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Heterogeneity of Mitral Leaflet Matrix Composition and Turnover Correlates with Regional Leaflet Strain

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Abstract

To determine how extracellular matrix and contractile valvular cells contribute to the heterogeneous motion and strain across the mitral valve (MV) during the cardiac cycle, regional MV material properties, matrix composition, matrix turnover, and cell phenotype were related to regional leaflet strain. Radiopaque markers were implanted into 14 sheep to delineate the septal (SEPT), lateral (LAT), and anterior and posterior commissural leaflets (ANT-C, POST-C). Videofluoroscopy imaging was used to calculate radial and circumferential strains. Mechanical properties were assessed using uniaxial tensile testing and micropipette aspiration. Matrix composition and cell phenotypes were immunohistochemically evaluated within each leaflet region [basal leaflet (BL), mid-leaflet (ML), and free edge]. SEPT-BL segments were stiffer and stronger than other valve tissues, while LAT segments demonstrated more extensibility and strain. Collagens I and III in SEPT were greater than in LAT, although LAT showed greater collagen turnover [matrix metalloprotease (MMP)-13, lysyl oxidase] and cell activation [smooth muscle alpha-actin (SMaA), and non-muscle myosin (NMM)]. MMP13, NMM, and SMaA were strongly correlated with each other, as well as with radial and circumferential strains in both SEPT and LAT. SMaA and MMP13 in POST-C ML was greater than ANT-C, corresponding to greater radial strains in POST-C. This work directly relates leaflet strain, material properties, and matrix turnover, and suggests a role for myofibroblasts in the heterogeneity of leaflet composition and strain. New approaches to MV repair techniques and ring design should preserve this normal coupling between leaflet composition and motion.

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Acknowledgments

The authors thank all the members of the Grande-Allen lab, especially Indrajit Nandi. The authors also appreciate the statistical expertise of Dr. Scott Baggett and use of the micropipette aspiration equipment from Dr. Robert Raphael.

Funding

Funding for this project came in part from graduate fellowships from the Hertz Foundation (EHS), National Institutes of Health (F30HL094019, EHS) and American Heart Association (13PRE14110003, PSC) and National Institutes of Health grants R01HL067025 and R01HL029589 (DCM).

Conflict of interest

Elizabeth H. Stephens was supported by individual graduate fellowships from the Hertz Foundation and NIH F30HL094019. Patrick S. Connell was supported by an individual fellowship from the American Heart Association 13PRE14110003. D. Craig Miller was supported by NIH R01 HL067025 and R01 HL029589. K. Jane Grande-Allen has served as a consultant for Edwards Lifesciences. Monica M. Fahrenholtz, Tomasz A. Timek, George T. Daughters, Joyce J. Kuo, Aaron M. Patton, Neil B. Ingels, Jr. have no conflict of interest.

Human Subjects Declaration

No human subjects studies were carried out by the authors for this article.

Animal Studies Declaration

The animal studies involved in this article were performed according to protocols approved by the Stanford University and Rice University Institutional Animal Care and Use Committees.

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, Columbia University School of Medicine, New York, NY, USA

    Elizabeth H. Stephens

  2. Department of Bioengineering, Rice University, Houston, TX, USA

    Elizabeth H. Stephens, Patrick S. Connell, Monica M. Fahrenholtz, Joyce J. Kuo, Aaron M. Patton & K. Jane Grande-Allen

  3. Department of Cardiothoracic Surgery, Meijer Heart and Vascular Institute, Spectrum Health, Grand Rapids, MI, USA

    Tomasz A. Timek

  4. Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA

    George T. Daughters, Neil B. Ingels & D. Craig Miller

  5. Department of Cardiovascular Physiology and Biophysics, Research Institute, Palo Alto Medical Foundation, Palo Alto, CA, USA

    Neil B. Ingels & D. Craig Miller

  6. Bioengineering, Rice University, MS142, PO Box 1892, Houston, TX, 77251-1892, USA

    K. Jane Grande-Allen

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  1. Elizabeth H. Stephens
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  2. Patrick S. Connell
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  10. K. Jane Grande-Allen
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Correspondence to K. Jane Grande-Allen.

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Associate Editor Karyn Kunzelman oversaw the review of this article.

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Stephens, E.H., Connell, P.S., Fahrenholtz, M.M. et al. Heterogeneity of Mitral Leaflet Matrix Composition and Turnover Correlates with Regional Leaflet Strain. Cardiovasc Eng Tech 6, 141–150 (2015). https://doi.org/10.1007/s13239-015-0214-1

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