INVITED REVIEW Intercellular and extracellular mechanotransduction in cardiac myocytes J. Yasha Kresh & Anant Chopra Received: 16 January 2011 /Revised: 1 March 2011 /Accepted: 2 March 2011 /Published online: 25 March 2011 # Springer-Verlag 2011 Abstract Adult cardiomyocytes are terminally differentiat- ed with minimal replicative capacity. Therefore, long-term preservation or enhancement of cardiac function depends on structural adaptation. Myocytes interact with the extracellular matrix, fibroblasts, and vascular cells and with each other (end to end; side to side). We review the current understanding of the mechanical determinants and environ- mental sensing systems that modulate and regulate myocyte molecular machinery and its structural organization. We feature the design and application of engineered cellular microenvironments to demonstrate the ability of cardiac cells to remodel their cytoskeletal organization and shape, including sarcomere/myofibrillar architectural topography. Cell shape-dependent functions result from complex me- chanical interactions between the cytoskeleton architecture and external conditions, be they cell–cell or cell–extracel- lular matrix (ECM) adhesion contact-mediated. This mechanobiological perspective forms the basis for viewing the cardiomyocyte as a mechanostructural anisotropic continuum, exhibiting constant mechanosensory-driven self-regulated adjustment of the cytoskeleton through tight interplay between its force generation activity and concur- rent cytoarchitectural remodeling. The unifying framework guiding this perspective is the observation that these emerging events and properties are initiated by and respond to cytoskeletal reorganization, regulated by cell–cell and cell–ECM adhesion and its corresponding (mutually inter- active) signaling machinery. It is important for future studies to elucidate how cross talk between these mechan- ical signals is coordinated to control myocyte structure and function. Ultimately, understanding how the highly inter- active mechanical signaling can give rise to phenotypic changes is critical for targeting the underlying pathways that contribute to cardiac remodeling associated with various forms of dilated and hypertrophic myopathies, myocardial infarction, heart failure, and reverse remodeling. Keywords Mechanobiology . Mechanosensing . Sarcomere . Microenvironment . Cytoskeletal remodeling . Cardiomyopathy Introduction The heart is a dynamic, mechanically active organ that self- generates contractile forces during ejection and active stretching strains during its cyclical life-sustaining function. Ultimately, preservation of global cardiac structure and function depends on the cell units that comprise its muscle tissue. In many forms of progressive heart failure, a mechanical substrate may cause changes in myocyte length that are largely responsible for chamber dilatation, whereas myocyte transverse growth (cross-sectional area) is responsible for wall thickening during cardiac hypertrophy. Especially compelling are the concurrent (micro–macro) changes in myocyte shape (length/width ratio) and diameter/wall thickness (d/h) ratio of the ventricular chamber; d/h ratio is a direct determinant of wall stress. These morphological changes occur This article is published as part of the DeTombe/Grazier Special Issue on The cytoskeleton and the cellular transduction of mechanical strain. J. Y. Kresh (*) Department of Cardiothoracic Surgery, Drexel University College of Medicine, 245 North 15th Street, MS 111, Philadelphia, PA 19102, USA e-mail: jkresh@drexelmed.edu J. Y. Kresh Departments of Cardiothoracic Surgery and Medicine, Drexel University College of Medicine, Philadelphia, PA, USA A. Chopra Department of Biomedical Engineering, Drexel University, Philadelphia, PA, USA Pflugers Arch - Eur J Physiol (2011) 462:75–87 DOI 10.1007/s00424-011-0954-1