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WIREs Syst Biol Med
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Exploring cardiac form and function: A length‐scale computational biology approach

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Abstract The ability to adequately pump blood throughout the body is the result of tightly regulated feedback mechanisms that exist across many spatial scales in the heart. Diseases which impede the function at any one of the spatial scales can cause detrimental cardiac remodeling and eventual heart failure. An overarching goal of cardiac research is to use engineered heart tissue in vitro to study the physiology of diseased heart tissue, develop cell replacement therapies, and explore drug testing applications. A commonality within the field is to manipulate the flow of mechanical signals across the various spatial scales to direct self‐organization and build functional tissue. Doing so requires an understanding of how chemical, electrical, and mechanical cues can be used to alter the cellular microenvironment. We discuss how mathematical models have been used in conjunction with experimental techniques to explore various structure–function relations that exist across numerous spatial scales. We highlight how a systems biology approach can be employed to recapitulate in vivo characteristics in vitro at the tissue, cell, and subcellular scales. Specific focus is placed on the interplay between experimental and theoretical approaches. Various modeling methods are showcased to demonstrate the breadth and power afforded to the systems biology approach. An overview of modeling methodologies exemplifies how the strengths of different scientific disciplines can be used to supplement and/or inspire new avenues of experimental exploration. This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Models of Systems Properties and Processes > Cellular Models Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Length‐scale separation within the heart. Spatial scales can be broken down into a hierarchical structure that spans several orders of magnitude. The various functional components can be studied either independently or in relation to one another
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The materials science tetrahedron. There are four interconnected categories that can be used to study the behavior of a material: structure, processing, properties, and performance. Changes in any one category will invariable influence the other three categories. This same categorization may be used to study the heart. (Adapted from Golob et al., )
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Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Models of Systems Properties and Processes > Cellular Models
Models of Systems Properties and Processes > Mechanistic Models

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