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Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction

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Abstract

Regional heterogeneity in mitral annular contraction, which is generally ascribed to the fibrous vs. muscular annular composition, ensures proper leaflet motion and timing of coaptation. It is unknown whether the fibroblast-like cells in the annulus modulate this heterogeneity, even though valvular interstitial cells (VICs) can be mechanically “activated.” Fourteen sheep underwent implantation of radiopaque markers around the mitral annulus defining four segments: septal (SEPT), lateral (LAT), and anterior (ANT-C) and posterior (POST-C) commissures. Segmental annular contraction was calculated using biplane videofluoroscopy. Immunohistochemistry of annular cross sections assessed regional matrix content, matrix turnover, and cell phenotype. Micropipette aspiration measured the effective modulus of the leaflets adjacent to the myocardial border. Whereas SEPT contained more collagen I and III, LAT demonstrated more collagen and elastin turnover as shown by greater decorin, lysyl oxidase, and matrix metalloprotease (MMP)-13 and smooth muscle alpha-actin (SMaA). This greater matrix turnover paralleled greater annular contraction in LAT vs. SEPT (22.5 vs. 4.1%). Similarly, POST-C had more SMaA and MMP13 than ANT-C, consistent with greater annular contraction in POST-C (18.8 vs. 11.1%). Interestingly, POST-C had the greatest effective modulus, significantly higher than LAT. These data suggest that matrix turnover by activated VICs relates to annular motion heterogeneity, maintains steady-state mechanical properties in the annulus, and could be a therapeutic target when annular motion is impaired. Conversely, alterations in this heterogeneous annular contraction, whether through disease or secondary to ring annuloplasty, could disrupt this normal pattern of cell-mediated matrix remodeling and further adversely impact mitral valve function.

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Acknowledgments

The authors appreciate assistance from Indrajit Nandi, the statistical expertise of Dr. Scott Baggett, and the micropipette aspiration equipment from Dr. Robert Raphael. 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 (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. 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 declares that she has no conflict of interest. Tomasz A. Timek declares that he has no conflict of interest. George T. Daughters declares that he has no conflict of interest. Joyce J. Kuo declares that she has no conflict of interest. Aaron M. Patton declares that he has no conflict of interest. Neil B. Ingels, Jr. declares that he has 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 Bioengineering, Rice University, PO Box 1892 – MS142, Houston, TX, 77251-1892, USA

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

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

    Elizabeth H. Stephens

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

    Tomasz A. Timek, George T. Daughters, Neil B. Ingels Jr. & D. Craig Miller

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

    Tomasz A. Timek

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

    Neil B. Ingels Jr. & D. Craig Miller

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  1. Elizabeth H. Stephens
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  2. Monica M. Fahrenholtz
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Correspondence to K. Jane Grande-Allen.

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Associate Editor Ajit P. Yoganathan oversaw the review of this article.

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Stephens, E.H., Fahrenholtz, M.M., Connell, P.S. et al. Cellular and Extracellular Matrix Basis for Heterogeneity in Mitral Annular Contraction. Cardiovasc Eng Tech 6, 151–159 (2015). https://doi.org/10.1007/s13239-014-0209-3

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