THE EFFECTS OF MYOFIBROBLASTS ON ELECTROMECHANICAL FUNCTION OF MODEL HEART TISSUE

描述（由申请人提供）：高血压或心肌梗死将正常的、相对静止的成纤维细胞转化为更大的更具收缩性的表型，即肌成纤维细胞（mFB）。mFB扰乱并中断正常组织良好的心肌，使其变硬并扭曲电脉冲的进展，从而触发心脏的有序收缩，引起折返性心律失常，有时导致猝死。为了了解如何避免或减轻这种后果，重要的是要知道mFB如何影响心脏的机电功能。这项工作的总体目的是了解mFB如何使用专门为此目的设计的计算和实验模型来干扰此功能。结果将是mFB对工程心肌模型的电和机械功能的影响的实验和计算模型。电和机械功能以及计算和实验模型的组合将超过当前心脏纤维化模型的范围和细节。由此产生的预测模型将有助于设计治疗高血压性心脏病和心肌梗死引起的纤维化。本工作基于以下假设：（1）纤维化心肌的收缩功能下降是由于电耦合引起的。 和与mFB相关的机械效应，它们对ECM的重塑，以及它们与心肌细胞（CM）的连接，以及（2）考虑CM和mFB的电相互作用，CM收缩的触发以及细胞和ECM的粘弹性，我们可以确定mFB对工程化心脏组织（EHT）的电和机械功能的影响，因此，为了有用的近似，在心肌中。例如，激发的扩展的延迟或片段化直接与激发的扩展的相应延长或片段化相关。 收缩性抽搐反应我们正在开发的计算和实验模型是专门为测试这一假设而设计的。计算模型在细胞水平上考虑了心脏的电活动与其机械行为的耦合，包括mFB在电功能和机械功能两者中的影响。该模型将参考对用mFB与心肌细胞（CM）的指定比率和mFB的规定空间模式组装的工程化心脏组织（EHT）进行的实验测量来改进。工作将通过一个递归过程进行，通过该过程，实验模型将测试计算模型，计算模型将建议EHT的设计，特别是证明mFB-CM相互作用对EHT机电功能的影响。

DESCRIPTION (provided by applicant): Hypertension or myocardial infarction converts normal, relatively quiescent fibroblasts to a larger more contractile phenotype, the myofibroblast (mFB). The mFBs disarrange and interrupt the normal well-organized cardiac muscle, stiffening it and distorting progression of the electrical impulse that triggers orderly contraction of the heart, causing reentrant arrhythmias sometimes leading to sudden death. To understand how to avert or alleviate this consequence, it is important to know how mFBs influence the electromechanical function of the heart. The overall purpose of this work is to gain an understanding of how mFBs perturb this function using computational and experimental models designed specifically for this purpose. The outcome will be experimental and computational models for the effects of mFBs on the electrical and mechanical function of an engineered heart muscle model. The combination of electrical and mechanical function as well as computational and experimental models will exceed the range and detail of current models of cardiac fibrosis. The resulting predictive model will assist in the design of therapies for fibrosis induced by hypertensive heart disease and myocardial infarction. This work is based on the hypotheses that (1) degradation of contractile function in fibrotic myocardium results from coupled electrical and mechanical effects associated with mFB, their remodeling of ECM, and their connectivity to cardiomyocytes (CM), and (2)Accounting for the electrical interactions of CM and mFB, the triggering of CM contraction and the viscoelastic properties of cells and ECM, we can determine the effects of mFB on the electrical and mechanical function of engineered heart tissues (EHTs) and, therefore, to a useful approximation, in heart muscle. For example, delay or fragmentation of the spread of excitation is directly related to a corresponding prolongation or fragmentation of the contractile twitch response. The computational and experimental models that we are developing are designed specifically to test this hypothesis. The computational model accounts at the cellular level for the coupling of the heart's electrical activity to its mechanical behavio, including the effects of mFBs in both electrical and mechanical functions. This model will be refined with reference to experimental measurements carried out on engineered heart tissues (EHTs) assembled with specified ratios of mFBs to cardiomyocytes (CMs) and prescribed spatial patterns of mFBs. Work will proceed through a recursive process by which the experimental model will test the computational model, and the computational model will suggest designs for EHTs that specifically demonstrate the effects of mFB-CM interactions on EHT electromechanical function.