THE EFFECTS OF MYOFIBROBLASTS ON ELECTROMECHANICAL FUNCTION OF MODEL HEART TISSUE

肌成纤维细胞对模型心脏组织机电功能的影响

• 批准号: 8297133
• 负责人: Elliot L. Elson
• 金额: $ 54.35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297133
• 关键词: Accounting; Architecture; Arrhythmia; Behavior; Biophysics; Cardiac; Cardiac Myocytes; Cells; Chickens; Computer Simulation; Coupled; Coupling; Data; Electrophysiology (science); Engineering; Experimental Models; Extracellular Matrix; Fibroblasts; Fibrosis; Fluorescent Dyes; Goals; Heart; Heart Diseases; Hypertension; In Vitro; Infarction; Measurement; Measures; Mechanics; Methods; Modeling; Molecular; Mus; Muscle Cells; Myocardial Contraction; Myocardial Infarction; Myocardium; Myofibroblast; Outcome; Pattern; Phenotype; Process; Property; Proteins; Spatial Distribution; Specific qualifier value; Sudden Death; Testing; Therapeutic; Tissue Engineering; Tissue Model; Tissues; Vision; Work; base; cell type; design; embryo cell; embryonic stem cell; engineering design; experience; heart electrical activity; heart function; hypertensive heart disease; interstitial; mechanical behavior; model design; predictive modeling; response; simulation; therapy design

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. PUBLIC HEALTH RELEVANCE: Heart attacks and high blood pressure trigger the formation of a type of cell that distorts the normal electrical and mechanical function of the heart. The proposed work uses experimental and computational models to discover the mechanisms by which this happens. The goal of the work is to produce computational and experimental models with which to design therapies that avert or alleviate the effects of these cells on heart function

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、更收缩的表型，即肌成纤维细胞（mFB）。mfb扰乱和中断了正常组织良好的心肌，使其变硬，扭曲了触发心脏有序收缩的电脉冲的进程，导致再入性心律失常，有时导致猝死。为了了解如何避免或减轻这种后果，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利用专门为此目的设计的计算和实验模型来了解mFBs如何干扰该函数。结果将是mFBs对工程心肌模型的电和机械功能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越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高血压心脏病和心肌梗死引起的纤维化的治疗方法。这项工作是基于以下假设：(1)纤维性心肌收缩功能的退化是由耦合电刺激引起的