Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1215, New York, NY 10029, USA.
Cardiovasc Res. 2013 May 1;98(2):233-9. doi: 10.1093/cvr/cvt026. Epub 2013 Feb 7.
Compelling recent experimental results make clear that sub-cellular structures are altered in ventricular myocytes during the development of heart failure, in both human samples and diverse experimental models. These alterations can include, but are not limited to, changes in the clusters of sarcoplasmic reticulum (SR) Ca(2+)-release channels, ryanodine receptors, and changes in the average distance between the cell membrane and ryanodine receptor clusters. In this review, we discuss the potential consequences of these structural alterations on the triggering of SR Ca(2+) release during excitation-contraction coupling. In particular, we describe how mathematical models of local SR Ca(2+) release can be used to predict functional changes resulting from diverse modifications that occur in disease states. We review recent studies that have used simulations to understand the consequences of sub-cellular structural changes, and we discuss modifications that will allow for future modelling studies to address unresolved questions. We conclude with a discussion of improvements in both experimental and mathematical modelling techniques that will be required to provide a stronger quantitative understanding of the functional consequences of changes in sub-cellular structure in heart disease.
最近的实验结果令人信服地表明，在心力衰竭的发展过程中，无论是在人类样本还是在各种实验模型中，心室肌细胞的亚细胞结构都发生了改变。这些改变包括但不限于肌浆网（SR）Ca2+释放通道、兰尼碱受体簇的变化，以及细胞膜和兰尼碱受体簇之间平均距离的变化。在这篇综述中，我们讨论了这些结构改变对兴奋-收缩偶联过程中 SR Ca2+释放触发的潜在影响。特别是，我们描述了如何使用局部 SR Ca2+释放的数学模型来预测疾病状态下发生的各种改变所导致的功能变化。我们回顾了最近使用模拟来理解亚细胞结构变化后果的研究，并讨论了将允许未来建模研究解决未解决问题的修改。最后，我们讨论了改进实验和数学建模技术的必要性，以便更深入地了解心脏病中亚细胞结构改变的功能后果。
