Skip to main content
SpringerLink
Log in

Eliminating Regurgitation Reduces Fibrotic Remodeling of Functional Mitral Regurgitation Conditioned Valves

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

Functional mitral regurgitation (FMR) is an insidious and poorly understood condition affecting patients with myocardial disease. While current treatments reduce regurgitation, their ability to reverse mitral valve pathology is unclear. We utilized a pseudo-physiological flow loop to study how repair impacted valve composition. Porcine mitral valves were cultured in control geometry (native papillary muscle position and annular area) or high-tension FMR geometry (5 mm apical and 5 mm lateral displacement of papillary muscles, 65% increased annular area) for 2 weeks. To mimic repair, a reversal condition was created by returning one-week FMR conditioned valves to a non-regurgitant geometry and culturing for 1 week. Valve composition and material properties were analyzed. After two-week culture, FMR conditioned tissues were stiffer and stronger than control and underwent extensive fibrotic remodeling, with increased prolyl-4-hydroxylase, lysyl oxidase, matrix metalloproteinase-1, and decorin. The reversal condition displayed a heterogeneous, leaflet- and orientation-dependent response. Reversal-conditioned anterior leaflets and circumferential tissue sections continued to have significant fibrotic remodeling compared to control, whereas reversal-conditioned posterior leaflets, chordae tendineae, and radial tissue sections had significantly decreased remodeling compared to FMR-conditioned tissues. These findings suggest current repairs only partially reverse pathology, underscoring the need for innovation in the treatment of FMR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

MV:

Mitral valve

FMR:

Functional mitral regurgitation

PM:

Papillary muscle

GAG:

Glycosaminoglycan

LOX:

Lysyl oxidase

MMP-1:

Matrix metalloproteinase-1

RUFLS:

Rice University flow loop system

VIC:

Valve interstitial cell

ECM:

Extracellular matrix

LVAD:

Left ventricular assist device

References

  1. Bail, D. H. L. Treatment of functional mitral regurgitation by percutaneous annuloplasty using the carillon mitral contour system-currently available data state. J. Interv. Cardiol. 30:156–162, 2017.

    Article  PubMed  Google Scholar 

  2. Balaoing, L. R., A. D. Post, H. Liu, K. T. Minn, and K. J. Grande-Allen. Age-related changes in aortic valve hemostatic protein regulation. Arterioscler. Thromb. Vasc. Biol. 34:72–80, 2014.

    Article  CAS  PubMed  Google Scholar 

  3. Carew, E. O., and I. Vesely. A new method of estimating gauge length for porcine aortic valve test specimens. J. Biomech. 36:1039–1042, 2003.

    Article  PubMed  Google Scholar 

  4. Connell, P. S., A. F. Azimuddin, S. E. Kim, F. Ramirez, M. S. Jackson, S. H. Little, and K. J. Grande-Allen. Regurgitation hemodynamics alone cause mitral valve remodeling characteristic of clinical disease states in vitro. Ann. Biomed. Eng. 44:954–967, 2016.

    Article  PubMed  Google Scholar 

  5. Connell, P. S., D. P. Vekilov, and K. J. Grande-Allen. Control of environment—redesign of flow loop bioreactor to control mitral valve regurgitation. In: Engineering 3D Tissue Test Systems, edited by K. J. L. Burg, D. Dreau, and T. Burg. Boca Raton: Taylor & Francis, 2017, pp. 61–73.

    Chapter  Google Scholar 

  6. Crick, S. J., M. N. Sheppard, S. Y. Ho, L. Gebstein, and R. H. Anderson. Anatomy of the pig heart : comparisons with normal human cardiac structure. J. Anat. 193:105–119, 1998.

    Article  PubMed  PubMed Central  Google Scholar 

  7. De Bonis, M., and O. Alfieri. The edge-to-edge technique for mitral valve repair. HSR Proc. Intensive Care Cardiovasc. Anesth. 2:7–17, 2010.

    PubMed  PubMed Central  Google Scholar 

  8. Fattouch, K., G. Murana, S. Castrovinci, C. Mossuto, R. Sampognaro, M. G. Borruso, E. C. Bertolino, G. Caccamo, G. Ruvolo, and P. Lancellotti. Mitral valve annuloplasty and papillary muscle relocation oriented by 3-dimensional transesophageal echocardiography for severe functional mitral regurgitation. J. Thorac. Cardiovasc. Surg. 143:S38–S42, 2012.

    Article  PubMed  Google Scholar 

  9. Feldman, T., S. Kar, M. Rinaldi, P. Fail, J. Hermiller, R. Smalling, P. L. Whitlow, W. Gray, R. Low, H. C. Herrmann, S. Lim, E. Foster, and D. Glower. Percutaneous mitral repair with the mitraclip system: safety and midterm durability in the initial everest (endovascular valve edge-to-edge repair study) cohort. J. Am. Coll. Cardiol. 54:686–694, 2009.

    Article  PubMed  Google Scholar 

  10. Fisher, L. W., J. T. Stubbs, and M. F. Young. Antisera and cdna probes to human and certain animal model bone matrix noncollagenous proteins. Acta Orthop. Scand. Suppl. 266:61–65, 1995.

    CAS  PubMed  Google Scholar 

  11. Fukamachi, K. Percutaneous and off-pump treatments for functional mitral regurgitation. J. Artif. Organs 11:12–18, 2008.

    Article  PubMed  Google Scholar 

  12. Fukamachi, K., Z. B. Popović, M. Inoue, K. Doi, S. Schenk, Y. Ootaki, M. W. Kopcak, and P. M. McCarthy. Changes in mitral annular and left ventricular dimensions and left ventricular pressure-volume relations after off-pump treatment of mitral regurgitation with the coapsys device. Eur. J. Cardio-Thorac. Surg. 25:352–357, 2004.

    Article  Google Scholar 

  13. Gheewala, N., K. A. Schwarz, and K. J. Grande-Allen. Organ culture of porcine mitral valves as a novel experimental paradigm. Cardiovasc. Eng. Technol. 4:139–150, 2013.

    Article  Google Scholar 

  14. Gheewala, N., and K. J. Grande-Allen. Design and mechanical evaluation of a physiological mitral valve organ culture system. Cardiovasc. Eng. Technol. 1:123–131, 2010.

    Article  Google Scholar 

  15. Grande-Allen, K. J., J. E. Barber, K. M. Klatka, P. L. Houghtaling, I. Vesely, C. S. Moravec, and P. M. McCarthy. Mitral valve stiffening in end-stage heart failure: evidence of an organic contribution to functional mitral regurgitation. J. Thorac. Cardiovasc. Surg. 130:783–790, 2005.

    Article  PubMed  Google Scholar 

  16. Grande-Allen, K. J., A. G. Borowski, R. W. Troughton, P. L. Houghtaling, N. R. Dipaola, C. S. Moravec, I. Vesely, and B. P. Griffin. Apparently normal mitral valves in patients with heart failure demonstrate biochemical and structural derangements: an extracellular matrix and echocardiographic study. J. Am. Coll. Cardiol. 45:54–61, 2005.

    Article  CAS  PubMed  Google Scholar 

  17. Harnek, J., J. G. Webb, K. H. Kuck, C. Tschope, A. Vahanian, C. E. Buller, S. K. James, C. P. Tiefenbacher, and G. W. Stone. Transcatheter implantation of the monarc coronary sinus device for mitral regurgitation. JACC Cardiovasc. Interv. 4:115–122, 2011.

    Article  PubMed  Google Scholar 

  18. He, S., A. A. Fontaine, E. Schwammenthal, A. P. Yoganathan, and R. A. Levine. Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies. Circulation 96:1826–1834, 1997.

    Article  CAS  PubMed  Google Scholar 

  19. Herovici, C. A polychrome stain for differentiating precollagen from collagen. Stain Technol. 38:204, 1963.

    Google Scholar 

  20. Jimenez, J. H., D. D. Soerensen, Z. He, S. He, and A. P. Yoganathan. Effects of a saddle shaped annulus on mitral valve function and chordal force distribution: an in vitro study. Ann. Biomed. Eng. 31:1171–1181, 2003.

    Article  PubMed  Google Scholar 

  21. Jimenez, J. H., D. D. Soerensen, Z. He, J. Ritchie, and A. P. Yoganathan. Effects of papillary muscle position on chordal force distribution: an in vitro study. J. Heart Valve Dis. 14:295–302, 2005.

    PubMed  Google Scholar 

  22. Klotz, S., and A. H. Jan. Danser, and D. Burkhoff. Impact of left ventricular assist device (lvad) support on the cardiac reverse remodeling process. Prog. Biophys. Mol. Biol. 97:479–496, 2008.

    Article  PubMed  Google Scholar 

  23. Levine, R. A., J. Hung, Y. Otsuji, E. Messas, N. Liel-Cohen, N. Nathan, M. D. Handschumacher, J. L. Guerrero, S. He, A. P. Yoganathan, and G. J. Vlahakes. Mechanistic insights into functional mitral regurgitation. Curr. Cardiol. Rep. 4:125–129, 2002.

    Article  PubMed  Google Scholar 

  24. Liel-Cohen, N., J. L. Guerrero, Y. Otsuji, M. D. Handschumacher, L. G. Rudski, P. R. Hunziker, H. Tanabe, M. Scherrer-Crosbie, S. Sullivan, and R. A. Levine. Design of a new surgical approach for ventricular remodeling to relieve ischemic mitral regurgitation: insights from 3-dimensional echocardiography. Circulation 101:2756–2763, 2000.

    Article  CAS  PubMed  Google Scholar 

  25. MacHaalany, J., L. Bilodeau, R. Hoffmann, S. Sack, H. Sievert, J. Kautzner, C. Hehrlein, P. Serruys, M. Sénéchal, P. Douglas, and O. F. Bertrand. Treatment of functional mitral valve regurgitation with the permanent percutaneous transvenous mitral annuloplasty system: results of the multicenter international percutaneous transvenous mitral annuloplasty system to reduce mitral valve regurgitation in patients with heart failure trial. Am. Heart J. 165:761–769, 2013.

    Article  PubMed  Google Scholar 

  26. Mishra, Y. K., S. Mittal, P. Jaguri, and N. Trehan. Coapsys mitral annuloplasty for chronic functional ischemic mitral regurgitation: 1-year results. Ann. Thorac. Surg. 81:42–46, 2006.

    Article  PubMed  Google Scholar 

  27. Morgan, J. A., R. J. Brewer, H. W. Nemeh, R. Murthy, C. T. Williams, D. E. Lanfear, C. Tita, and G. Paone. Left ventricular reverse remodeling with a continuous flow left ventricular assist device measured by left ventricular end-diastolic dimensions and severity of mitral regurgitation. ASAIO J. 58:574–577, 2012.

    Article  PubMed  Google Scholar 

  28. Mozaffarian, D., et al. Heart disease and stroke statistics-2016 update a report from the american heart association. Circulation 133:e38–e48, 2016.

    Article  PubMed  Google Scholar 

  29. Padala, M., L. Gyoneva, and A. P. Yoganathan. Effect of anterior strut chordal transection on the force distribution on the marginal chordae of the mitral valve. J. Thorac. Cardiovasc. Surg. 144:624–633, 2012.

    Article  PubMed  Google Scholar 

  30. Padala, M., R. A. Hutchison, L. R. Croft, J. H. Jimenez, R. C. Gorman, J. H. Gorman, M. S. Sacks, A. P. Yoganathan, and A. P. Yoganathan. Saddle shape of the mitral annulus reduces systolic strains on the p2 segment of the posterior mitral leaflet. Ann. Thorac. Surg. 88:1499–1504, 2009.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Pedersen, W. R., P. Block, M. Leon, P. Kramer, S. Kapadia, V. Babaliaros, S. Kodali, E. M. Tuzcu, and T. Feldman. Icoapsys mitral valve repair system: percutaneous implantation in an animal model. Catheter. Cardiovasc. Interv. 72:125–131, 2008.

    Article  PubMed  Google Scholar 

  32. Rich, L., and P. Whittaker. Collagen and picrosirius red staining: a polarized light assessment of fibrillar hue and spatial distribution. Braz. J. Morphol. Sci. 22:97–104, 2005.

    Google Scholar 

  33. Rossi, A., F. L. Dini, P. Faggiano, E. Agricola, M. Cicoira, S. Frattini, A. Simioniuc, M. Gullace, S. Ghio, M. Enriquez-Sarano, and P. L. Temporelli. Independent prognostic value of functional mitral regurgitation in patients with heart failure. a quantitative analysis of 1256 patients with ischaemic and non-ischaemic dilated cardiomyopathy. Heart 97:1675–1680, 2011.

    Article  PubMed  Google Scholar 

  34. Sakamuri, S. S. V. P., A. Takawale, R. Basu, P. W. M. Fedak, D. Freed, C. Sergi, G. Y. Oudit, and Z. Kassiri. Differential impact of mechanical unloading on structural and nonstructural components of the extracellular matrix in advanced human heart failure. Transl. Res. 172:30–44, 2016.

    Article  PubMed  Google Scholar 

  35. Stephens, E. H., and K. J. Grande-Allen. Age-related changes in collagen synthesis and turnover in porcine heart valves. J. Heart Valve Dis. 16:672–682, 2007.

    PubMed  Google Scholar 

  36. Stephens, E. H., T. C. Nguyen, A. Itoh, N. B. Ingels, D. C. Miller, and K. J. Grande-Allen. The effects of mitral regurgitation alone are sufficient for leaflet remodeling. Circulation 118:S243–S249, 2008.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Taramasso, M., P. Denti, N. Buzzatti, M. De Bonis, G. La Canna, A. Colombo, O. Alfieri, and F. Maisano. Mitraclip therapy and surgical mitral repair in patients with moderate to severe left ventricular failure causing functional mitral regurgitation: a single-centre experience. Eur. J. Cardiothorac. Surg. 42:920–926, 2012.

    Article  PubMed  Google Scholar 

  38. Timek, T. A., P. Dagum, D. T. Lai, D. Liang, G. T. Daughters, N. B. Ingels, and D. C. Miller. Pathogenesis of mitral regurgitation in tachycardia-induced cardiomyopathy. Circulation 104:i47–i53, 2001.

Download references

Acknowledgements

The authors would like to acknowledge Dr. Larry Fisher, NIH for his gift of decorin antibody used in this research.

Conflicts of interest

Dr. Connell reports personal fees from Polyvascular Corporation, outside the submitted work. Other authors have no disclosures.

Funding

This work was supported by the National Science Foundation Graduate Research Fellowship Program [1450681 to D.V.]; and an American Heart Association Predoctoral Fellowship [13PRE14110003 to P.C.].

Author information

Author notes

  1. Patrick S. Connell and Dragoslava P. Vekilov have contributed equally to this work.

Authors and Affiliations

  1. Department of Bioengineering, Rice University, 6100 Main St., MS 142, Houston, TX, 77005, USA

    Patrick S. Connell, Dragoslava P. Vekilov, Christine M. Diaz, Seulgi E. Kim & K. Jane Grande-Allen

  2. Department of Pediatrics, Texas Children’s Hospital and Baylor College of Medicine, Houston, TX, USA

    Patrick S. Connell

Authors
  1. Patrick S. Connell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dragoslava P. Vekilov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine M. Diaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seulgi E. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Jane Grande-Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Jane Grande-Allen.

Additional information

Associate Editor Arash Kheradvar oversaw the review of this article.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Connell, P.S., Vekilov, D.P., Diaz, C.M. et al. Eliminating Regurgitation Reduces Fibrotic Remodeling of Functional Mitral Regurgitation Conditioned Valves. Ann Biomed Eng 46, 670–683 (2018). https://doi.org/10.1007/s10439-018-1987-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-018-1987-9

Keywords

Search

Navigation