的影响已经注意到在实验模型的心力衰竭。心动过速性心力衰竭患者t-小管高分辨率成像显示t-小管结构紊乱。在正常人心脏中，t-小管主要沿径向延伸，而心力衰竭样本中的t-小管则更多地朝向细胞的长轴。此外，t-小管可能会扩张和分叉。我们的数据表明，与兴奋-收缩偶联相关的细胞和膜结构的微结构的变化，结合早期动作电位构型的变化，可以降低Ca 2+通过DHPR内流激活SR钙释放和心脏收缩的效率。虽然这些影响的根本原因尚不清楚，我们的数据表明，几何因素可以发挥重要作用，在人类心脏衰竭的病理生理。
Using a Monte-Carlo model of L-type Ca2+ channel (DHPR) gating, we have examined the effect of changes in the early time course of the action potential as seen in human heart failure on excitation contraction coupling. The time course of DHPR Ca2+ influx was coupled into a simple model of sarcoplasmic reticulum Ca2+ release. Our model shows that the loss of the initial spike in human heart failure should reduce the synchrony of Ca2+ spark production and lead to the appearance of late Ca2+ sparks and greater non-uniformity of intracellular Ca2+. Within the junctional space of the cardiac dyad, a small increase in the mean distance of a DHPR from a RyR results in a marked decrease in the ability of the DHPR-mediated increase in local [Ca2+] concentration to activate RyRs. This suggests that the efficiency of EC coupling may be reduced if changes in micro-architecture develop and such effects have been noted in experimental models of heart failure. High resolution imaging of t-tubules in tachycardia-induced heart failure show deranged t-tubule structure. While in normal human hearts t-tubules run mainly in a radial direction, t-tubules in the heart failure samples were oriented more toward the long axis of the cell. In addition, t-tubules may become dilated and bifurcated. Our data suggest that changes in the micro-architecture of the cell and membrane structures associated with excitation-contraction coupling, combined with changes in early action potential configuration can reduce the efficiency by which Ca2+ influx via DHPRs can activate SR calcium release and cardiac contraction. While the underlying cause of these effects is unclear, our data suggest that geometric factors can play an important role in the pathophysilogy of the human heart in failure.