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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Krull, Holly
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Washington University
Schools of Medicine
Saint Louis
United States
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