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Experimental Models of Cardiovascular Diseases pp 295–308Cite as

Ovine Model of Ischemic Mitral Regurgitation

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 1816))

Abstract

Ischemic mitral regurgitation (IMR) is a common complication of ischemic heart disease that doubles mortality after myocardial infarction and is a major driving factor increasing heart failure. IMR is caused by left ventricular (LV) remodeling which displaces the papillary muscles that tether the mitral valve leaflets and restrict their closure. IMR frequently recurs even after surgical treatment. Failed repair associates with lack of reduction or increase in LV remodeling, and increased heart failure and related readmissions. Understanding mechanistic and molecular mechanisms of IMR has largely attributed to the development of large animal models. Newly developed therapeutic interventions targeted to the primary causes can also be tested in these models. The sheep is one of the most suitable models for the development of IMR. In this chapter, we describe the protocols for inducing IMR in sheep using surgical ligation of obtuse marginal branches. After successful posterior myocardial infarction involving posterior papillary muscle, animals develop significant mitral regurgitation around 2 months after the surgery.

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References

  1. Grigioni F, Detaint D, Avierinos JF, Scott C, Tajik J, Enriquez-Sarano M (2005) Contribution of ischemic mitral regurgitation to congestive heart failure after myocardial infarction. J Am Coll Cardiol 45(2):260–267

    Article  PubMed  Google Scholar 

  2. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ (2001) Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 103(13):1759–1764

    Article  CAS  PubMed  Google Scholar 

  3. Lamas GA, Mitchell GF, Flaker GC, Smith SC Jr, Gersh BJ, Basta L, Moye L, Braunwald E, Pfeffer MA (1997) Clinical significance of mitral regurgitation after acute myocardial infarction. Survival and ventricular enlargement investigators. Circulation 96(3):827–833

    Article  CAS  PubMed  Google Scholar 

  4. Birnbaum Y, Chamoun AJ, Conti VR, Uretsky BF (2002) Mitral regurgitation following acute myocardial infarction. Coron Artery Dis 13(6):337–344

    Article  PubMed  Google Scholar 

  5. Trichon BH, Felker GM, Shaw LK, Cabell CH, O'Connor CM (2003) Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol 91(5):538–543

    Article  PubMed  Google Scholar 

  6. Popovic ZB, Martin M, Fukamachi K, Inoue M, Kwan J, Doi K, Qin JX, Shiota T, Garcia MJ, McCarthy PM, Thomas JD (2005) Mitral annulus size links ventricular dilatation to functional mitral regurgitation. J Am Soc Echocardiogr 18(9):959–963

    Article  PubMed  Google Scholar 

  7. Tibayan FA, Rodriguez F, Langer F, Zasio MK, Bailey L, Liang D, Daughters GT, Ingels NB Jr, Miller DC (2003) Annular remodeling in chronic ischemic mitral regurgitation: ring selection implications. Ann Thorac Surg 76(5):1549–1554. discussion 1554-1545

    Article  PubMed  Google Scholar 

  8. Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ (2000) Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 102(12):1400–1406

    Article  CAS  PubMed  Google Scholar 

  9. Otsuji Y, Handschumacher MD, Schwammenthal E, Jiang L, Song JK, Guerrero JL, Vlahakes GJ, Levine RA (1997) Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation 96(6):1999–2008

    Article  CAS  PubMed  Google Scholar 

  10. Kono T, Sabbah HN, Rosman H, Alam M, Jafri S, Goldstein S (1992) Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure. J Am Coll Cardiol 20(7):1594–1598

    Article  CAS  PubMed  Google Scholar 

  11. Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Hjortnaes J, Beaudoin J, Szymanski C, Bartko PE, Seybolt MM, Handschumacher MD, Sullivan S, Garcia ML, Mauskapf A, Titus JS, Wylie-Sears J, Irvin WS, Chaput M, Messas E, Hagege AA, Carpentier A, Levine RA, Leducq Transatlantic Mitral N (2016) Myocardial infarction alters adaptation of the tethered mitral valve. J Am Coll Cardiol 67(3):275–287

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chaput M, Handschumacher MD, Tournoux F, Hua L, Guerrero JL, Vlahakes GJ, Levine RA (2008) Mitral leaflet adaptation to ventricular remodeling: occurrence and adequacy in patients with functional mitral regurgitation. Circulation 118(8):845–852

    Article  PubMed  PubMed Central  Google Scholar 

  13. Boltwood CM, Tei C, Wong M, Shah PM (1983) Quantitative echocardiography of the mitral complex in dilated cardiomyopathy: the mechanism of functional mitral regurgitation. Circulation 68(3):498–508

    Article  CAS  PubMed  Google Scholar 

  14. Burch GE, De Pasquale NP, Phillips JH (1963) Clinical manifestations of papillary muscle dysfunction. Arch Intern Med 112:112–117

    Article  CAS  PubMed  Google Scholar 

  15. Cochran RP, Kunzelman KS (1998) Effect of papillary muscle position on mitral valve function: relationship to homografts. Ann Thorac Surg 66(6 Suppl):S155–S161

    Article  CAS  PubMed  Google Scholar 

  16. Gorman RC, McCaughan JS, Ratcliffe MB, Gupta KB, Streicher JT, Ferrari VA, St John-Sutton MG, Bogen DK, Edmunds LH Jr (1995) Pathogenesis of acute ischemic mitral regurgitation in three dimensions. J Thorac Cardiovasc Surg 109(4):684–693

    Article  CAS  PubMed  Google Scholar 

  17. He S, Fontaine AA, Schwammenthal E, Yoganathan AP, Levine RA (1997) Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies. Circulation 96(6):1826–1834

    Article  CAS  PubMed  Google Scholar 

  18. Kaul S, Spotnitz WD, Glasheen WP, Touchstone DA (1991) Mechanism of ischemic mitral regurgitation. An experimental evaluation. Circulation 84(5):2167–2180

    Article  CAS  PubMed  Google Scholar 

  19. Komeda M, Glasson JR, Bolger AF, Daughters GT 2nd, MacIsaac A, Oesterle SN, Ingels NB Jr, Miller DC (1997) Geometric determinants of ischemic mitral regurgitation. Circulation 96(9 Suppl):II-128–II-133

    Google Scholar 

  20. Kono T, Sabbah HN, Stein PD, Brymer JF, Khaja F (1991) Left ventricular shape as a determinant of functional mitral regurgitation in patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol 68(4):355–359

    Article  CAS  PubMed  Google Scholar 

  21. Llaneras MR, Nance ML, Streicher JT, Lima JA, Savino JS, Bogen DK, Deac RF, Ratcliffe MB, Edmunds LH Jr (1994) Large animal model of ischemic mitral regurgitation. Ann Thorac Surg 57(2):432–439

    Article  CAS  PubMed  Google Scholar 

  22. Llaneras MR, Nance ML, Streicher JT, Linden PL, Downing SW, Lima JA, Deac R, Edmunds LH Jr (1993) Pathogenesis of ischemic mitral insufficiency. J Thorac Cardiovasc Surg 105(3):439–442; discussion 442–433.

    PubMed  CAS  Google Scholar 

  23. Mittal AK, Langston M Jr, Cohn KE, Selzer A, Kerth WJ (1971) Combined papillary muscle and left ventricular wall dysfunction as a cause of mitral regurgitation. An experimental study. Circulation 44(2):174–180

    Article  CAS  PubMed  Google Scholar 

  24. Otsuji Y, Handschumacher MD, Liel-Cohen N, Tanabe H, Jiang L, Schwammenthal E, Guerrero JL, Nicholls LA, Vlahakes GJ, Levine RA (2001) Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation. J Am Coll Cardiol 37(2):641–648

    Article  CAS  PubMed  Google Scholar 

  25. Godley RW, Wann LS, Rogers EW, Feigenbaum H, Weyman AE (1981) Incomplete mitral leaflet closure in patients with papillary muscle dysfunction. Circulation 63(3):565–571

    Article  CAS  PubMed  Google Scholar 

  26. Levine RA, Schwammenthal E (2005) Ischemic mitral regurgitation on the threshold of a solution: from paradoxes to unifying concepts. Circulation 112(5):745–758

    Article  PubMed  Google Scholar 

  27. Calafiore AM, Gallina S, Di Mauro M, Gaeta F, Iaco AL, D'Alessandro S, Mazzei V, Di Giammarco G (2001) Mitral valve procedure in dilated cardiomyopathy: repair or replacement? Ann Thorac Surg 71(4):1146–1152. discussion 1152-1143

    Article  CAS  PubMed  Google Scholar 

  28. Grossi EA, Goldberg JD, LaPietra A, Ye X, Zakow P, Sussman M, Delianides J, Culliford AT, Esposito RA, Ribakove GH, Galloway AC, Colvin SB (2001) Ischemic mitral valve reconstruction and replacement: comparison of long-term survival and complications. J Thorac Cardiovasc Surg 122(6):1107–1124

    Article  CAS  PubMed  Google Scholar 

  29. Hung J, Papakostas L, Tahta SA, Hardy BG, Bollen BA, Duran CM, Levine RA (2004) Mechanism of recurrent ischemic mitral regurgitation after annuloplasty: continued LV remodeling as a moving target. Circulation 110(11 Suppl 1):II85–II90

    PubMed  Google Scholar 

  30. Kuwahara E, Otsuji Y, Iguro Y, Ueno T, Zhu F, Mizukami N, Kubota K, Nakashiki K, Yuasa T, Yu B, Uemura T, Takasaki K, Miyata M, Hamasaki S, Kisanuki A, Levine RA, Sakata R, Tei C (2006) Mechanism of recurrent/persistent ischemic/functional mitral regurgitation in the chronic phase after surgical annuloplasty: importance of augmented posterior leaflet tethering. Circulation 114(1 Suppl):I529–I534

    PubMed  Google Scholar 

  31. McGee EC, Gillinov AM, Blackstone EH, Rajeswaran J, Cohen G, Najam F, Shiota T, Sabik JF, Lytle BW, McCarthy PM, Cosgrove DM (2004) Recurrent mitral regurgitation after annuloplasty for functional ischemic mitral regurgitation. J Thorac Cardiovasc Surg 128(6):916–924

    Article  PubMed  Google Scholar 

  32. Tahta SA, Oury JH, Maxwell JM, Hiro SP, Duran CM (2002) Outcome after mitral valve repair for functional ischemic mitral regurgitation. J Heart Valve Dis 11(1):11–18. discussion 18-19

    PubMed  Google Scholar 

  33. Acker MA, Parides MK, Perrault LP, Moskowitz AJ, Gelijns AC, Voisine P, Smith PK, Hung JW, Blackstone EH, Puskas JD, Argenziano M, Gammie JS, Mack M, Ascheim DD, Bagiella E, Moquete EG, Ferguson TB, Horvath KA, Geller NL, Miller MA, Woo YJ, D'Alessandro DA, Ailawadi G, Dagenais F, Gardner TJ, O'Gara PT, Michler RE, Kron IL (2013) Mitral-valve repair versus replacement for severe ischemic mitral regurgitation. N Engl J Med 370:23–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Goldstein D, Moskowitz AJ, Gelijns AC, Ailawadi G, Parides MK, Perrault LP, Hung JW, Voisine P, Dagenais F, Gillinov AM, Thourani V, Argenziano M, Gammie JS, Mack M, Demers P, Atluri P, Rose EA, O'Sullivan K, Williams DL, Bagiella E, Michler RE, Weisel RD, Miller MA, Geller NL, Taddei-Peters WC, Smith PK, Moquete E, Overbey JR, Kron IL, O'Gara PT, Acker MA, CTSN (2015) Two-year outcomes of surgical treatment of severe ischemic mitral regurgitation. N Engl J Med 374:344–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kron IL, Hung J, Overbey JR, Bouchard D, Gelijns AC, Moskowitz AJ, Voisine P, O’Gara PT, Argenziano M, Michler RE, Gillinov M, Puskas JD, Gammie JS, Mack MJ, Smith PK, Sai-Sudhakar C, Gardner TJ, Ailawadi G, Zeng X, O'Sullivan K, Parides MK, Swayze R, Thourani V, Rose EA, Perrault LP, Acker MA (2015) Predicting recurrent mitral regurgitation after mitral valve repair for severe ischemic mitral regurgitation. J Thorac Cardiovasc Surg 149(3):752–761.e751

    Article  PubMed  Google Scholar 

  36. Kron IL, Perrault LP, Acker MA (2015) We need a better way to repair ischemic mitral regurgitation. J Thorac Cardiovasc Surg 150(2):428

    Article  PubMed  Google Scholar 

  37. Vassileva CM, Boley T, Markwell S, Hazelrigg S (2011) Meta-analysis of short-term and long-term survival following repair versus replacement for ischemic mitral regurgitation. Eur J Cardiothorac Surg 39(3):295–303

    Article  PubMed  Google Scholar 

  38. Scheuer J (1982) Effects of physical training on myocardial vascularity and perfusion. Circulation 66(3):491–495

    Article  CAS  PubMed  Google Scholar 

  39. Milani-Nejad N, Janssen PM (2014) Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharmacol Ther 141(3):235–249

    Article  CAS  PubMed  Google Scholar 

  40. Gorman JH 3rd, Gorman RC, Plappert T, Jackson BM, Hiramatsu Y, St John-Sutton MG, Edmunds LH Jr (1998) Infarct size and location determine development of mitral regurgitation in the sheep model. J Thorac Cardiovasc Surg 115(3):615–622

    Article  PubMed  Google Scholar 

  41. Hutchison J, Rea P (2015) A comparative study of the morphology of mammalian chordae tendineae of the mitral and tricuspid valves. Vet Rec Open 2(2):e000150

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hill AJ, Iaizzo PA (2009) Comparative cardiac anatomy. In: Iaizzo PA (ed) Handbook of cardiac anatomy, physiology, and devices. Humana Press, Totowa, NJ, pp 87–108. https://doi.org/10.1007/978-1-60327-372-5_6

    Chapter  Google Scholar 

  43. Olsson K, Hansson K, Hydbring E, von Walter LW, Häggström J (2001) A serial study of heart function during pregnancy, lactation and the dry period in dairy goats using echocardiography. Exp Physiol 86(1):93–99

    Article  CAS  PubMed  Google Scholar 

  44. Vloumidi EI, Fthenakis GC (2017) Ultrasonographic examination of the heart in sheep. Small Rumin Res 152(Supplement C):119–127

    Article  Google Scholar 

  45. Bartko PE, Dal-Bianco JP, Guerrero JL, Beaudoin J, Szymanski C, Kim DH, Seybolt MM, Handschumacher MD, Sullivan S, Garcia ML, Titus JS, Wylie-Sears J, Irvin WS, Messas E, Hagege AA, Carpentier A, Aikawa E, Bischoff J, Levine RA, Leducq Transatlantic Mitral N (2017) Effect of losartan on mitral valve changes after myocardial infarction. J Am Coll Cardiol 70(10):1232–1244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Handschumacher MD, Sullivan S, Johnson B, Titus JS, Iwamoto Y, Wylie-Sears J, Levine RA, Carpentier A (2009) Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation. Circulation 120(4):334–342

    Article  PubMed  PubMed Central  Google Scholar 

  47. Poser H, Semplicini L, De Benedictis GM, Gerardi G, Contiero B, Maschietto N, Valerio E, Milanesi O, Semplicini A, Bernardini D (2013) Two-dimensional, M-mode and Doppler-derived echocardiographic parameters in sedated healthy growing female sheep. Lab Anim 47(3):194–202

    Article  CAS  PubMed  Google Scholar 

  48. Locatelli P, Olea FD, De Lorenzi A, Salmo F, Vera Janavel GL, Hnatiuk AP, Guevara E, Crottogini AJ (2011) Reference values for echocardiographic parameters and indexes of left ventricular function in healthy, young adult sheep used in translational research: comparison with standardized values in humans. Int J Clin Exp Med 4(4):258–264

    PubMed  PubMed Central  Google Scholar 

  49. Moses BL, Ross JN Jr (1987) M-mode echocardiographic values in sheep. Am J Vet Res 48(9):1313–1318

    PubMed  CAS  Google Scholar 

  50. Becker AE (1991) Anatomy of the coronary arteries with resepct to chronic ischemic mitral regurgitation. In: Vetter HO, Hetzer R, Schmutzler H (eds) Ischemic mitral incompetence. Steinkopff, Heidelberg, pp 17–24. https://doi.org/10.1007/978-3-662-08027-6_2

    Chapter  Google Scholar 

  51. Gorman JH 3rd, Jackson BM, Gorman RC, Kelley ST, Gikakis N, Edmunds LH Jr (1997) Papillary muscle discoordination rather than increased annular area facilitates mitral regurgitation after acute posterior myocardial infarction. Circulation 96(9 Suppl):II-124–II-127

    Google Scholar 

  52. Group EUCCS, Regitz-Zagrosek V, Oertelt-Prigione S, Prescott E, Franconi F, Gerdts E, Foryst-Ludwig A, Maas AH, Kautzky-Willer A, Knappe-Wegner D, Kintscher U, Ladwig KH, Schenck-Gustafsson K, Stangl V (2016) Gender in cardiovascular diseases: impact on clinical manifestations, management, and outcomes. Eur Heart J 37(1):24–34

    Article  CAS  Google Scholar 

  53. Ahlberg SE, Bateman MG, Eggen MD, Quill JL, Richardson ES, Iaizzo PA (2013) Animal models for cardiac valve research. In: Iaizzo PA, Bianco RW, Hill AJ, St. Louis JD (eds) Heart valves: from design to clinical implantation. Springer US, Boston, MA, pp 343–357. https://doi.org/10.1007/978-1-4614-6144-9_14

    Chapter  Google Scholar 

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Acknowledgments

This study was supported in part by NIH grants R01 HL128099 and HL141917, and by support from the Ellison Foundation, Boston, MA.

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Authors and Affiliations

  1. Cardiac Imaging Center, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea

    Dae-Hee Kim

  2. Division of Cardiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea

    Dae-Hee Kim

  3. Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Dae-Hee Kim, Judy Hung & Robert A. Levine

  4. Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Brittan Morris, J. Luis Guerrero & Suzanne M. Sullivan

Authors
  1. Dae-Hee Kim
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  2. Brittan Morris
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  3. J. Luis Guerrero
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  4. Suzanne M. Sullivan
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  5. Judy Hung
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  6. Robert A. Levine
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Corresponding author

Correspondence to Robert A. Levine .

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Editors and Affiliations

  1. Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Kiyotake Ishikawa

1 Electronic Supplementary Material

Movie clips of baseline (normal) short axis images (a, b) and posterior infarction with PM involvement (c, d, and e). The PM does not contract; not moving toward the center in short axis (c, d) and the base in long axis (e) (MP4 520 kb)

Movie clips of baseline (normal) short axis images (a, b) and posterior infarction with PM involvement (c, d, and e). The PM does not contract; not moving toward the center in short axis (c, d) and the base in long axis (e) (MP4 537 kb)

Movie clips of baseline (normal) short axis images (a, b) and posterior infarction with PM involvement (c, d, and e). The PM does not contract; not moving toward the center in short axis (c, d) and the base in long axis (e) (MP4 550 kb)

Movie clips of baseline (normal) short axis images (a, b) and posterior infarction with PM involvement (c, d, and e). The PM does not contract; not moving toward the center in short axis (c, d) and the base in long axis (e) (MP4 541 kb)

Movie clips of baseline (normal) short axis images (a, b) and posterior infarction with PM involvement (c, d, and e). The PM does not contract; not moving toward the center in short axis (c, d) and the base in long axis (e) (MP4 714 kb)

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Kim, DH., Morris, B., Guerrero, J.L., Sullivan, S.M., Hung, J., Levine, R.A. (2018). Ovine Model of Ischemic Mitral Regurgitation. In: Ishikawa, K. (eds) Experimental Models of Cardiovascular Diseases. Methods in Molecular Biology, vol 1816. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8597-5_23

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  • DOI: https://doi.org/10.1007/978-1-4939-8597-5_23

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