doi: 10.1161/01.RES.0000269327.83426.d9
© 2007 American Heart Association, Inc.
Editorials |
New Insights Into the Developmental Biomechanics of the Atrioventricular Valves
From the Professor of Pediatrics and Director, Pediatric Innovative Biomedical Technology Development, Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC.
Correspondence to Bradley B. Keller, Division of Pediatric Cardiology, Heart Center, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail Bradley.Keller{at}chp.edu
See related article, pages 1503–1511
Key Words: cardiac morphogenesis • biomechanics • atrioventricular valves
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Introduction |
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 Top Introduction Insights into the Role...Insights into the Molecular...The Application of Biomechanical...Implications For the Generation...References |
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In this issue, Butcher et al,1 provide elegant data on the mechanical performance and material properties of stage 17, 21, and 25 chick embryonic atrioventricular (AV) cushions during normal development and following the selective digestion of AV cushion constituents. These data are then interpreted using a strain-energy based pseudoelasticity theory to determine maturational changes in AV cushion material coefficients and effective modulus. The experimental approach developed by Butcher and colleagues and their observation that developmental changes in AV cushion function are because of changes in cushion constituents and material properties represent an important advance in our understanding of the role of tissue composition on valve morphogenesis. Further, this study represents the first direct correlation of in vivo AV cushion kinematics and blood velocity with biomechanical properties during AV valve morphogenesis that includes experimental validation via the selective enzymatic digestion of either glycosaminoglycans or collagens to alter cushion properties.
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Insights into the Role of AV Cushion Maturation on Embryonic Cardiac Function |
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TopIntroductionInsights into the Role...Insights into the Molecular...The Application of Biomechanical...Implications For the Generation...References |
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As the first functioning organ, experimental data from numerous animal model systems show that the embryonic heart generates forward blood flow while transforming from a contracting linear tube into the multi-chambered heart.2–6 From the onset of the heart beat, the AV cushions coapt to prevent retrograde flow during ventricular systole,7,8 and have a delayed depolarization velocity relative to the surrounding myocardium to facilitate forward flow.9 Recently, confocal laser slit-scanning microscopy has revealed dynamic AV cushion deformation patterns during morphogenesis consistent with the transition from a peristaltic (suction) to a pulsatile ventricular pump.10 The data from Butcher et al confirm these findings and note that AV cushion deformation patterns are consistent with maturation associated increased AV cushion stiffness because of decreasing glycosaminoglycan and increasing collagen content.1
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Insights into the Molecular Regulation of AV Valve Morphogenesis and the Relationship Between Cushion Constituents and Valve Function |
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TopIntroductionInsights into the Role...Insights into the Molecular...The Application of Biomechanical...Implications For the Generation...References |
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Following the pioneering studies of Runyan and Markwald in the early 1980s,11,12 subsequent investigation has shown that transformation of the amorphous endocardial cushions into mature valve leaflets involves temporally and spatially specific gene and protein expression patterns, cell migration and differentiation within the cushions (termed endothelial-mesenchymal transformation, EMT), extracellular matrix synthesis and degradation, and cell death, and tissue remodeling.13–16 Errors along these developmental cascades produce aberrant endocardial cushions, dysplastic cardiac valves, and are often embryo lethal. A number of human candidate genes have now been associated with congenital AV valve defects, and as expected these candidate genes are involved in matrix synthesis and remodeling.17 The data from Butcher et al support the paradigm that altered matrix composition is likely to impact both AV cushion material properties and function.
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The Application of Biomechanical Engineering Analyses to the Developing Heart |
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TopIntroductionInsights into the Role...Insights into the Molecular...The Application of Biomechanical...Implications For the Generation...References |
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The availability of experimental data from the embryonic heart has been critical to the evolution of biomechanical models of cardiac morphogenesis. Perhaps the first investigation of cardiac cushion material properties was performed by Frank Manasek and colleagues to measure the deformation (and material properties) of the embryonic chick heart.18 These experimental results were used by Taber and colleagues in a biomechanical model for the developing embryonic ventricle19 and stimulated the refinement of experimental methods to generate stress-strain data from the embryonic heart for model validation.20,21 Although several studies have investigated the passive properties of the embryonic myocardium, the studies by Butcher et al are the first to provide material properties data on the developing cardiac valves.
In the current study by Butcher and colleagues, composite material properties of the developing embryonic AV cushions were calculated using data from micropipette aspirations of normal stage 17 to stage 25 in chick embryo AV cushion explants and following the selected digestion of glycosaminoglycans, collagens, and cell-matrix attachments. Data were fit using a stain-energy based pseudoeleastic model with the assumption that the cushion material was homogenous, isotropic, and nonlinear hyperelastic. This approach represented the use of current published approaches that acknowledge the limitations of representing complex biologic structures using numerical models.22–24 Mixture theory was used to predict the impact of altered cushion constituents (volume fractions) on material properties. As might be expected, AV cushions were the most pliable at stage 17 and became more rigid during cushion morphogenesis consistent with increased cellularity and matrix maturation. Increased rigidity is consistent with the shift from wave-like cushion deformations at stage 17 heart to more rigid cushion motion at stage 25. As would also be expected, the enzymatic digestion of glycosaminoglycans resulted in increased cushion rigidity while collagen digestion in increased cushion fragility and produced a more linear elastic behavior. The approach of Butcher et al can now be used to investigate models of aberrant AV valve development associated with altered cushion matrix synthesis, cross-linking, or degradation, recognizing the limitations of generalizing local material property measurements to global valve behavior.
Altered AV cushion properties (and deformation) likely impact valve morphogenesis. Several recent reports have described changes in the expression of shear-responsive genes on the endothelial surfaces of cardiac cushions during normal and experimentally altered loading conditions.25 Myofibroblasts within the developing AV cushions likely sense biomechanical events with subsequent effects on cell migration, proliferation, differentiation, and survival.26–28 Thus, another potential mechanism for abnormal cushion maturation and remodeling may be abnormal signal transduction of biomechanical cues during morphogenesis.
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Implications For the Generation of Tissue-Engineered Valves |
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TopIntroductionInsights into the Role...Insights into the Molecular...The Application of Biomechanical...Implications For the Generation...References |
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The biomechanical testing of mature AV valves has focused, primarily, on determining the "ideal" material properties for tissue engineered, replacement cardiac valves. In the study by Butcher et al, a biomechanics approach is used to determine changes in material properties during normal valve development to develop insights into the processes that regulate AV cushion morphogenesis. These insights are likely to be critical to identifying the anisotropic material properties,29 and unique biomechanically sensitive cell populations28–31 required to manufacture durable cardiac valves.
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Acknowledgments |
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Sources of Funding
Our laboratory is supported by grants from the National Heart, Lung, and Blood Institute and by the Children’s Hospital of Pittsburgh Foundation.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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Related Article:
Circ. Res. 2007 100: 1503-1511.
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