Skip to main content
SpringerLink
Log in

Microvascular Obstruction: The No-Reflow Phenomenon in Animal Models of Myocardial Ischemia and Reperfusion

  • Chapter
  • First Online:
Management of Myocardial Reperfusion Injury

  • 889 Accesses

Abstract

In animal models of coronary artery occlusion and reopening of the ­epicardial artery, perfusion defects within the area at risk may develop during reperfusion despite complete reopening of the epicardial artery. These anatomical areas of no-reflow are confined to areas of myocardial necrosis and substantially expand during ongoing reperfusion. This reperfusion injury at the microvascular level may be related to ultrastructural alterations of the microvasculature, production of reactive oxygen species during reperfusion, leukocyte accumulation, and release of vasoconstrictive agents. Myocardial infarct size appears to be the major determinant of no-reflow, and cardioprotective interventions leading to smaller infarcts result in reduced microvascular obstruction in most of the models. Several therapeutic strategies have been developed to reduce no-reflow; however, in most of these investigations it was difficult to dissociate no-reflow from infarct size. Transfer to the clinical setting of myocardial infarction shows many similarities, but additional mechanisms such as coronary microembolization significantly contribute to clinical no-reflow.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Davies MJ, Woolf N, Robertson WB. Pathology of acute myocardial infarction with particular reference to coronary thrombi. Br Heart J. 1976;38:659–64.

    Article  PubMed  CAS  Google Scholar 

  2. Reffelmann T, Kloner RA. The “no-reflow” phenomenon: basic science and clinical correlates. Heart. 2002;87:162–8.

    Article  PubMed  Google Scholar 

  3. The Gusto Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–82.

    Article  Google Scholar 

  4. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13–20.

    Article  PubMed  Google Scholar 

  5. Bekkers SCAM, Yazdani SK, Virmani R, Waltenberger J. Microvascular obstruction. J Am Coll Cardiol. 2010;55:1649–60.

    Article  PubMed  Google Scholar 

  6. Reffelmann T, Kloner RA. The no-reflow phenomenon: a basic mechanism of myocardial ­ischemia and reperfusion. Basic Res Cardiol. 2006;101:359–72.

    Article  PubMed  Google Scholar 

  7. Krug A, de Rochemont WM, Korb G. Blood supply to the myocardium after temporary coronary artery occlusion. Circ Res. 1966;19:57–62.

    Article  PubMed  CAS  Google Scholar 

  8. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in dogs. J Clin Invest. 1974;54:1496–508.

    Article  PubMed  CAS  Google Scholar 

  9. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation. 1998;97:65–72.

    Google Scholar 

  10. Morishima I, Sone T, Okumara K, et al. Angiographic no-reflow as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first myocardial infarction. J Am Coll Cardiol. 2000;36:1202–9.

    Article  PubMed  CAS  Google Scholar 

  11. Lepper W, Hoffmann R, Kamp O, et al. Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal coronary angiography in patients with acute myocardial infarction. Circulation. 2000;101:2368–74.

    Article  PubMed  CAS  Google Scholar 

  12. Fishbein MC, Y-Rit J, Lando U, Kanmatsuse K, Mercier JC, Ganz W. The relationship of vascular injury and myocardial hemorrhage to necrosis after reperfusion. Circulation. 1980;62:1274–9.

    Article  PubMed  CAS  Google Scholar 

  13. Reffelmann T, Kloner RA. Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit. Am J Physiol Heart Circ Physiol. 2002;283:h1099–107.

    PubMed  CAS  Google Scholar 

  14. Kaeffer N, Richard V, Francois A, Lallemand F, Henry JP, Thuillez C. Preconditioning prevents chronic reperfusion-induced coronary endothelial dysfunction in rats. Am J Physiol Heart Circ Physiol. 1996;271:H842–9.

    CAS  Google Scholar 

  15. Kloner RA, Giacomelli F, Alker KJ, Hale SL, Mathey R, Bellows S. Influx of neutrophils into the wall of large epicardial coronary arteries in response to ischemia/reperfusion. Circulation. 1991;84:1758–72.

    Article  PubMed  CAS  Google Scholar 

  16. Piana RN, Paik GY, Mascucci M, et al. Incidence and treatment of ‘no-reflow’ after percutaneous coronary intervention. Circulation. 1994;89:2514–8.

    Article  PubMed  CAS  Google Scholar 

  17. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty for first acute myocardial infarction. Circulation. 1996;93:1993–9.

    Article  PubMed  CAS  Google Scholar 

  18. Ragosta M, Camarano G, Kaul S, et al. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction: new insights using myocardial contrast echocardiography. Circulation. 1994;89:2562–9.

    Article  PubMed  CAS  Google Scholar 

  19. Sakuma T, Hayashi Y, Sumii K, et al. Prediction of short and intermediate-term prognosis of patients with acute myocardial infarction using myocardial contrast echocardiography one day after recanalization. J Am Coll Cardiol. 1998;32:890–7.

    Article  PubMed  CAS  Google Scholar 

  20. Rochitte CE, Lima JA, Bluemke DA, et al. Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation. 1998;98:1006–14.

    Article  PubMed  CAS  Google Scholar 

  21. Gerber BL, Rochitte CE, Melin JA, et al. Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation. 2000;101:2734–41.

    Article  PubMed  CAS  Google Scholar 

  22. Weir RA, Murphy CA, Petrie CJ, et al. Microvascular obstruction remains a portent of adverse remodeling in optimally-treated patients with left ventricular systolic dysfunction after acute myocardial infarction. Circ Cardiovasc Imaging. 2010;3(4):360–7. Epub 2010 Mar 26.

    Article  PubMed  Google Scholar 

  23. Topol EJ, Yadav JS. Recognition of the importance of microembolization in atherosclerotic vascular disease. Circulation. 2000;101:570–80.

    Article  PubMed  CAS  Google Scholar 

  24. Silva-Orrego P, Colombo P, Bigi R, et al. Thrombus aspiration before myocardial reperfusion in acute myocardial infarction. The DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) Study. J Am Coll Cardiol. 2006;48:1552–9.

    Article  PubMed  Google Scholar 

  25. Stone GW, Webb J, Cox DA, et al. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction. A randomized controlled trial. JAMA. 2005;293:1063–72.

    Article  PubMed  CAS  Google Scholar 

  26. Roe MT, Ohman M, Maas ACP, et al. Shifting the open artery hypothesis downstream: the quest for optimal reperfusion. J Am Coll Cardiol. 2001;37:9–18.

    Article  PubMed  CAS  Google Scholar 

  27. Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LWV, Braunwald E. Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion. Which comes first? Circulation. 1980;62:945–52.

    Article  PubMed  CAS  Google Scholar 

  28. Reffelmann T, Hale SL, Li G, Kloner RA. Relationship between no reflow and infarct size as influenced by the duration of ischemia and reperfusion. Am J Physiol Heart Circ Physiol. 2002;282:H766–72.

    PubMed  CAS  Google Scholar 

  29. Hale S, Dae MW, Kloner RA. Hypothermia during reperfusion limits ‘no-reflow’ injury in a rabbit myocardial infarct model. Cardiovasc Res. 2003;59:715–22.

    Article  PubMed  CAS  Google Scholar 

  30. Hale SL, Kloner RA. The antianginal agent, ranolazine, reduces myocardial infarct size but does not alter anatomic no-reflow or regional myocardial blood flow in ischemia/reperfusion in the rabbit. J Cardiovasc Pharmacol Ther. 2008;13:226–32.

    Article  PubMed  CAS  Google Scholar 

  31. Reffelmann T, Kloner RA. Is microvascular protection by cariporide and ischemic preconditioning causally linked to myocardial salvage? Am J Physiol Heart Circ Physiol. 2003;284:H1134–41.

    PubMed  CAS  Google Scholar 

  32. Ambrosio G, Weissmann HF, Mannisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation. 1989;80:1846–61.

    Article  PubMed  CAS  Google Scholar 

  33. Geft IL, Fishbein MC, Hashida J, et al. Effects of late coronary artery reperfusion after myocardial necrosis is complete. Am Heart J. 1984;107:623–9.

    Article  PubMed  CAS  Google Scholar 

  34. Garcia-Dorado D, Théroux P, Solares J, et al. Determinants of hemorrhagic infarcts. Histologic observations from experiments involving coronary occlusion, coronary reperfusion, and reocclusion. Am J Pathol. 1990;137:301–11.

    PubMed  CAS  Google Scholar 

  35. Higginson LA, White F, Heggtveit HA, Sanders TM, Bloor CM, Covell JW. Determinants of myocardial hemorrhage after coronary reperfusion in the anesthetized dog. Circulation. 1982;65:62–9.

    Article  PubMed  CAS  Google Scholar 

  36. McNamara JJ, Lacro RV, Yee M, Smith GT. Hemorrhagic infarction and coronary reperfusion. J Thorac Cardiovasc Surg. 1981;81:498–501.

    PubMed  CAS  Google Scholar 

  37. Kloner RA, Alker KJ. The effect of streptokinase on intramyocardial hemorrhage, infarct size, and the no-reflow phenomenon during coronary reperfusion. Circulation. 1984;70:513–21.

    Article  PubMed  CAS  Google Scholar 

  38. Ganame J, Messalli G, Dymarkowski S, Rademakers FE, van de Werf R, Bogaert J. Impact of myocardial haemorrhage on left ventricular function and remodeling in patients with reperfused acute myocardial infarction. Eur Heart J. 2009;30:1440–9.

    Article  PubMed  Google Scholar 

  39. Asanuma T, Tanabe K, Ochiai K, et al. Relationship between progressive microvascular ­damage and intramyocardial hemorrhage in patients with reperfused anterior myocardial infarction: myocardial contrast echocardiographic study. Circulation. 1997;96:448–53.

    Article  PubMed  CAS  Google Scholar 

  40. Beek AM, Nijveldt R, van Rossum AC. Intramyocardial hemorrhage and microvascular obstruction after primary percutaneous coronary intervention. Int J Cardiovasc Imaging. 2010;26:49–55.

    Article  PubMed  CAS  Google Scholar 

  41. Kloner RA, Alker K, Campbell C, Figures G, Eisenhauer A, Hale S. Does tissue-plasminogen activator have direct beneficial effects on the myocardium independent of its ability to lyse intracoronary thrombi? Circulation. 1989;79:1125–36.

    Article  PubMed  CAS  Google Scholar 

  42. Duilio C, Ambrosio G, Kuppusamy P, DiPaula A, Becker LC, Zweier JL. Neutrophils are primary source of O2 radicals during reperfusion after prolonged myocardial ischemia. Am J Physiol Heart Circ Physiol. 2001;280:H2649–57.

    PubMed  CAS  Google Scholar 

  43. Ambrosio G, Becker LC, Hutchins GM, Weisman HF, Weisfeldt ML. Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury. Circulation. 1986;74:1424–33.

    Article  PubMed  CAS  Google Scholar 

  44. Przyklenk K, Kloner RA. “Reperfusion injury” by oxygen-derived free radicals? Effect of superoxide dismutase plus catalase, given at the time of reperfusion, on myocardial infarct size, contractile function, coronary microvasculature, and regional myocardial blood flow. Circ Res. 1989;64:86–96.

    Article  PubMed  CAS  Google Scholar 

  45. Tranum-Jensen J, Janse MJ, Fiolet JWT, Krieger WJG, D’Alnoncourt CN, Durrer D. Tissue osmolality, cell swelling, and reperfusion in acute regional myocardial ischemia in the isolated porcine heart. Circ Res. 1981;49:364–81.

    Article  PubMed  CAS  Google Scholar 

  46. Manciet LH, Poole DC, McDonagh PF, Copeland JG, Mathieu-Costello O. Microvascular compression during myocardial ischemia: mechanistic basis for no-reflow phenomenon. Am J Physiol Heart Circ Physiol. 1994;266:H1541–50.

    CAS  Google Scholar 

  47. Willerson JT, Watson JT, Hutton I, Fixler DE, Curry CG, Templeton GH. The influence of hypertonic mannitol on regional myocardial blood flow during acute and chronic myocardial ischemia in anaesthetized and awake dogs. J Clin Invest. 1975;55:892–902.

    Article  PubMed  CAS  Google Scholar 

  48. Carlson RE, Aisen AM, Buda AJ. Effect of reduction in myocardial edema on myocardial blood flow and ventricular function after coronary reperfusion. Am J Physiol Heart Circ Physiol. 1992;262:H641–8.

    CAS  Google Scholar 

  49. Engler RL, Schmid-Schönbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol. 1983;111:98–111.

    PubMed  CAS  Google Scholar 

  50. Martin SE, Chenoweth DE, Engler RL, Roth DM, Longhurst JC. C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism. Circ Res. 1988;63:483–91.

    Article  PubMed  CAS  Google Scholar 

  51. Galinanes M, Lawson CS, Ferrari R, Limb GA, Derias NW, Hearse DJ. Early and late effects of leukopenic reperfusion on the recovery of cardiac contractile function studies in the transplanted and isolated blood-perfused rat heat. Circulation. 1993;88:673–83.

    Article  PubMed  CAS  Google Scholar 

  52. Kolodgie FD, Virmani R, Frab A. Limitation of no-reflow injury by blood-free reperfusion with oxygenated perfluorochemical (Fluoso-DA 20%). J Am Coll Cardiol. 1991;18:215–23.

    Article  PubMed  CAS  Google Scholar 

  53. Litt MR, Jeremy RW, Weisman HF, Winckelstein JA, Becker LC. Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia. Evidence for neutrophil-mediated reperfusion injury. Circulation. 1989;80:1816–27.

    Article  PubMed  CAS  Google Scholar 

  54. Golino P, Ragni M, Cirillo P, et al. Recombinant human, active site-blocked factor VIIa reduces infarct size and no-reflow phenomenon in rabbits. Am J Physiol Heart Circ Physiol. 2000;278:H1507–16.

    PubMed  CAS  Google Scholar 

  55. Golino P, Ragni M, Cirillo P, et al. Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion. Nat Med. 1996;2:35–41.

    Article  PubMed  CAS  Google Scholar 

  56. Reffelmann T, Kloner RA. Effects of adenosine and verapamil on anatomic no-reflow in a ­rabbit model of coronary artery occlusion and reperfusion. J Cardiovasc Pharmacol. 2004;43:580–6.

    Article  PubMed  CAS  Google Scholar 

  57. Reffelmann T, Kloner RA. Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation. Cardiovasc Res. 2003;98:275–84.

    Google Scholar 

  58. Villari B, Ambrosio G, Golino P, et al. The effects of calcium channel antagonist treatment and oxygen radical scavenging on infarct size and no-reflow phenomenon in reperfused hearts. Am Heart J. 1993;125:11–23.

    Article  PubMed  CAS  Google Scholar 

  59. Watt JA, Hawes EM, Jenkins SH, Williams TC. Effects of nisoldipine on the no-reflow phenomenon in globally ischemic rat hearts. J Cardiovasc Pharmacol. 1990;14:487–94.

    Article  Google Scholar 

  60. Babbit DG, Virmani R, Forman MB. Intracoronary adenosine administered after reperfusion limits vascular injury after prolonged ischemia in the canine model. Circulation. 1989;80:1388–99.

    Article  Google Scholar 

  61. Pitarys CJ, Virmani R, Vildibill HD, Jackson EK, Forman MB. Reduction of myocardial ­reperfusion injury by intravenous adenosine administered during the early reperfusion period. Circulation. 1991;83:237–47.

    Article  PubMed  Google Scholar 

  62. Homeister JW, Hoff PT, Fletcher DD, Lucchesi BR. Combined adenosine and lidocaine administration limits myocardial reperfusion injury. Circulation. 1990;82:595–608.

    Article  PubMed  CAS  Google Scholar 

  63. Marzilli M, Orsini E, Marraccini P, Testa R. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation. 2000;101:2154–9.

    Article  PubMed  CAS  Google Scholar 

  64. Taniyama Y, Ito H, Iwakura K, et al. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction. J Am Coll Cardiol. 1997;30:1193–9.

    Article  PubMed  CAS  Google Scholar 

  65. Galiuto I, DeMaria AN, del Balzo U, et al. Ischemia-reperfusion injury at the microvascular level treatment by endothelin-A selective antagonist and evaluation by myocardial contrast echocardiography. Circulation. 2000;102:311–3116.

    Article  Google Scholar 

  66. Amado LC, Kraitchman DL, Gerber BL, et al. Reduction of “no-reflow” phenomenon by intra-aortic balloon counterpulsation in a randomized magnetic resonance imaging experimental study. J Am Coll Cardiol. 2004;43:1291–8.

    Article  PubMed  Google Scholar 

  67. Hale SL, Mehra A, Leeka J, Kloner RA. Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2008;294:H421–5.

    Article  PubMed  CAS  Google Scholar 

  68. Yang YJ, Zhao JL, You SJ, et al. Different effects of tirofiban and aspirin plus clopidogrel on myocardial no-reflow in a mini-swine model of acute myocardial infarction ad reperfusion. Heart. 2006;92:1131–8.

    Article  PubMed  CAS  Google Scholar 

  69. Hale SL, Kloner RA. Cardioprotection with adenosine-regulating agent, GP531: effects on no-reflow, infarct size, and blood flow following ischemia/reperfusion in the rabbit. J Cardiovasc Pharmacol Ther. 2010;15:60–7.

    Article  PubMed  CAS  Google Scholar 

  70. Reffelmann T, Hale SL, Dow JS, Kloner RA. No-reflow phenomenon persists long-term after ischemia/reperfusion in the rat and predicts infarct expansion. Circulation. 2003;108:2911–7.

    Article  PubMed  Google Scholar 

  71. Hamm CW, Heeschen C, Goldman B, et al. Benefits of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med. 1999;340:1623–9.

    Article  PubMed  CAS  Google Scholar 

  72. Deibele AJ, Jennings LK, Tcheng JE, Neva C, Earhart AD, Gibson CM. Intracoronary eptifibatide bolus administration during percutaneous coronary revascularization for acute coronary syndromes with evaluation of platelet glycoprotein IIb/IIIa receptor occupancy and platelet function: the Intracoronary Eptifibatide (ICE) Trial. Circulation. 2010;121:784–91.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik und Poliklinik fur Innere Medizin B, Universitatsklinik der Ernst-Moritz-Amdt-Universitat Greifswald, Friedrich-Loffler-Str.23a, Greifswald, 17485, Germany

    Thorsten Reffelmann M.D.

  2. Department of Medicine, Division of Cardiovascular Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA

    Robert A. Kloner M.D., Ph.D.

  3. The Heart Institute, Good Samaritan Hospital, Los Angeles, CA, USA

    Robert A. Kloner M.D., Ph.D.

  4. Division of Cardiology, Keck School of Medicine, University of Southern California, 1225 Wilshire Blvd., Los Angeles, 90017-2395, CA, USA

    Robert A. Kloner M.D., Ph.D.

Authors
  1. Thorsten Reffelmann M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert A. Kloner M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thorsten Reffelmann M.D. .

Editor information

Editors and Affiliations

  1. Medical School, Coronary Artery Disease, Research Group, St George's Hospital, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Juan Carlos Kaski

  2. Hatter Cardiovascular Inst., Div. Medicine, University College London, Chenies Mews 67, London, WC1E 6HX, United Kingdom

    Derek J. Hausenloy

  3. Mayo Graduate School of Medicine, Dept. Cardiovascular Diseases, Mayo Clinic, First Street SW. 200, Rochester, 55905, Minnesota, USA

    Bernard John Gersh

  4. Hatter Cardiovascular Institute, University College London, Chenies Mews 67, London, WC1E 6HX, United Kingdom

    Derek M. Yellon

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag London

About this chapter

Cite this chapter

Reffelmann, T., Kloner, R.A. (2012). Microvascular Obstruction: The No-Reflow Phenomenon in Animal Models of Myocardial Ischemia and Reperfusion. In: Kaski, J., Hausenloy, D., Gersh, B., Yellon, D. (eds) Management of Myocardial Reperfusion Injury. Springer, London. https://doi.org/10.1007/978-1-84996-019-9_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-84996-019-9_3

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-84996-018-2

  • Online ISBN: 978-1-84996-019-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation