Instrumentation and computational modeling tools for cardiac electrophysiology

小鼠和大鼠通常用作心血管疾病的模型。特别地，大鼠心脏长期以来一直是在开发和测试新药剂的背景下非常频繁使用的实验模型。这产生了对用于评估小鼠和大鼠的心血管功能的仪器和方法的需要，以及对鼠（小鼠和大鼠）心脏的更好理解的需要。该建议旨在开发一种实验和计算机建模技术的组合，特别适用于小鼠心脏的电生理学。通过密切协调实验研究和计算机模拟，我们希望获得比两者单独进行时更多的信息。计算机建模结果可以，例如，有助于突出理论预测与实验观察不同的地方。实验观察可以通过提供额外的数据来帮助改进计算描述。该提案的重点是用于测量心脏相邻细胞之间的电耦合的方法，这是一种经常受到心脏病影响的特性。提出的主要实验方法是光学映射，它使用插入细胞膜的电压敏感染料。这些染料发出的荧光信号与细胞膜上的电压成正比。通过用摄像机记录该信号，可以获得心脏电激活的非接触式记录。这使研究人员能够量化心脏不同部位的激活模式（顺序）以及心脏电激活的传导速度。将用这种技术获得的结果与心脏组织阻抗的电测量以及用相应的计算机模型获得的结果进行比较。总体而言，目标是建立1）关于电耦合如何影响心脏行为的知识和2）测量电耦合的工具。这些结果将用于基础医学研究以及心脏病药物治疗的开发。

Mice and rats are commonly used as models of cardiovascular disease. In particular, the rat heart has long been a very frequently used experimental model in the context of development and testing of new pharmaceutical agents. This has created a need for instrumentation and methods for assessing cardiovascular function in mice and rats, and for a better understanding of the murine (mouse and rat) heart. This proposal aims to develop a combination of experimental and computer modeling techniques applicable specifically to the electrophysiology of the murine heart. By closely coordinating experimental research and computer modeling, we hope to obtain more information than could be obtained if the two were carried out separately. Computer modeling results can, e.g., help highlight areas where theoretical predictions differ from experimental observations. Experimental observations can help refine computational descriptions by providing additional data. The focus of this proposal is on methods used to measure electrical coupling among neighbouring cells in the heart, a property which is frequently affected by heart disease. Optical mapping, the primary experimental method proposed, uses voltage-sensitive dyes that insert into the cell membrane. These dyes emit a fluorescent signal that is proportional to the voltage across the cell membrane. By recording this signal with a video camera, one can obtain non-contact recordings of electrical activation of the heart. This allows the researcher to quantify the pattern (order) of activation of different parts of the heart as well as the speed of conduction of electrical activation across the heart. The results obtained with this technique will be compared to electrical measurements of the impedance of heart tissue, as well as to results obtained with corresponding computer models. Overall, the objective is to establish 1) knowledge about how electrical coupling affects the behaviour of the heart and 2) tools for measuring electrical coupling. These outcomes will be of use in basic medical research as well as for development of pharmaceutical therapies for heart disease.