Tracing ischemic memory by metabolic pathways: BMIPP and beyond

Document Type : Review Article


Department of Nuclear Medicine & PET/CT, Amrita Institute of Medical Sciences, Cochin, Kerala, India


Myocardial ischemia (MI) resulting in infarction is an important cause of mortality and morbidity worldwide. Acute ischaemia rapidly impairs myocardial contractile function. Myocardial dysfunction persisting for several hours after transient non-lethal ischaemia, eventually resulting in full functional recovery is termed as myocardial stunning. Hibernation is now thought to be the consequence of repetitive bouts of ischaemia and stunning due to normally occurring increases in myocardial metabolic demand in the setting of significant coronary stenoses.We need robust investigations to identify and treat MI early. Myocardial perfusion imaging has established itself as the earliest investigation that can identify ischemia with or without infarction in an acute setting. However, recent data reveals that metabolic changes precede perfusion abnormalities during an ischemic or infarction episode; thus the renewed interest in the myocardial metabolic imaging. Concept of myocardial metabolic imaging is gaining momentum with the wider availability of positron emitting radio isotopes. Myocardial metabolism has been widely studied using 123I-BMIPP [15-(p-Iodophenyl)-3-methylpentadecanoic acid] and BMIPP was synonymous for ischemic memory imaging, (IMI). It was based on the fact that one can capture the still picture of the ongoing ischemic insult as a “memory image” past the acute episode. BMIPP imaging was primarily based on its ability to memorize the area at risk for a couple of weeks, even after reperfusion therapy. We aim to elaborate in this review the various radiotracers that can be used to identify myocardial metabolic disorders at its inception so that it may be possible to provide early management options.


Main Subjects

Chen IY, Wu JC. Cardiovascular molecular imaging: focus on clinical translation. Circulation. 2011 Feb 1;123(4):425-43.
Taegtmeyer H. Tracing cardiac metabolism in vivo: one substrate at a time. J Nucl Med. 2010 May 1;51 Suppl 1:80S-87S.
Sokolova RI, Zhdanov VS. Hibernation and stunning as manifestations of ischemic dysfunction of the myocardium. Kardiologiia. 2005;45(9):73-8.
Vanoverschelde JL, Pasquet A, Gerber B, Melin JA. Pathophysiology of myocardial hibernation. Implications for the use of dobutamine echocardiography to identify myocardial viability. Heart. 1999 Nov;82 Suppl 3:III1-7.
Rahimtoola SH. The hibernating myocardium. Am Heart J. 1989 Jan;117(1):211-21.
Quyyumi AA. Circadian rhythms in cardiovascular disease. Am Heart J. 1990 Sep;120(3):726-33.
Beierwaltes WH, Ice RD, Shaw MJ, Ryo UY. Myocardial uptake of labeled oleic and linoleic acids. J Nucl Med. 1975 Sep;16(9):842-5.
Palaniswamy SS, Padma S. Cardiac fatty acid metabolism and ischemic memory imaging with nuclear medicine techniques. Nucl Med Commun. 2011 Aug;32(8):672-7.
Poe ND, Robinson GD Jr, Graham LS, MacDonald NS. Experimental basis of myocardial imaging with 123I-labeled hexadecenoic acid. J Nucl Med. 1976 Dec;17(12):1077-82.
Ambrose KR, Owen BA, Goodman MM, Knapp FF Jr. Evaluation of the metabolism in rat hearts of two new radioiodinated 3-methyl-branched fatty acid myocardial imaging agents. Eur J Nucl Med. 1987;12(10):486-91.
Corbett JR. Fatty acids for myocardial imaging. Semin Nucl Med. 1999 Jul;29(3):237-58.
Hosokawa R, Nohara R, Fujibayashi Y, Okuda K, Ogino M, Hata T, Fujita M, Tamaki N, Konishi J, Sasayama S. Myocardial kinetics of iodine-123-BMIPP in canine myocardium after regional ischemia and reperfusion: implications for clinical SPECT. J Nucl Med. 1997 Dec;38(12):1857-63.
Knapp FF Jr, Kropp J. Iodine-123-labelled fatty acids for myocardial single-photon emission tomography: current status and future perspectives. Eur J Nucl Med. 1995 Apr;22(4):361-81.
Osterholt M, Sen S, Dilsizian V, Taegtmeyer H. Targeted metabolic imaging to improve the management of heart disease. JACC Cardiovasc Imaging. 2012 Feb;5(2):214-26.
Takeishi Y, Sukekawa H, Saito H, Nishimura S, Shibu T, Sasaki Y, Tomoike H. Impaired myocardial fatty acid metabolism detected by 123I-BMIPP in patients with unstable angina pectoris: comparison with perfusion imaging by 99mTc-sestamibi. Ann Nucl Med. 1995 Aug;9(3):125-30.
Taki J, Nakajima K, Matsunari I, Bunko H, Takada S, Tonami N. Impairment of regional fatty acid uptake in relation to wall motion and thallium-201 uptake in ischaemic but viable myocardium: assessment with iodine-123-labelled beta-methyl-branched fatty acid. Eur J Nucl Med. 1995 Dec;22(12):1385-92.
Kontos MC, Dilsizian V, Weiland F, DePuey G, Mahmarian JJ, Iskandrian AE, Bateman TM, Heller GV, Ananthasubramaniam K, Li Y, Goldman JL, Armor T, Kacena KA, LaFrance ND, Garcia EV, Babich JW, Udelson JE. Iodofiltic acid I 123 (BMIPP) fatty acid imaging improves initial diagnosis in emergency department patients with suspected acute coronary syndromes: a multicenter trial. J Am Coll Cardiol. 2010 Jul 20;56(4):290-9.
Taki J, Matsunari I. Metabolic imaging using SPECT. Eur J Nucl Med Mol Imaging. 2007 Jun;34 Suppl 1:S34-48.
Schelbert HR, Henze E, Phelps ME, Kuhl DE. Assessment of regional myocardial ischemia by positron-emission computed tomography. Am Heart J. 1982 Apr;103(4 Pt 2):588-97.
McFalls EO, Murad B, Her D, Liow JS, Kelly R, Marx D, Sikora J, Ward HB. Repetitive supply-demand ischemia with dobutamine increases glucose uptake in postischemic and remote myocardium. J Nucl Med. 2003 Jan;44(1):85-91.
Tillisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern M, Phelps M, Schelbert H. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med. 1986 Apr 3;314(14):884-8.
Russell RR 3rd, Bergeron R, Shulman GI, Young LH. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol. 1999 Aug;277(2 Pt 2):H643-9.
Tong H, Chen W, London RE, Murphy E, Steenbergen C. Preconditioning enhanced glucose uptake is mediated by p38 MAP kinase not by phosphatidylinositol 3-kinase. J Biol Chem. 2000 Apr 21;275(16):11981-6.
Dilsizian V. 18F-FDG uptake as a surrogate marker for antecedent ischemia. J Nucl Med. 2008 Dec;49(12):1909-11.
Dou KF, Yang MF, Yang YJ, Jain D, He ZX. Myocardial 18F-FDG uptake after exercise-induced myocardial ischemia in patients with coronary artery disease. J Nucl Med. 2008 Dec;49(12):1986-91.
Gropler RJ, Siegel BA, Lee KJ, Moerlein SM, Perry DJ, Bergmann SR, Geltman EM. Nonuniformity in myocardial accumulation of fluorine-18-fluorodeoxyglucose in normal fasted humans. J Nucl Med. 1990 Nov;31(11):1749-56.
Beinert H, Green DE, Hele P, Hift H, Von Korff RW, Ramakrishnan CV. The acetate activating enzyme system of heart muscle. J Biol Chem. 1953 Jul;203(1):35-45.
Walsh MN, Geltman EM, Brown MA, Henes CG, Weinheimer CJ, Sobel BE, Bergmann SR. Noninvasive estimation of regional myocardial oxygen consumption by positron emission tomography with carbon-11 acetate in patients with myocardial infarction. J Nucl Med. 1989 Nov;30(11):1798-808.
Schoenheimer R, Rittenberg D. The study of intermediary metabolism of animals with the aid of isotopes. Physiol Rev. 1940;20:218–48.
Guertl B, Noehammer C, Hoefler G. Metabolic cardiomyopathies. Int J Exp Pathol. 2000 Dec;81(6):349-72.
Huang Y, Zhou M, Sun H, Wang Y. Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit? Cardiovasc Res. 2011 May 1;90(2):220-3.
Taegtmeyer H, Peterson MB, Ragavan VV, Ferguson AG, Lesch M. De novo alanine synthesis in isolated oxygen-deprived rabbit myocardium. J Biol Chem. 1977 Jul 25;252(14):5010-18.
Taegtmeyer H. Metabolic responses to cardiac hypoxia. Increased production of succinate by rabbit papillary muscles. Circ Res. 1978 Nov;43(5):808-15.
Mudge GH Jr, Mills RM Jr, Taegtmeyer H, Gorlin R, Lesch M. Alterations of myocardial amino acid metabolism in chronic ischemic heart disease. J Clin Invest. 1976 Nov;58(5):1185-92.
Zimmermann R, Tillmanns H, Knapp WH, Helus F, Georgi P, Rauch B, Neumann FJ, Girgensohn S, Maier-Borst W, Kübler W. Regional myocardial nitrogen-13 glutamate uptake in patients with coronary artery disease: inverse post-stress relation to thallium-201 uptake in ischemia. J Am Coll Cardiol. 1988 Mar;11(3):549-56.
Knapp WH, Helus F, Ostertag H, Tillmanns H, Kübler W. Uptake and turnover of L-(13N)-glutamate in the normal human heart and in patients with coronary artery disease. Eur J Nucl Med. 1982;7(5):211-5.
Krivokapich J, Barrio JR, Huang SC, Schelbert HR. Dynamic positron tomographic imaging with nitrogen-13 glutamate in patients with coronary artery disease: comparison with nitrogen-13 ammonia and fluorine-18 fluorodeoxyglucose imaging. J Am Coll Cardiol. 1990 Nov;16(5):1158-67.
Taki J, Wakabayashi H, Inaki A, Imanaka-Yoshida K, Hiroe M, Ogawa K, Morooka M, Kubota K, Shiba K, Yoshida T, Kinuya S. 14C-Methionine uptake as a potential marker of inflammatory processes after myocardial ischemia and reperfusion. J Nucl Med. 2013 Mar;54(3):431-6.
Morooka M, Kubota K, Kadowaki H, Ito K, Okazaki O, Kashida M, Mitsumoto T, Iwata R, Ohtomo K, Hiroe M. 11C-methionine PET of acute myocardial infarction. J Nucl Med. 2009 Aug;50(8):1283-7.
Langer O, Halldin C. PET and SPET tracers for mapping the cardiac nervous system. Eur J Nucl Med Mol Imaging. 2002 Mar;29(3):416-34.
Allman KC, Wieland DM, Muzik O, Degrado TR, Wolfe ER Jr, Schwaiger M. Carbon-11 hydroxyephedrine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans. J Am Coll Cardiol. 1993 Aug;22(2):368-75. 
Bonte FJ, Parkey RW, Graham KD, Moore J, Stokely EM. A new method for radionuclide imaging of myocardial infarcts. Radiology. 1974 Feb;110(2):473-4.
Khaw BA. The current role of infarct avid imaging. Semin Nucl Med. 1999 Jul;29(3):259-70.
Rude RE, Parkey RW, Bonte FJ, Lewis SE, Twieg D, Buja LM, Willerson JT. Clinical implications of the technetium-99m stannous pyrophosphate myocardial scintigraphic "doughnut" pattern in patients with acute myocardial infarcts. Circulation. 1979 Apr;59(4):721-30.
Beller GA, Khaw BA, Haber E, Smith TW. Localization of radiolabeled cardiac myosin-specific antibody in myocardial infarcts. Comparison with technetium-99m stannous pyrophosphate. Circulation. 1977 Jan;55(1):74-8.
Narula J, Petrov A, Pak KY, Lister BC, Khaw BA. Very early noninvasive detection of acute experimental nonreperfused myocardial infarction with 99mTc-labeled glucarate. Circulation. 1997;95(6):1577-84.
Khaw BA, Nakazawa A, O'Donnell SM, Pak KY, Narula J. Avidity of technetium 99m glucarate for the necrotic myocardium: in vivo and in vitro assessment. J Nucl Cardiol. 1997 Jul-Aug;4(4):283-90.
Dewanjee MK, Kahn PC. Mechanism of localization of 99mTc-labeled pyrophosphate and tetracycline in infarcted myocardium. J Nucl Med. 1976 Jul;17(7):639-46.
Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007 Jun;35(4):495-516.
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239-57.
Kietselaer BL, Reutelingsperger CP, Heidendal GA, Daemen MJ, Mess WH, Hofstra L, Narula J. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med. 2004 Apr 1;350(14):1472-3.
Leuschner F, Nahrendorf M. Molecular imaging of coronary atherosclerosis and myocardial infarction: considerations for the bench and perspectives for the clinic. Circ Res. 2011 Mar 4;108(5):593-606.
Kenis H, Zandbergen HR, Hofstra L, Petrov AD, Dumont EA, Blankenberg FD, Haider N, Bitsch N, Gijbels M, Verjans JW, Narula N, Narula J, Reutelingsperger CP. Annexin A5 uptake in ischemic myocardium: demonstration of reversible phosphatidylserine externalization and feasibility of radionuclide imaging. J Nucl Med. 2010 Feb;51(2):259-67.
Zhao M, Zhu X, Ji S, Zhou J, Ozker KS, Fang W, Molthen RC, Hellman RS. 99mTc-labeled C2A domain of synaptotagmin I as a target-specific molecular probe for noninvasive imaging of acute myocardial infarction. J Nucl Med. 2006 Aug;47(8):1367-74. 
Zhu X, Li Z, Zhao M. Imaging acute cardiac cell death: temporal and spatial distribution of 99mTc-labeled C2A in the area at risk after myocardial ischemia and reperfusion. J Nucl Med. 2007 Jun;48(6):1031-6.  
Fang W, Wang F, Ji S, Zhu X, Meier HT, Hellman RS, Brindle KM, Davletov B, Zhao M. SPECT imaging of myocardial infarction using 99mTc-labeled C2A domain of synaptotagmin I in a porcine ischemia-reperfusion model. Nucl Med Biol. 2007 Nov;34(8):917-23.  
Zhu X, Migrino RQ, Hellman RS, Brahmbhatt T, Zhao M. Early uptake of 99mTc-C2A in the acute phase of myocardial infarction as a prognostic indicator for follow-up cardiac dysfunction. Nucl Med Commun. 2008 Sep;29(9):764-9.
Cona MM, Feng Y, Li Y, Chen F, Vunckx K, Zhou L, Van Slambrouck K, Rezaei A, Gheysens O, Nuyts J, Verbruggen A, Oyen R, Ni Y. Comparative study of iodine-123-labeled hypericin and (99m)Tc-labeled hexakis [2-methoxy isobutyl isonitrile] in a rabbit model of myocardial infarction. J Cardiovasc Pharmacol. 2013 Sep;62(3):304-11.
Falborg L, Waehrens LN, Alsner J, Bluhme H, Frøkiaer J, Heegaard CW, Horsman MR, Rasmussen JT, Rehling M. Biodistribution of 99mTc-HYNIC-lactadherin in mice--a potential tracer for visualizing apoptosis in vivo. Scand J Clin Lab Invest. 2010 Apr 19;70(3):209-16. 
Belhocine TZ, Prato FS. Transbilayer phospholipids molecular imaging. EJNMMI Res. 2011 Aug 22;1(1):17.
Dilsizian V, Bateman TM, Bergmann SR, Des Prez R, Magram MY, Goodbody AE, Babich JW, Udelson JE.  Metabolic imaging with beta-methyl-p-[(123)I]-iodophenyl-pentadecanoic acid identifies ischemic memory after demand ischemia. Circulation. 2005 Oct 4;112(14):2169-74.
Tamaki N, Yoshinaga K. Novel iodinated tracers, MIBG and BMIPP, for nuclear cardiology. J Nucl Cardiol. 2011 Feb;18(1):135-43. 
Kawai Y, Tsukamoto E, Nozaki Y, Morita K, Sakurai M, Tamaki N. Significance of reduced uptake of iodinated fatty acid analogue for the evaluation of patients with acute chest pain. J Am Coll Cardiol. 2001 Dec;38(7):1888-94.
Messina SA, Aras O, Dilsizian V. Delayed recovery of fatty acid metabolism after transient myocardial ischemia: a potential imaging target for "ischemic memory". Curr Cardiol Rep. 2007 Apr;9(2):159-65.
Ueshima K, Miyakawa T, Taniguchi Y, Nishiyama O, Musha T, Saitoh M, Kamata J, Okajima T, Aisaka M, Nagamine M, Hiramori K. The incidence of discrepant regional myocardial uptake between 201 thallium and 123 I-BMIPP SPECT in patients with coronary heart disease. Int J Cardiovasc Imaging. 2002 Aug;18(4):273-8.
Mochizuki T, Murase K, Higashino H, Miyagawa M, Sugawara Y, Kikuchi T, Ikezoe J. Ischemic "memory image" in acute myocardial infarction of 123I-BMIPP after reperfusion therapy: a comparison with 99mTc-pyrophosphate and 201Tl dual-isotope SPECT. Ann Nucl Med. 2002 Dec;16(8):563-8.
Grandin C, Wijns W, Melin JA, Bol A, Robert AR, Heyndrickx GR, Michel C, Vanoverschelde JL. Delineation of myocardial viability with PET. J Nucl Med. 1995 Sep;36(9):1543-52.
Yu M, Nekolla SG, Schwaiger M, Robinson SP. The next generation of cardiac positron emission tomography imaging agents: discovery of flurpiridaz F-18 for detection of coronary disease. Semin Nucl Med. 2011 Jul;41(4):305-13.
Gurm GS, Danik SB, Shoup TM, Weise S, Takahashi K, Laferrier S, Elmaleh DR, Gewirtz H.  4-[18F]-tetraphenylphosphonium as a PET tracer for myocardial mitochondrial membrane potential. JACC Cardiovasc Imaging. 2012 Mar;5(3):285-92.
Schutters K, Reutelingsperger C. Phosphatidylserine targeting for diagnosis and treatment of human diseases. Apoptosis. 2010 Sep;15(9):1072-82.
Muzard J, Sarda-Mantel L, Loyau S, Meulemans A, Louedec L, Bantsimba-Malanda C, Hervatin F, Marchal-Somme J, Michel JB, Le Guludec D, Billiald P, Jandrot-Perrus M. Non-invasive molecular imaging of fibrosis using a collagen-targeted peptidomimetic of the platelet collagen receptor glycoprotein VI. PLoS One. 2009;4(5):e5585.
Verjans JW, Lovhaug D, Narula N, Petrov AD, Indrevoll B, Bjurgert E, Krasieva TB, Petersen LB, Kindberg GM, Solbakken M, Cuthbertson A, Vannan MA, Reutelingsperger CP, Tromberg BJ, Hofstra L, Narula J. Noninvasive imaging of angiotensin receptors after myocardial infarction. JACC Cardiovasc Imaging. 2008 May;1(3):354-62.
Gao XM, White DA, Dart AM, Du XJ. Post-infarct cardiac rupture: recent insights on pathogenesis and therapeutic interventions. Pharmacol Ther. 2012 May;134(2):156-79.
Su H, Spinale FG, Dobrucki LW, Song J, Hua J, Sweterlitsch S, Dione DP, Cavaliere P, Chow C, Bourke BN, Hu XY, Azure M, Yalamanchili P, Liu R, Cheesman EH, Robinson S, Edwards DS, Sinusas AJ. Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling. Circulation. 2005 Nov 15;112(20):3157-67.
Chen J, Tung CH, Allport JR, Chen S, Weissleder R, Huang PL. Near-infrared fluorescent imaging of matrix metalloproteinase activity after myocardial infarction. Circulation. 2005 Apr 12;111(14):1800-5.