Basic Research in Cardiology

, Volume 103, Issue 2, pp 95–104 | Cite as

Annexin A5: an imaging biomarker of cardiovascular risk

  • Edward M. Laufer
  • Chris P. M. Reutelingsperger
  • Jagat Narula
  • Leonard HofstraEmail author


Apoptosis, a form of programmed cell death (PCD), plays an important role in the initiation and progression of a number of cardiovascular disease, such as heart failure, myocardial infarction, and atherosclerosis. One of the most prominent characteristics of apoptosis is the externalisation of phosphatidylserine (PS), a plasma cell membrane phospholipid, which in healthy cells only is present on the inner leaflet of the plasma cell membrane. Annexin A5, a 35 kD plasma protein, has strong affinity for PS in the nano-molar range. Through the coupling of Annexin A5 to contrast agents, visualization of apoptotic cell death in vivo in animal models and in patients has become feasible. These imaging studies have provided novel insight into the extent and kinetics of apoptosis in cardiovascular disease. Furthermore, Annexin A5 imaging has proven to be a suitable imaging biomarker for the evaluation of cell death modifying compounds and plaque stabilizing strategies. Recent insight in PS biology has shown that PS externalisation not only occurs in apoptosis, but is also observed in activated macrophages and stressed cells. In addition, it has been shown that Annexin A5 not only binds to exteriorized PS, but is also internalized through an Annexin A5 specific mechanism. These latter findings indicate that Annexin A5 imaging is not exclusively valuable for apoptosis detection, but can also be used to visualize inflammation and cell stress. This will open novel opportunities for imaging and drug delivery strategies. In this review we will discuss the introduction of Annexin A5 in preclinical and clinical imaging studies and provide an outlook on novel opportunities of Annexin A5 based targeting of PS.

Key words

Annexin A5 apoptosis unstable plaque cardiovascular risk imaging 


Conflict of Interest



  1. 1.
    Bialik S, Geenen DL, Sasson IE, Cheng R, Horner JW, Evans SM, Lord EM, Koch CJ, Kitsis RN (1997) Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. J Clin Invest 100:1363–1372PubMedCrossRefGoogle Scholar
  2. 2.
    Bonow RO (2003) The challenge of balancing scientific discovery and translation. Circulation 107:358–362PubMedCrossRefGoogle Scholar
  3. 3.
    Bonow RO (2002) Primary prevention of cardiovascular disease: a call to action. Circulation 106:3140–3141PubMedCrossRefGoogle Scholar
  4. 4.
    Bonow RO, Smaha LA, Smith SC Jr., Mensah GA, Lenfant C (2002) World Heart Day 2002: the international burden of cardiovascular disease: responding to the emerging global epidemic. Circulation 106:1602–1605PubMedCrossRefGoogle Scholar
  5. 5.
    Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R (1997) Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 336:1276–1282PubMedCrossRefGoogle Scholar
  6. 6.
    Davies JR, Rudd JH, Weissberg PL, Narula J (2006) Radionuclide imaging for the detection of inflammation in vulnerable plaques. J Am Coll Cardiol 47:C57–C68PubMedCrossRefGoogle Scholar
  7. 7.
    Dumont EA, Reutelingsperger CP, Smits JF, Daemen MJ, Doevendans PA, Wellens HJ, Hofstra L (2001) Real-time imaging of apoptotic cell-membrane changes at the single-cell level in the beating murine heart. Nat Med 7:1352–1355PubMedCrossRefGoogle Scholar
  8. 8.
    Garg S, Hofstra L, Reutelingsperger C, Narula J (2003) Apoptosis as a therapeutic target in acutely ischemic myocardium. Curr Opin Cardiol 18:372–377PubMedCrossRefGoogle Scholar
  9. 9.
    Gheorghiade M, Sopko G, De Luca L, Velazquez EJ, Parker JD, Binkley PF, Sadowski Z, Golba KS, Prior DL, Rouleau JL, Bonow RO (2006) Navigating the crossroads of coronary artery disease and heart failure. Circulation 114:1202–1213PubMedCrossRefGoogle Scholar
  10. 10.
    Haider N, Narula N, Narula J (2002) Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling. J Card Fail 8:S512–S517PubMedCrossRefGoogle Scholar
  11. 11.
    Hartung D, Sarai M, Petrov A, Kolodgie F, Narula N, Verjans J, Virmani R, Reutelingsperger C, Hofstra L, Narula J (2005) Resolution of apoptosis in atherosclerotic plaque by dietary modification and statin therapy. J Nucl Med 46:2051–2056PubMedGoogle Scholar
  12. 12.
    Hayakawa Y, Chandra M, Miao W, Shirani J, Brown JH, Dorn GW 2nd, Armstrong RC, Kitsis RN (2003) Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation 108:3036–3041PubMedCrossRefGoogle Scholar
  13. 13.
    Hofstra L, Liem IH, Dumont EA, Boersma HH, van Heerde WL, Doevendans PA, De Muinck E, Wellens HJ, Kemerink GJ, Reutelingsperger CP, Heidendal GA (2000) Visualisation of cell death in vivo in patients with acute myocardial infarction. Lancet 356:209–212PubMedCrossRefGoogle Scholar
  14. 14.
    Jaffer FA, Libby P, Weissleder R (2006) Molecular and cellular imaging of atherosclerosis: emerging applications. J Am Coll Cardiol 47:1328–1338PubMedCrossRefGoogle Scholar
  15. 15.
    Jaffer FA, Weissleder R (2005) Molecular imaging in the clinical arena. Jama 293:855–862PubMedCrossRefGoogle Scholar
  16. 16.
    Johnson LL, Schofield L, Donahay T, Narula N, Narula J (2005) 99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. J Nucl Med 46:1186–1193PubMedGoogle Scholar
  17. 17.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  18. 18.
    Kietselaer BL, Reutelingsperger CP, Boersma HH, Heidendal GA, Liem IH, Crijns HJ, Narula J, Hofstra L (2007) Noninvasive detection of programmed cell loss with 99mTc-labeled annexin A5 in heart failure. J Nucl Med 48:562–567PubMedCrossRefGoogle Scholar
  19. 19.
    Kietselaer BL, Reutelingsperger CP, Heidendal GA, Daemen MJ, Mess WH, Hofstra L, Narula J (2004) Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med 350:1472–1473PubMedCrossRefGoogle Scholar
  20. 20.
    Kitsis RN, Mann DL (2005) Apoptosis and the heart: a decade of progress. J Mol Cell Cardiol 38:1–2PubMedCrossRefGoogle Scholar
  21. 21.
    Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, Farb A, Guerrero LJ, Hayase M, Kutys R, Narula J, Finn AV, Virmani R (2003) Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 349:2316–2325PubMedCrossRefGoogle Scholar
  22. 22.
    Kolodgie FD, Narula J, Burke AP, Haider N, Farb A, Hui-Liang Y, Smialek J, Virmani R (2000) Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 157:1259–1268PubMedGoogle Scholar
  23. 23.
    Kolodgie FD, Petrov A, Virmani R, Narula N, Verjans JW, Weber DK, Hartung D, Steinmetz N, Vanderheyden JL, Vannan MA, Gold HK, Reutelingsperger CP, Hofstra L, Narula J (2003) Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: a technique with potential for noninvasive imaging of vulnerable plaque. Circulation 108:3134–3139PubMedCrossRefGoogle Scholar
  24. 24.
    Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, van Oers MH (1994) Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 84:1415–1420PubMedGoogle Scholar
  25. 25.
    Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874PubMedCrossRefGoogle Scholar
  26. 26.
    Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143PubMedCrossRefGoogle Scholar
  27. 27.
    Libby P, Theroux P (2005) Pathophysiology of coronary artery disease. Circulation 111:3481–3488PubMedCrossRefGoogle Scholar
  28. 28.
    Naghavi M, Falk E, Hecht HS, Jamieson MJ, Kaul S, Berman D, Fayad Z, Budoff MJ, Rumberger J, Naqvi TZ, Shaw LJ, Faergeman O, Cohn J, Bahr R, Koenig W, Demirovic J, Arking D, Herrera VL, Badimon J, Goldstein JA, Rudy Y, Airaksinen J, Schwartz RS, Riley WA, Mendes RA, Douglas P, Shah PK (2006) From vulnerable plaque to vulnerable patient–Part III: executive summary of the screening for heart attack prevention and education (SHAPE) task force report. Am J Cardiol 98:2H–15HPubMedCrossRefGoogle Scholar
  29. 29.
    Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, Badimon JJ, Stefanadis C, Moreno P, Pasterkamp G, Fayad Z, Stone PH, Waxman S, Raggi P, Madjid M, Zarrabi A, Burke A, Yuan C, Fitzgerald PJ, Siscovick DS, de Korte CL, Aikawa M, Airaksinen KE, Assmann G, Becker CR, Chesebro JH, Farb A, Galis ZS, Jackson C, Jang IK, Koenig W, Lodder RA, March K, Demirovic J, Navab M, Priori SG, Rekhter MD, Bahr R, Grundy SM, Mehran R, Colombo A, Boerwinkle E, Ballantyne C, Insull W Jr., Schwartz RS, Vogel R, Serruys PW, Hansson GK, Faxon DP, Kaul S, Drexler H, Greenland P, Muller JE, Virmani R, Ridker PM, Zipes DP, Shah PK, Willerson JT (2003) From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 108:1772–1778PubMedCrossRefGoogle Scholar
  30. 30.
    Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, Khaw BA (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189PubMedCrossRefGoogle Scholar
  31. 31.
    Narula J, Strauss HW (2003) Invited commentary: P.S.* I love you: implications of phosphatidyl serine (PS) reversal in acute ischemic syndromes. J Nucl Med 44:397–399PubMedGoogle Scholar
  32. 32.
    Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O’Shaughnessy C, Ganz P (2005) Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 352:29–38PubMedCrossRefGoogle Scholar
  33. 33.
    Pfeffer MA, Braunwald E (1990) Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81:1161–1172PubMedGoogle Scholar
  34. 34.
    Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell CJ, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y (2007) Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115:e69–e171PubMedCrossRefGoogle Scholar
  35. 35.
    Thimister PW, Hofstra L, Liem IH, Boersma HH, Kemerink G, Reutelingsperger CP, Heidendal GA (2003) In vivo detection of cell death in the area at risk in acute myocardial infarction. J Nucl Med 44:391–396PubMedGoogle Scholar
  36. 36.
    van Kimmenade RR, Januzzi JL Jr., Baggish AL, Lainchbury JG, Bayes-Genis A, Richards AM, Pinto YM (2006) Amino-terminal pro-brain natriuretic peptide, renal function, and outcomes in acute heart failure: redefining the cardiorenal interaction? J Am Coll Cardiol 48:1621–1627PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Edward M. Laufer
    • 1
  • Chris P. M. Reutelingsperger
    • 1
    • 3
  • Jagat Narula
    • 1
    • 4
  • Leonard Hofstra
    • 1
    • 2
    Email author
  1. 1.Dept. of CardiologyUniversity of MaastrichtMaastrichtThe Netherlands
  2. 2.Dept. of CardiologyThe NetherlandsMaastrichtNetherlands
  3. 3.Dept. of BiochemistryUniversity of MaastrichtMaastrichtThe Netherlands
  4. 4.Dept. of Cardiology, Irvine Medical CenterUniversity of CaliforniaOrangeUSA

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