THE EFFECTS OF MYOFIBROBLASTS ON ELECTROMECHANICAL FUNCTION OF MODEL HEART TISSUE

描述(申请人提供)：高血压或心肌梗塞将正常的、相对静止的成纤维细胞转化为更大、更收缩的表型，即肌成纤维细胞(MFB)。Mfs扰乱并干扰正常组织良好的心肌，使其僵硬，并扭曲触发心脏有序收缩的电脉冲的发展，导致折返性心律失常，有时会导致猝死。为了了解如何避免或减轻这种后果，了解mfb如何影响心脏的机电功能是很重要的。这项工作的总体目的是通过专门为此目的设计的计算和实验模型来了解mfb是如何干扰这一功能的。其结果将是关于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。电气和机械功能以及计算和实验模型的结合将超出目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心脏病和心肌梗死引起的纤维化的方法。这项工作是基于如下假设：(1)纤维化心肌的收缩功能退化是由耦合的电信号引起的 (2)考虑MFB和MFB的电相互作用、CM收缩的触发以及细胞和ECM的粘弹特性，我们可以确定MFB对工程心脏组织(EHTS)的电和机械功能的影响，从而得出一个有用的近似值，即在心肌中。例如，激励传播的延迟或碎裂直接与相应的延长或碎裂有关 收缩抽搐反应。我们正在开发的计算和实验模型就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方面的影响。该模型将参照在工程心脏组织(EHTS)上进行的实验测量进行改进，该组织由特定的mFBs与心肌细胞(CMS)的比例和mFBs的指定空间模式组装而成。工作将通过递归过程进行，通过该过程，实验模型将测试计算模型，计算模型将建议EHTS的设计，具体演示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.