Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Intramyocardial haemorrhage after acute myocardial infarction

Key Points

  • Intramyocardial haemorrhage arises owing to impairment of microvascular function and myocardial perfusion after reperfusion therapy, despite restoration of epicardial vessel patency

  • This major adverse event is associated with large infarct size, adverse left ventricular remodelling, major adverse cardiac events, and death

  • Although intramyocardial haemorrhage has been recognized since the early 1960s, the pathophysiology remains largely unclear

  • During thrombotic occlusion of a coronary artery, cleavage of adherence and tight-junction proteins in the ischaemic endothelium occurs, which leads to extravasation of erythrocytes into the myocardium upon reperfusion

  • Potential therapeutic strategies for the prevention or attenuation of intramyocardial haemorrhage will include protection of the microvasculature or adjustments to reperfusion

Abstract

In patients with acute myocardial infarction (AMI), the guideline-recommended treatment is mechanical revascularization by percutaneous coronary intervention (PCI), which is effective at reducing mortality. However, a substantial proportion of patients with AMI develop chronic cardiac failure owing to poor restoration of microvascular function and myocardial perfusion, despite restoration of epicardial vessel patency. This occurrence is called the 'no-reflow' phenomenon. Although pathological and clinical observations initially seemed to support the hypothesis that no-reflow was the result of microvascular obstruction, irreversible microvascular injury and subsequent intramyocardial haemorrhage are now also thought to be important factors in this process. Intramyocardial haemorrhage shares several pathophysiological features with the haemorrhagic transformation that occurs after ischaemic stroke. Understanding of the role of intramyocardial haemorrhage in the no-reflow phenomenon and myocardial injury is crucial to the development of new therapeutic strategies to treat AMI. In this Review, we provide a comprehensive overview of the pathogenesis and clinical relevance of intramyocardial haemorrhage, and discuss diagnostic options and future therapeutic strategies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Possible mechanisms underlying the development of intramyocardial haemorrhage.
Figure 2: Histopathological differences between the core and border zones in infarcted porcine myocardium.
Figure 3: Intramyocardial haemorrhage on cardiac MRI.

References

  1. 1

    Levi, F., Lucchini, F., Negri, E. & La Vecchia, C. Trends in mortality from cardiovascular and cerebrovascular diseases in Europe and other areas of the world. Heart 88, 119–124 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Rezkalla, S. H., Dharmashankar, K. C., Abdalrahman, I. B. & Kloner, R. A. No-reflow phenomenon following percutaneous coronary intervention for acute myocardial infarction: incidence, outcome, and effect of pharmacologic therapy. J. Interv. Cardiol. 23, 429–436 (2010).

    Article  PubMed  Google Scholar 

  3. 3

    Kloner, R. A., Ganote, C. E. & Jennings, R. B. The no-reflow phenomenon after temporary coronary occlusion in the dog. J. Clin. Invest. 54, 1496–1508 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Haeck, J. D. et al. Randomized comparison of primary percutaneous coronary intervention with combined proximal embolic protection and thrombus aspiration versus primary percutaneous coronary intervention alone in ST-segment elevation myocardial infarction: the PREPARE (PRoximal Embolic Protection in Acute myocardial infarction and Resolution of ST-Elevation) study. JACC Cardiovasc. Interv. 2, 934–943 (2009).

    Article  PubMed  Google Scholar 

  5. 5

    Mongeon, F. P., Bélisle, P., Joseph, L., Eisenberg, M. J. & Rinfret, S. Adjunctive thrombectomy for acute myocardial infarction: a bayesian meta-analysis. Circ. Cardiovasc. Interv. 3, 6–16 (2010).

    Article  PubMed  Google Scholar 

  6. 6

    Wu, X. et al. The relationship between attenuated plaque identified by intravascular ultrasound and no-reflow after stenting in acute myocardial infarction: the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc. Interv. 4, 495–502 (2011).

    Article  PubMed  Google Scholar 

  7. 7

    Limbruno, U. et al. Distal embolization during primary angioplasty: histopathologic features and predictability. Am. Heart J. 150, 102–108 (2005).

    Article  PubMed  Google Scholar 

  8. 8

    Falk, E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 71, 699–708 (1985).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Sakuma, T., Leong-Poi, H., Fisher, N. G., Goodman, N. C. & Kaul, S. Further insights into the no-reflow phenomenon after primary angioplasty in acute myocardial infarction: the role of microthromboemboli. J. Am. Soc. Echocardiogr. 16, 15–21 (2003).

    Article  PubMed  Google Scholar 

  10. 10

    Wu, K. C. CMR of microvascular obstruction and hemorrhage in myocardial infarction. J. Cardiovasc. Magn. Res. 14, 68 (2012).

    Article  Google Scholar 

  11. 11

    Amabile, N. et al. Incidence, predictors, and prognostic value of intramyocardial hemorrhage lesions in ST elevation myocardial infarction. Catheter. Cardiovasc. Interv. 79, 1101–1108 (2012).

    Article  PubMed  Google Scholar 

  12. 12

    Robbers, L. F. et al. Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Eur. Heart J. 34, 2346–2353 (2013).

    Article  CAS  Google Scholar 

  13. 13

    Ganame, J. et al. Impact of myocardial haemorrhage on left ventricular function and remodelling in patients with reperfused acute myocardial infarction. Eur. Heart J. 30, 1440–1449 (2009).

    Article  PubMed  Google Scholar 

  14. 14

    Husser, O. et al. Cardiovascular magnetic resonance-derived intramyocardial hemorrhage after STEMI: Influence on long-term prognosis, adverse left ventricular remodeling and relationship with microvascular obstruction. Int. J. Cardiol. 167, 2047–2054 (2012).

    Article  PubMed  Google Scholar 

  15. 15

    Ochiai, K. et al. Hemorrhagic myocardial infarction after coronary reperfusion detected in vivo by magnetic resonance imaging in humans: prevalence and clinical implications. J. Cardiovasc. Magn. Reson. 1, 247–256 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Asanuma, T. et al. Relationship between progressive microvascular damage and intramyocardial hemorrhage in patients with reperfused anterior myocardial infarction: myocardial contrast echocardiographic study. Circulation 96, 448–453 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Mather, A. N., Fairbairn, T. A., Ball, S. G., Greenwood, J. P. & Plein, S. Reperfusion haemorrhage as determined by cardiovascular MRI is a predictor of adverse left ventricular remodelling and markers of late arrhythmic risk. Heart 97, 453–459 (2011).

    Article  PubMed  Google Scholar 

  18. 18

    Cokic, I. et al. Iron deposition following chronic myocardial infarction as a substrate for cardiac electrical anomalies: initial findings in a canine model. PLoS ONE 8, e73193 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Goldfarb, J. W., Hasan, U., Zhao, W. & Han, J. Magnetic resonance susceptibility weighted phase imaging for the assessment of reperfusion intramyocardial hemorrhage. Magn. Reson. Med. 71, 1210–1220 (2014).

    Article  PubMed  Google Scholar 

  20. 20

    Kali, A. et al. Chronic manifestation of postreperfusion intramyocardial hemorrhage as regional iron deposition: a cardiovascular magnetic resonance study with ex vivo validation. Circ. Cardiovasc. Imaging 6, 218–228 (2013).

    Article  PubMed  Google Scholar 

  21. 21

    Vahanian, A. Thrombolytic therapy in Europe: current status. Eur. Heart J. 17 (Suppl. E), 21–27 (1996).

    Article  PubMed  Google Scholar 

  22. 22

    Mathey, D. G. et al. Improved survival up to four years after early coronary thrombolysis. Am. J. Cardiol. 61, 524–529 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Deloche, A. et al. Effect of coronary-artery reperfusion on extent of myocardial-infarction. Am. Heart J. 93, 358–366 (1977).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    Jennings, R. B., Sommers, H. M., Smyth, G. A., Flack, H. A. & Linn., N. H. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch. Pathol. 70, 68–78 (1960).

    CAS  PubMed  Google Scholar 

  25. 25

    Braunwald, E. & Kloner, R. A. Myocardial reperfusion: a double-edged sword? J. Clin. Invest. 76, 1713–1719 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Maxwell, L. & Gavin, J. B. The role of post-ischaemic reperfusion in the development of microvascular incompetence and ultrastructural damage in the myocardium. Basic Res. Cardiol. 86, 544–553 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Nevalainen, T. J., Armiger, L. C. & Gavin, J. B. Effects of ischaemia on vasculature. J. Mol. Cell. Cardiol. 18 (Suppl. 4), 7–10 (1986).

    Article  PubMed  Google Scholar 

  28. 28

    Bresnahan, G. F., Roberts, R., Shell, W. E., Ross, J. Jr & Sobel, B. E. Deleterious effects due to hemorrhage after myocardial reperfusion. Am. J. Cardiol. 33, 82–86 (1974).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Kloner, R. A. et al. Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion. Circulation 84, 1758–1772 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Ambrosio, G., Weisman, H. F., Mannisi, J. A. & Becker, L. C. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation 80, 1846–1861 (1989).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Tsao, P. S., Aoki, N., Lefer, D. J., Johnson, G. III & Lefer, A. M. Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. Circulation 82, 1402–1412 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Zaman, A. K., French, C. J., Spees, J. L., Binbrek, A. S. & Sobel, B. E. Vascular rhexis in mice subjected to non-sustained myocardial ischemia and its therapeutic implications. Exp. Biol. Med. (Maywood) 236, 598–603 (2011).

    Article  CAS  Google Scholar 

  33. 33

    French, C. J., Zaman, A. K. M. T., Kelm, R. J. Jr Spees, J. L. & Sobel, B. E. Vascular rhexis: loss of integrity of coronary vasculature in mice subjected to myocardial infarction. Exp. Biol. Med. (Maywood) 235, 966–973 (2010).

    Article  CAS  Google Scholar 

  34. 34

    Goddard, L. M. & Iruela-Arispe, M. L. Cellular and molecular regulation of vascular permeability. Thromb. Haemost. 109, 407–415 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Frohlich, G. M., Meier, P., White, S. K., Yellon, D. M. & Hausenloy, D. J. Myocardial reperfusion injury: looking beyond primary PCI. Eur. Heart J. 34, 1714–1722 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Augustin, H. G., Koh, G. Y., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat. Rev. Mol. Cell Biol. 10, 165–177 (2009).

    Article  CAS  Google Scholar 

  37. 37

    Benest, A. V. et al. Angiopoietin-2 is critical for cytokine-induced vascular leakage. PLoS ONE 8, e70459 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Fiedler, U. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 103, 4150–4156 (2004).

    Article  CAS  Google Scholar 

  39. 39

    Felcht, M. et al. Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J. Clin. Invest. 122, 1991–2005 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Galaup, A. et al. Protection against myocardial infarction and no-reflow through preservation of vascular integrity by angiopoietin-like 4. Circulation 125, 140–149 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Bouleti, C. et al. Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke. Eur. Heart J. 34, 3657–3668 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Roy, D. et al. Role of reactive oxygen species on the formation of the novel diagnostic marker ischaemia modified albumin. Heart 92, 113–114 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Rodrigo, R., Libuy, M., Feliú, F. & Hasson, D. Oxidative stress-related biomarkers in essential hypertension and ischemia-reperfusion myocardial damage. Dis. Markers 35, 773–790 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Eitel, I. et al. Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging. Am. Heart J. 159, 882–890 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Kurnik, P. B., Courtois, M. R. & Ludbrook, P. A. Diastolic stiffening induced by acute myocardial infarction is reduced by early reperfusion. J. Am. Coll. Cardiol. 12, 1029–1036 (1988).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Ghugre, N. R., Pop, M., Barry, J., Connelly, K. A. & Wright, G. A. Quantitative magnetic resonance imaging can distinguish remodeling mechanisms after acute myocardial infarction based on the severity of ischemic insult. Magn. Reson. Med. 70, 1095–1105 (2013).

    Article  PubMed  Google Scholar 

  47. 47

    Garcia-Dorado, D. et al. Determinants of hemorrhagic infarcts. Histologic observations from experiments involving coronary occlusion, coronary reperfusion, and reocclusion. Am. J. Pathol. 137, 301–311 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Fishbein, M. C. et al. The relationship of vascular injury and myocardial hemorrhage to necrosis after reperfusion. Circulation 62, 1274–1279 (1980).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Willerson, J. T. et al. Abnormal myocardial fluid retention as an early manifestation of ischemic injury. Am. J. Pathol. 87, 159–188 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Reffelmann, T. & Kloner, R. A. Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit. Am. J. Physiol. Heart Circ. Physiol. 283, H1099–H1107 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    Higginson, L. A. et al. Determinants of myocardial hemorrhage after coronary reperfusion in the anesthetized dog. Circulation 65, 62–69 (1982).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Basso, C. & Thiene, G. The pathophysiology of myocardial reperfusion: a pathologist's perspective. Heart 92, 1559–1562 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Olafsson, B. et al. Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon. Circulation 76, 1135–1145 (1987).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    Kumar, A. et al. Detection and quantification of myocardial reperfusion hemorrhage using T2*-weighted CMR. JACC Cardiovasc. Imaging 4, 1274–1283 (2011).

    Article  PubMed  Google Scholar 

  55. 55

    Marra, M. P. et al. The contribution of intramyocardial hemorrhage to the “no-reflow phenomenon”: a study performed by cardiac magnetic resonance. Echocardiography 27, 1120–1129 (2010).

    Article  PubMed  Google Scholar 

  56. 56

    Pislaru, S. V. et al. Infarct size, myocardial hemorrhage, and recovery of function after mechanical versus pharmacological reperfusion: effects of lytic state and occlusion time. Circulation 96, 659–666 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Capone, R. J. & Most, A. S. Myocardial hemorrhage after coronary reperfusion in pigs. Am. J. Cardiol. 41, 259–266 (1978).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Mathur, V. S., Guinn, G. A. & Burris, W. H. Maximal revascularization (reperfusion) in intact conscious dogs after 2 to 5 hours of coronary-occlusion. Am. J. Cardiol. 36, 252–261 (1975).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    Kloner, R. A., Ganote, C. E., Jennings, R. B. & Reimer, K. A. Demonstration of the “no-reflow” phenomenon in the dog heart after temporary ischemia. Recent Adv. Stud. Cardiac Struct. Metab. 10, 463–474 (1975).

    CAS  PubMed  Google Scholar 

  60. 60

    Chappell, D. et al. Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc. Res. 83, 388–396 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Maksimenko, A. V. & Turashev, A. D. No-reflow phenomenon and endothelial glycocalyx of microcirculation. Biochem. Res. Int. 2012, 859231 (2012).

    Article  PubMed  Google Scholar 

  62. 62

    Kloner, R. A. Does reperfusion injury exist in humans. J. Am. Coll. Cardiol. 21, 537–545 (1993).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Kloner, R. A. et al. Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first? Circulation 62, 945–952 (1980).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    van der Pouw Kraan, T. C. et al. Systemic toll-like receptor and interleukin-18 pathway activation in patients with acute ST elevation myocardial infarction. J. Mol. Cell. Cardiol. 67, 94–102 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Burger, D. & Touyz, R. M. Cellular biomarkers of endothelial health: microparticles, endothelial progenitor cells, and circulating endothelial cells. J. Am. Soc. Hypertens. 6, 85–99 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Laskowitz, D. T., Kasner, S. E., Saver, J., Remmel, K. S. & Jauch, E. C. Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study. Stroke 40, 77–85 (2009).

    Article  PubMed  Google Scholar 

  67. 67

    Jugdutt, B. I. et al. Aging-related early changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model: effect of early therapy with an angiotensin II type 1 receptor blocker. Circulation 122, 341–351 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Dignat-George, F. & Boulanger, C. M. The many faces of endothelial microparticles. Arterioscler. Thromb. Vasc. Biol. 31, 27–33 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Maroko, P. R. et al. Coronary-artery reperfusion. I. Early effects on local myocardial function and extent of myocardial necrosis. J. Clin. Invest. 51, 2710–2716 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Ginks, W. R. et al. Coronary-artery reperfusion. II. Reduction of myocardial infarct size at 1 week after coronary occlusion. J. Clin. Invest. 51, 2717–2723 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Viehman, G. E., Ma, X. L., Lefer, D. J. & Lefer, A. M. Time course of endothelial dysfunction and myocardial injury during coronary arterial occlusion. Am. J. Physiol. 261, H874–H881 (1991).

    CAS  PubMed  Google Scholar 

  72. 72

    Lang, T. W. et al. Consequences of reperfusion after coronary-occlusion—effects on hemodynamic and regional myocardial metabolic function. Am. J. Cardiol. 33, 69–81 (1974).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Morishima, I. et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J. Am. Coll. Cardiol. 36, 1202–1209 (2000).

    Article  CAS  Google Scholar 

  74. 74

    Haeck, J. D. et al. Proximal embolic protection in patients undergoing primary angioplasty for acute myocardial infarction (PREPARE): core lab adjudicated angiographic outcomes of a randomised controlled trial. Neth. Heart J. 18, 531–536 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Echavarría-Pinto, M. et al. Safety and efficacy of intense antithrombotic treatment and percutaneous coronary intervention deferral in patients with large intracoronary thrombus. Am. J. Cardiol. 111, 1745–1750 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Sezer, M. et al. Intracoronary streptokinase after primary percutaneous coronary intervention. N. Engl. J. Med. 356, 1823–1834 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Reimer, K. A., Lowe, J. E., Rasmussen, M. M. & Jennings, R. B. Wavefront phenomenon of ischemic cell-death. 1. Myocardial infarct size vs duration of coronary-occlusion in dogs. Circulation 56, 786–794 (1977).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    McNamara, J. J., Lacro, R. V., Yee, M. & Smith, G. T. Hemorrhagic infarction and coronary reperfusion. J. Thorac. Cardiovasc. Surg. 81, 498–501 (1981).

    CAS  PubMed  Google Scholar 

  79. 79

    Driesen, R. B. et al. Histological correlate of a cardiac magnetic resonance imaged microvascular obstruction in a porcine model of ischemia-reperfusion. Cardiovasc. Pathol. 21, 129–131 (2012).

    Article  PubMed  Google Scholar 

  80. 80

    Gertz, S. D., Kalan, J. M., Kragel, A. H., Roberts, W. C. & Braunwald, E. Cardiac morphologic findings in patients with acute myocardial infarction treated with recombinant tissue plasminogen activator. Am. J. Cardiol. 65, 953–961 (1990).

    Article  CAS  PubMed  Google Scholar 

  81. 81

    Fujiwara, H. et al. A clinicopathologic study of patients with hemorrhagic myocardial infarction treated with selective coronary thrombolysis with urokinase. Circulation 73, 749–757 (1986).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Mathey, D. G., Schofer, J., Kuck, K. H., Beil, U. & Klöppel, G. Transmural, haemorrhagic myocardial infarction after intracoronary streptokinase. Clinical, angiographic, and necropsy findings. Br. Heart J. 48, 546–551 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Matsuda, M. et al. Quantitative analysis of infarct size, contraction band necrosis, and coagulation necrosis in human autopsied hearts with acute myocardial infarction after treatment with selective intracoronary thrombolysis. Circulation 76, 981–989 (1987).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    Wu, D. J. et al. Clinicopathological study of myocardial infarction with normal or nearly normal extracardiac coronary arteries. Quantitative analysis of contraction band necrosis, coagulation necrosis, hemorrhage, and infarct size. Heart Vessels 6, 55–62 (1990).

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Waller, B. F. et al. Status of the myocardium and infarct-related coronary artery in 19 necropsy patients with acute recanalization using pharmacologic (streptokinase, r-tissue plasminogen activator), mechanical (percutaneous transluminal coronary angioplasty) or combined types of reperfusion therapy. J. Am. Coll. Cardiol. 9, 785–801 (1987).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Topol, E. J., Herskowitz, A. & Hutchins, G. M. Massive hemorrhagic myocardial-infarction after coronary thrombolysis. Am. J. Med. 81, 339–343 (1986).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Kali, A., Tang, R. L., Kumar, A., Min, J. K. & Dharmakumar, R. Detection of acute reperfusion myocardial hemorrhage with cardiac mr imaging: T2 versus T2*. Radiology 269, 387–395 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Kidambi, A. et al. The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 15, 58 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Beek, A. M., Nijveldt, R. & van Rossum, A. C. Intramyocardial hemorrhage and microvascular obstruction after primary percutaneous coronary intervention. Int. J. Cardiovasc. Imaging 26, 49–55 (2010).

    Article  CAS  Google Scholar 

  90. 90

    Nordmann, A. J., Bucher, H., Hengstler, P., Harr, T. & Young, J. Primary stenting versus primary balloon angioplasty for treating acute myocardial infarction. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD005313. http://dx.doi.org/10.1002/14651858.CD005313.

  91. 91

    Ito, H. et al. Clinical implications of the 'no reflow' phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 93, 223–228 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Ndrepepa, G. et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J. Am. Coll. Cardiol. 55, 2383–2389 (2010).

    Article  PubMed  Google Scholar 

  93. 93

    Payne, A. R. et al. Bright-blood T2-weighted MRI has higher diagnostic accuracy than dark-blood short tau inversion recovery MRI for detection of acute myocardial infarction and for assessment of the ischemic area at risk and myocardial salvage. Circ. Cardiovasc. Imaging 4, 210–219 (2011).

    Article  PubMed  Google Scholar 

  94. 94

    Choi, S. H. et al. Investigation of T2-weighted signal intensity of infarcted myocardium and its correlation with delayed enhancement magnetic resonance imaging in a porcine model with reperfused acute myocardial infarction. Int. J. Cardiovasc. Imaging 25 (Suppl. 1), 111–119 (2009).

    Article  PubMed  Google Scholar 

  95. 95

    Pedersen, S. F. et al. Assessment of intramyocardial hemorrhage by T1-weighted cardiovascular magnetic resonance in reperfused acute myocardial infarction. J. Cardiovasc. Magn. Reson. 14, 59 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    O'Regan, D. P. et al. Assessment of severe reperfusion injury with T2* cardiac MRI in patients with acute myocardial infarction. Heart 96, 1885–1891 (2010).

    Article  PubMed  Google Scholar 

  97. 97

    Bradley, W. G. Jr MR appearance of hemorrhage in the brain. Radiology 189, 15–26 (1993).

    Article  PubMed  Google Scholar 

  98. 98

    Basso, C. et al. Morphologic validation of reperfused hemorrhagic myocardial infarction by cardiovascular magnetic resonance. Am. J. Cardiol. 100, 1322–1327 (2007).

    Article  PubMed  Google Scholar 

  99. 99

    Bekkers, S. C. et al. Clinical implications of microvascular obstruction and intramyocardial haemorrhage in acute myocardial infarction using cardiovascular magnetic resonance imaging. Eur. Radiol. 20, 2572–2578 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Eitel, I. et al. Prognostic value and determinants of a hypointense infarct core in T2-weighted cardiac magnetic resonance in acute reperfused ST-elevation-myocardial infarction. Circ. Cardiovasc. Imaging 4, 354–362 (2011).

    Article  Google Scholar 

  101. 101

    Weaver, J. C. et al. Dynamic changes in ST segment resolution after myocardial infarction and the association with microvascular injury on cardiac magnetic resonance imaging. Heart Lung Circ. 20, 111–118 (2011).

    Article  PubMed  Google Scholar 

  102. 102

    Malek, L. A. et al. Platelet reactivity and intramyocardial hemorrhage in patients with ST-segment elevation myocardial infarction. Clin. Appl. Thromb. Hemost. 20, 553–558 (2013).

    Article  PubMed  Google Scholar 

  103. 103

    Tritto, I., Zuchi, C., Vitale, S. & Ambrosio, G. Therapy against reperfusion-induced microvascular injury. Curr. Pharm. Des. 19, 4586–4596 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Foltz, W. D. et al. MRI relaxation fluctuations in acute reperfused hemorrhagic infarction. Magn. Reson. Med. 56, 1311–1319 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    White, S. K., Hausenloy, D. J. & Moon, J. C. Imaging the myocardial microcirculation post-myocardial infarction. Curr. Heart Fail. Rep. 9, 282–292 (2012).

    Article  Google Scholar 

  106. 106

    O'Regan, D. P. et al. Reperfusion hemorrhage following acute myocardial infarction: assessment with T2* mapping and effect on measuring the area at risk. Radiology 250, 916–922 (2009).

    Article  PubMed  Google Scholar 

  107. 107

    Bekkers, S. C. et al. Detection and characteristics of microvascular obstruction in reperfused acute myocardial infarction using an optimized protocol for contrast-enhanced cardiovascular magnetic resonance imaging. Eur. Radiol. 19, 2904–2912 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Bogaert, J., Kalantzi, M., Rademakers, F. E., Dymarkowski, S. & Janssens, S. Determinants and impact of microvascular obstruction in successfully reperfused ST-segment elevation myocardial infarction. Assessment by magnetic resonance imaging. Eur. Radiol. 17, 2572–2580 (2007).

    Article  PubMed  Google Scholar 

  109. 109

    Ye, Y. X. et al. Monitoring of monocyte recruitment in reperfused myocardial infarction with intramyocardial hemorrhage and microvascular obstruction by combined fluorine 19 and proton cardiac magnetic resonance imaging. Circulation 128, 1878–1888 (2013).

    Article  PubMed  Google Scholar 

  110. 110

    Wolfe, C. L. et al. Assessment of myocardial salvage after ischemia and reperfusion using magnetic resonance imaging and spectroscopy. Circulation 80, 969–982 (1989).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Ikeno, F., Inagaki, K., Rezaee, M. & Mochly-Rosen, D. Impaired perfusion after myocardial infarction is due to reperfusion-induced δPKC-mediated myocardial damage. Cardiovasc. Res. 73, 699–709 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. 112

    Higginson, L. A., Beanlands, D. S., Nair, R. C., Temple, V. & Sheldrick, K. The time course and characterization of myocardial hemorrhage after coronary reperfusion in the anesthetized dog. Circulation 67, 1024–1031 (1983).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Reffelmann, T., Hale, S. L., Li, G. & Kloner, R. A. Relationship between no reflow and infarct size as influenced by the duration of ischemia and reperfusion. Am. J. Physiol. Heart Circ. Physiol. 282, H766–H772 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    van der Hoeven, N. W. et al. Clinical parameters associated with collateral development in patients with chronic total coronary occlusion. Heart 99, 1100–1105 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Teunissen, P. F., Horrevoets, A. J. & van Royen, N. The coronary collateral circulation: genetic and environmental determinants in experimental models and humans. J. Mol. Cell. Cardiol. 52, 897–904 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Stork, A. et al. Characterization of the peri-infarction zone using T2-weighted MRI and delayed-enhancement MRI in patients with acute myocardial infarction. Eur. Radiol. 16, 2350–2357 (2006).

    Article  PubMed  Google Scholar 

  117. 117

    Tartan, Z. et al. Metabolic syndrome is a predictor for an ECG sign of no-reflow after primary PCI in patients with acute ST-elevation myocardial infarction. Nutr. Metab. Cardiovasc. Dis. 18, 441–447 (2008).

    Article  PubMed  Google Scholar 

  118. 118

    Copin, J. C. & Gasche, Y. Effect of the duration of middle cerebral artery occlusion on the risk of hemorrhagic transformation after tissue plasminogen activator injection in rats. Brain Res. 1243, 161–166 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Moulin, T., Crépin-Leblond, T., Chopard, J. L. & Bogousslavsky, J. Hemorrhagic infarcts. Eur. Neurol. 34, 64–77 (1994).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Alexandrov, A. V., Black, S. E., Ehrlich, L. E., Caldwell, C. B. & Norris, J. W. Predictors of hemorrhagic transformation occurring spontaneously and on anticoagulants in patients with acute ischemic stroke. Stroke 28, 1198–1202 (1997).

    Article  CAS  PubMed  Google Scholar 

  121. 121

    Molina, C. A. et al. Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke 32, 1079–1084 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Jickling, G. C. et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J. Cereb. Blood Flow Metab. 34, 185–199 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Sussman, E. S. & Connolly, E. S. Jr. Hemorrhagic transformation: a review of the rate of hemorrhage in the major clinical trials of acute ischemic stroke. Front. Neurol. 4, 69 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Jauch, E. C. et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44, 870–947 (2013).

    Article  PubMed  Google Scholar 

  125. 125

    Arboix, A. & Alio, J. Cardioembolic stroke: clinical features, specific cardiac disorders and prognosis. Curr. Cardiol. Rev. 6, 150–161 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Ames, A., Wright, R. L., Kowada, M., Thurston, J. M. & Majno, G. Cerebral ischemia. II. The no-reflow phenomenon. Am. J. Pathol. 52, 437–453 (1968).

    PubMed  PubMed Central  Google Scholar 

  127. 127

    Heusch, G. Reduction of infarct size by ischaemic post-conditioning in humans: fact or fiction? Eur. Heart J. 33, 13–15 (2012).

    Article  PubMed  Google Scholar 

  128. 128

    Garcia-Dorado, D. et al. Intracoronary infusion of superoxide dismutase and reperfusion injury in the pig heart. Basic Res. Cardiol. 85, 619–629 (1990).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Turer, A. T. & Hill, J. A. Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am. J. Cardiol. 106, 360–368 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Hausenloy, D. J. & Yellon, D. M. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J. Clin. Invest. 123, 92–100 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Yellon, D. M. & Hausenloy, D. J. Myocardial reperfusion injury. N. Engl. J. Med. 357, 1121–1135 (2007).

    Article  CAS  Google Scholar 

  132. 132

    Kloner, R. A. Current state of clinical translation of cardioprotective agents for acute myocardial infarction. Circ. Res. 113, 451–463 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Zhang, J. et al. Collagen-targeting vascular endothelial growth factor improves cardiac performance after myocardial infarction. Circulation 119, 1776–1784 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. 134

    Zan, L. et al. Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion. Neuroscience 262, 118–128 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Huang, R. L. et al. ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters. Blood 118, 3990–4002 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Sandhu, R. et al. Reciprocal regulation of angiopoietin-1 and angiopoietin-2 following myocardial infarction in the rat. Cardiovasc. Res. 64, 115–124 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. 137

    Lee, S. W. et al. Angiopoietin-1 protects heart against ischemia/reperfusion injury through VE-cadherin dephosphorylation and myocardiac integrin-β1/ERK/caspase-9 phosphorylation cascade. Mol. Med. 17, 1095–1106 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Inzitari, D. et al. MMP9 variation after thrombolysis is associated with hemorrhagic transformation of lesion and death. Stroke 44, 2901–2903 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    Hlatky, M. A. et al. Matrix metalloproteinase circulating levels, genetic polymorphisms, and susceptibility to acute myocardial infarction among patients with coronary artery disease. Am. Heart J. 154, 1043–1051 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Sumii, T. & Lo, E. H. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33, 831–836 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    Simpson, P. J., Fantone, J. C., Mickelson, J. K., Gallagher, K. P. & Lucchesi, B. R. Identification of a time window for therapy to reduce experimental canine myocardial injury—suppression of neutrophil activation during 72 hours of reperfusion. Circ. Res. 63, 1070–1079 (1988).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Litt, M. R., Jeremy, R. W., Weisman, H. F., Winkelstein, J. A. & Becker, L. C. Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia. Evidence for neutrophil-mediated reperfusion injury. Circulation 80, 1816–1827 (1989).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Romson, J. L. et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67, 1016–1023 (1983).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Okamura, K., Tsubokawa, T., Johshita, H., Miyazaki, H. & Shiokawa, Y. Edaravone, a free radical scavenger, attenuates cerebral infarction and hemorrhagic infarction in rats with hyperglycemia. Neurol. Res. 36, 65–69 (2014).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Feng, S. et al. Edaravone for acute ischaemic stroke. Cochrane Database of Systematic Reviews. Issue 12. Art. No.: CD007230. http://dx.doi.org/14651858.CD007230.pub2.

  146. 146

    Jang, J. W. et al. Melatonin reduced the elevated matrix metalloproteinase-9 level in a rat photothrombotic stroke model. J. Neurol. Sci. 323, 221–227 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Zhang, L. et al. Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats. J. Cereb. Blood Flow Metab. 29, 1816–1824 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Machado, L. S. et al. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 7, 56 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Slavic, S. et al. Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome. J. Mol. Med. (Berl.) 91, 811–823 (2013).

    Article  CAS  Google Scholar 

  150. 150

    Isahaya, K. et al. Effects of edaravone, a free radical scavenger, on serum levels of inflammatory biomarkers in acute brain infarction. J. Stroke Cerebrovasc. Dis. 21, 102–107 (2012).

    Article  PubMed  Google Scholar 

  151. 151

    Copin, J. C., Merlani, P., Sugawara, T., Chan, P. H. & Gasche, Y. Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats. Exp. Neurol. 213, 196–201 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  153. 153

    Lindahl, P., Johansson, B. R., Levéen, P. & Betsholtz, C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245 (1997).

    Article  CAS  PubMed  Google Scholar 

  154. 154

    Hellström, M. et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J. Cell Biol. 153, 543–553 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Hall, C. N. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Motiejūnaite, R. & Kazlauskas, A. Pericytes and ocular diseases. Exp. Eye Res. 86, 171–177 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. 157

    O'Farrell, F. M. & Attwell, D. A role for pericytes in coronary no-reflow. Nat. Rev. Cardiol. 11, 427–432 (2014).

    Article  PubMed  Google Scholar 

  158. 158

    Sato, H., Jordan, J. E., Zhao, Z. Q., Sarvotham, S. S. & Vinten-Johansen, J. Gradual reperfusion reduces infarct size and endothelial injury but augments neutrophil accumulation. Ann. Thorac. Surg. 64, 1099–1107 (1997).

    Article  CAS  PubMed  Google Scholar 

  159. 159

    Okamoto, F., Allen, B. S., Buckberg, G. D., Bugyi, H. & Leaf, J. Reperfusion conditions: importance of ensuring gentle versus sudden reperfusion during relief of coronary occlusion. J. Thorac. Cardiovasc. Surg. 92, 613–620 (1986).

    CAS  PubMed  Google Scholar 

  160. 160

    Heusch, G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381, 166–175 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  161. 161

    Bodi, V. et al. Effect of ischemic postconditioning on microvascular obstruction in reperfused myocardial infarction. Results of a randomized study in patients and of an experimental model in swine. Int. J. Cardiol. 175, 138–146 (2014).

    Article  PubMed  Google Scholar 

  162. 162

    Lindal, S. et al. Endothelial injury and trapping of blood cells in human myocardium following coronary bypass surgery. Scand. Cardiovasc. J. 33, 143–150 (1999).

    Article  CAS  PubMed  Google Scholar 

  163. 163

    Peng, C. F. et al. The adverse effect of systemic hypertension following myocardial reperfusion. J. Surg. Res. 34, 59–67 (1983).

    Article  CAS  PubMed  Google Scholar 

  164. 164

    Garcia-Dorado, D. et al. Diltiazem and progression of myocardial ischemic damage during coronary artery occlusion and reperfusion in porcine hearts. J. Am. Coll. Cardiol. 10, 906–911 (1987).

    Article  CAS  PubMed  Google Scholar 

  165. 165

    Nanas, J. N. et al. Moderate systemic hypotension during reperfusion reduces the coronary blood flow and increases the size of myocardial infarction in pigs. Chest 125, 1492–1499 (2004).

    Article  PubMed  Google Scholar 

  166. 166

    Kunadian, V. et al. Intracoronary pharmacotherapy in the management of coronary microvascular dysfunction. J. Thromb. Thrombolysis 26, 234–242 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. 167

    Ibanez, B. et al. The cardioprotection granted by metoprolol is restricted to its administration prior to coronary reperfusion. Int. J. Cardiol. 147, 428–432 (2011).

    Article  Google Scholar 

  168. 168

    Pizarro, G. et al. Long term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction). J. Am. Coll. Cardiol. 63, 2356–2362 (2014).

    Article  CAS  Google Scholar 

  169. 169

    Movahed, M. R. & Butman, S. M. The pathogenesis and treatment of no-reflow occurring during percutaneous coronary intervention. Cardiovasc. Revasc. Med. 9, 56–61 (2008).

    Article  PubMed  Google Scholar 

  170. 170

    Wolfe, C. L., Donnelly, T. J., Sievers, R. & Parmley, W. W. Myocardial protection with verapamil during ischemia and reperfusion: dissociation between myocardial salvage and the degree of ATP depletion during ischemia. Cardiovasc. Res. 25, 101–109 (1991).

    Article  CAS  PubMed  Google Scholar 

  171. 171

    Rousseau, G. et al. Diltiazem at reperfusion reduces neutrophil accumulation and infarct size in dogs with ischemic myocardium. Cardiovasc. Res. 25, 319–329 (1991).

    Article  CAS  PubMed  Google Scholar 

  172. 172

    Di Pasquale, P., Paterna, S., Cannizzaro, S. & Bucca, V. Does captopril treatment before thrombolysis in acute myocardial-infarction attenuate reperfusion damage short-term and long-term effects. Int. J. Cardiol. 43, 43–50 (1994).

    Article  CAS  PubMed  Google Scholar 

  173. 173

    O'Gara, P. T. et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 127, e362–e425 (2013).

    PubMed  Google Scholar 

  174. 174

    De Luca, G., Navarese, E. & Marino, P. Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials. Eur. Heart J. 30, 2705–2713 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175

    Petronio, A. S. et al. Impact of early abciximab administration on infarct size in patients with ST-elevation myocardial infarction. Int. J. Cardiol. 155, 230–235 (2012).

    Article  PubMed  Google Scholar 

  176. 176

    Buszman, P. P. et al. Controlled reperfusion with intravenous bivalirudin and intracoronary abciximab combination therapy in the porcine myocardial infarction model. Thromb. Res. 130, 265–272 (2012).

    Article  CAS  PubMed  Google Scholar 

  177. 177

    Rodríguez-González, R. et al. Platelet derived growth factor-CC isoform is associated with hemorrhagic transformation in ischemic stroke patients treated with tissue plasminogen activator. Atherosclerosis 226, 165–171 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. 178

    Fredriksson, L., Li, H., Fieber, C., Li, X. & Eriksson, U. Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J. 23, 3793–3802 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Li, X. et al. PDGF-C is a new protease-activated ligand for the PDGF α-receptor. Nat. Cell Biol. 2, 302–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Su, E. J. et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat. Med. 14, 731–737 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

R.P.B and G.A.d.W. contributed equally to this article. R.P.B. researched data for the article, made substantial contribution to discussion of the content, and wrote the manuscript. N.v.R. and G.A.d.W. made substantial contribution to discussion of the content, wrote, reviewed, and edited the manuscript before submission. R.N. and A.M.B. made substantial contribution to discussion of the content, reviewed, and edited the manuscript before submission. J.E. wrote, reviewed, and edited the manuscript before submission.

Corresponding author

Correspondence to Niels van Royen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Betgem, R., de Waard, G., Nijveldt, R. et al. Intramyocardial haemorrhage after acute myocardial infarction. Nat Rev Cardiol 12, 156–167 (2015). https://doi.org/10.1038/nrcardio.2014.188

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing