Structure and Mechanics of Healing Myocardial Infarcts

Holmes, Jeffrey W.; Borg, Thomas K.; Covell, James W.

doi:10.1146/annurev.bioeng.7.060804.100453

Cited by 346 publications

(337 citation statements)

References 122 publications

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“…It might be extrapolated that native tissues, which have been loaded for extremely long time periods, will likely require a long time to remodel as well. Indeed, the process of structural remodeling in healing myocardial infarcts occurs over a timeframe of weeks 16 . This is also consistent with a study by Sipkema and co-workers 29 in which four hours of cyclic axial deformation of rat renal arteries caused no apparent change in endothelial cell alignment, although actin stress fibers within the cells did reorient 90° from the axial to the circumferential direction.…”

Section: Discussionmentioning

confidence: 99%

“…From the tissue engineering perspective, it is important to understand what happens when a highly aligned tissue construct is subjected to an abrupt change in loading conditions that may conflict with the mechanical and contact guidance cues established in the laboratory, as might arise due to surgical implantation in a site with abnormal biomechanics due to injury or disease 16 . One must determine whether the pre-existing structure will adequately sustain the functional characteristics designed in the laboratory, or whether the living engineered replacement tissue (or the surrounding native tissue) is sufficiently adaptable to undergo an appreciable degree of remodeling that might result in adverse structural and mechanical properties after implantation.…”

Section: Introductionmentioning

confidence: 99%

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Remodeling of Engineered Tissue Anisotropy in Response to Altered Loading Conditions

2008

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Structural and mechanical anisotropy are critical to the function of many engineered tissues. This study examined the ability of anisotropic tissue constructs to overcome contact guidance cues and remodel in response to altered mechanical loading conditions. Square tissues engineered from dermal fibroblasts and type-I collagen were uniaxially loaded to induce cell and matrix alignment. After an initial time, t*, of 5 to 72 hrs, loading was switched from the x-axis to the y-axis. Cell alignment was examined throughout the experiment until a steady state was reached. Before t*, cells spontaneously aligned in the x-direction. After t*, the strength of alignment transiently decreased then increased, and mean cell orientation transitioned from the x-to the y-direction following an exponential time course with a time constant that increased with t*. Collagen fiber orientation exhibited similar trends that could not be explained by passive kinematics alone. Structural realignment resulted in concomitant changes in biaxial tissue mechanical properties. The findings suggest that even highly aligned engineered tissue constructs retain the capacity to remodel in response to altered mechanical stimuli. This may have important functional consequences when an anisotropic engineered tissue designed in vitro is surgically implanted into a mechanically complex graft site.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Remodeling of Engineered Tissue Anisotropy in Response to Altered Loading Conditions

2008

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“…Over the past decade, it has become clear that the mechanical changes that occur after MI must be considered when developing post-MI therapies [35,41,42]. MI leads to extracellular matrix (ECM) breakdown and results in geometric changes in both the infarcted and healthy myocardium.…”

Section: Injectable Hydrogels As Bulking Agentsmentioning

confidence: 99%

Injectable Acellular Hydrogels for Cardiac Repair

Tous

Purcell

Ifkovits

et al. 2011

J. of Cardiovasc. Trans. Res.

152

136

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Injectable hydrogels are being developed as potential translatable materials to influence the cascade of events that occur after myocardial infarction. These hydrogels, consisting of both synthetic and natural materials, form through numerous chemical crosslinking and assembly mechanisms and can be used as bulking agents or for the delivery of biological molecules. Specifically, a range of materials are being applied that alter the resulting mechanical and biological signals after infarction and have shown success in reducing stresses in the myocardium and limiting the resulting adverse left ventricular (LV) remodeling. Additionally, the delivery of molecules from injectable hydrogels can influence cellular processes such as apoptosis and angiogenesis in cardiac tissue or can be used to recruit stem cells for repair. There is still considerable work to be performed to elucidate the mechanisms of these injectable hydrogels and to optimize their various properties (e.g., mechanics and degradation profiles). Furthermore, although the experimental findings completed to date in small animals are promising, future work needs to focus on the use of large animal models in clinically relevant scenarios. Interest in this therapeutic approach is high due to the potential for developing percutaneous therapies to limit LV remodeling and to prevent the onset of congestive heart failure that occurs with loss of global LV function. This review focuses on recent efforts to develop these injectable and acellular hydrogels to aid in cardiac repair.

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“…Scars form in injured human hearts, which results in decreased cardiac performance and the eventual development of heart failure (2). In contrast to humans, zebrafish and newts have remarkable regenerative abilities (3,4).…”

mentioning

confidence: 99%

PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts

Kim¹,

Wu²,

Zhang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

182

187

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A zebrafish heart can fully regenerate after amputation of up to 20% of its ventricle. During this process, newly formed coronary blood vessels revascularize the regenerating tissue. The formation of coronary blood vessels during zebrafish heart regeneration likely recapitulates embryonic coronary vessel development, which involves the activation and proliferation of the epicardium, followed by an epithelial-to-mesenchymal transition. The molecular and cellular mechanisms underlying these processes are not well understood. We examined the role of PDGF signaling in explantderived primary cultured epicardial cells in vitro and in regenerating zebrafish hearts in vivo. We observed that mural and mesenchymal cell markers, including pdgfrβ, are up-regulated in the regenerating hearts. Using a primary culture of epicardial cells derived from heart explants, we found that PDGF signaling is essential for epicardial cell proliferation. PDGF also induces stress fibers and loss of cell-cell contacts of epicardial cells in explant culture. This effect is mediated by Rhoassociated protein kinase. Inhibition of PDGF signaling in vivo impairs epicardial cell proliferation, expression of mesenchymal and mural cell markers, and coronary blood vessel formation. Our data suggest that PDGF signaling plays important roles in epicardial function and coronary vessel formation during heart regeneration in zebrafish.epicardium | mesenchymal cells | mural cells | zebrafish heart regeneration C oronary heart disease is among the leading causes of disability and mortality in the United States and worldwide (1). Scars form in injured human hearts, which results in decreased cardiac performance and the eventual development of heart failure (2). In contrast to humans, zebrafish and newts have remarkable regenerative abilities (3, 4). After 20% resection of the ventricle, zebrafish fully regenerate lost heart tissue (3, 4). During this process, newly formed coronary blood vessels vascularize the regenerating myocardium (5, 6). Expression of the embryonic epicardial markers tbx18 and raldh2 is induced in the epicardium of adult regenerating hearts (5, 6), suggesting that an embryonic gene expression program in the epicardium is activated in response to injury. This activation starts throughout the entire ventricle and gradually becomes localized to the apex. The activated epicardium proliferates from 3 to 7 d postamputation (dpa) (5). A previous study suggested that the activated epicardium undergoes an epithelial-to-mesenchymal transition (EMT) and subsequently contributes to newly formed coronary blood vessels (5). The lineages of the different cell types in blood vessels formed during zebrafish heart regeneration have not yet been conclusively determined.Zebrafish heart regeneration, at least in part, likely recapitulates embryonic heart development. EMT is a key step during heart development in mice and chicks, wherein the epicardium forms epicardium-derived cells (EPDCs), which then differentiate into fibroblasts, smooth muscle cells (7-9)...

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Structure and Mechanics of Healing Myocardial Infarcts

Cited by 346 publications

References 122 publications

Remodeling of Engineered Tissue Anisotropy in Response to Altered Loading Conditions

Remodeling of Engineered Tissue Anisotropy in Response to Altered Loading Conditions

Injectable Acellular Hydrogels for Cardiac Repair

PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts

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