IACC Vol . 17. No. I January 1711 :270-1
270
Editorial Comment Quantitative Determination of Regional Myocardial Blood Flow : Can It Be Accurately Measured Noninvasively?* DENNY D- WATSON, PHD, GEORGE A . BELLER, MD, FACC Charlorresvilie, Virginia
In the past decade significant advances have been made in our ability to assess noninvasively regional myocardial blood flow utilizing radionuclide imaging techniques . Conventional single photon myocardial perfusion imaging approaches with a gat:ima scintillation camera using either planar or SPECT methodology and tracers such as thallium-201 or technetium99m isonttriles permit evaluation of only relative alterations in regional flow under stress conditions or at rest . Absolute quatimdon of flow in mllmin per g has not been accomplished . The present study. In this issue of the Journal, Nienaber et al . (II describe a method far quamitation of regional myocardial blood flow after intravenous injection of nitrogen-13 (N-13) ammonia and rapid sequential imaging by dynamic positron emission tomography (PET). PET imaging permits tomographic reconstruction that reflects radietracer concentrations in the heart relatively unaffected by tissue attenuation (2) . N-13 ammonia (half-life 10 min) is cyclotronproduced aid after intravenous injection is extracted by the myocardium and metabolically trapped by the gtutamine synthetase reaction producing N-13-labeled gtutamine (3-7), Retention half-times of the N-13 atom in the myocardium range from 60 to 120 min, which is sufficient for acquisition of high quality tomographic images of the heart . Clinical imaging of relative myocardial blood flow with this tracer has successfully been accomplished employing exercise or pharmacologic stress (8,9). The capability and usefulness of PET with N-13 ammonia to quantitate absolute flow under stress conditions in the clinical setting has not yet been clearly demonstrated . The experimental work described in recent publications
awlaoals published in Jcwnnl ofCta A, vokox reatcl the views ofthe authors and do not aeceesadly 1ACC or the American Coleus orcardiology. Fmm The Division of Centiotaar, Department
f Cu 44.g, represent the slaws of
College
or Medicine, and the Division of Medical lmnging, Department of Radology, University or Virginia aeet Seknces Center. Charlottesville, Virginia . Address fonepdms- Gmrge A. Belkr, MU. Division ofCaruiology, Bos 151, University of Virginia HcJ1h Sciences Cmmr. Charlottesville. Virginia 22M.
olOOt by the Ae adcen Culk, of Csrdinloay
(10 .11) and in the current report by Nienaber et al . (1) is an important contribution in making progress toward clinical quantitative PET imaging. The main feature of this work is that tracer kinetic principles have been applied to develop quantitative measurements of regional flow . This is accomplished using an arterial sample to obtain an input function that is then combined with data from high temporal myocardial sampling to compute the index of myocardial blood flow . Two features of this approach are notable . First is the sampling of the arterial input function . After intravenous injection of any tracer, spreading of the tracer bolus, which occurs before it reaches the coronary artery, will affect the shape of the indicator-dilution curve sampled within the capillary bed so that sampling the myocardial tracer concentradon alone will not yield an accurate indication of regional myocardial flow. Nienaber et al . (l) use a simple but apparently adequate method to correct upstream bolus spreading . Concentrations of N-13 activity in blood were derived from a small region of interest located in the center of the left ventricular blood pool. A second narabtefeaatre oftllis work is the recognition of nonliner tracer extracrion as a funrifan of blood flaw. The extraction of N-I3 ammonia is observed to follow the model of Renkin and Crone, which predicts an exponential relation between blood now and tracer extrctfun . This model predicts progressively lower tracer extraction across a capillary membrane as the flow velocity through the capillary becomes greater. The regression equation inherent in the model permits direct conversion of observed net extractions of N- 13 ammonia to blood flow, which compensates for the flow-dependenl decrease in net extraction . The model is a general one that should apply to single photon tracers such as thallium-201 and the new technetium-99m perfusion agents, as well as to ammonia . Recognition and correction of the effect of flow dependency an extraction is necessary before tracer uptake can be accurately related to myocardial blood flow over a wide flow range using any extractable tracer . Clinical appltcabilly . Does this work presage general clinical utilization of PET? Although PET offers unique clinical capability, in this era of cost containment it is perhaps difficult to predict rapid growth of such a complex and expensive technology . It seems more likely that for the time being PET will continue as a primarily investigative tool . The study by Nienaber et al. (1) is a good example of methodology developed for PET, which can influence similar developments with other imaging modalities. For example, digital fluoroscopy oilers the potential to perform similar indicator dilution analyses . To similarly quantify myocardial blood flow might require the development of extractable contrast agents but the PET work could demonstrate the utility of such development. Contrast agents (microbubbles) used with eehocardiography have been detected in left ventricular myocardium after intravenous injection and similar methods could be used for analysis of contrast echo 0735-m097191153.50
JACC Vp1, 17. No. I January 1991 :210-1
WATSON AND SELLER EDITORIAL COMMENT
indicator-dilution data . Magnetic resonance imaging is now capable of detecting indicators in large vessels and myocardium using flash reconstruction techniques . Single photon radionuclide indicators offer similar possibilities than could become three-dimensional with the development of rapid SPECT imaging . Compared With PET, these alternatives offer formidable challenges and would require more development to be useful. However, an important role for PET may be to lead the way toward such advances . To what extent will improved quantitative regional myocardial bloodflow imaging be clinically useful? The amount of effort to be expended on developing regional myocardial flow quantitation might well depend on the clinical importance of having this capability. Will enhanced blood flow quantitation lead to improved detection of physiologically relevant coronary artery stenoses in patients with underlying coronary artery disease? Recent data (12,13) using PET and rubidium-82 for semiquantitative assessment of blood flow after dipyridamole stress are encouraging in this regard. However, it is still not clear whether stenoses detection rates utilizing PET methodology will be greatly superior to carefully performed quantitative single photon planar or SPECT imaging of regional myocardial perfusion . Will improved blood flow determination with corresponding regional myocardial metabolism measurements with PET prove to be the ultimate in vivo "gold standard - of myocardial viability? Significant progress has indeed been made in imaging of myocardial metabolism with PET employing fluorine-IS 2-deoxyglaense (14,15) and C-11 acetate (16). Thus, the work from research centers with PET capability will be of utmost importance in seeking answers to such questions regarding the clinical applicability of quantitative myocardial blood flow imaging .
References I . Member CA .amibO,Gumbhir5S.erat .Aquantitativeindouufrcgiaeal blood flow in canine myocardium derived noninvasisely with N-13 ammonia and dynamic positron emission tomogaphy . l Am Call Cardiol 1991 :17 :266-92. Schelbett HR. Current status and prospects of new radionuclides and
271
mmopsarmatenlicals Inn asrdiovareulur oaten medicine- Semis Null Med 1987 ;17:,45-SS . 3 . SubrlharnHR,PheipsME .HUangSC .Mat .N-13ammonuasaninduatue of myocardial blood flow. Circulation 1981 ;63:1259-72. a . aergman SR, Hack 5, Tewson T. e1 d. The dependence of accanalafwn of "NH, myocardium an melebalie factor., mid its implttations for quantitative assessmem of perfusion. Cinalatiao 1980x31 :34-43. S. Wisenberg G . Schetbees HR, Hofman RI, et a1 . In viva geantitatios of regional myocardial blood flow by posilmn-emisn!nn computed tomography. Circulation 1981 :63 :1248-58 . 6. Shah A . SchnBxrs MR. Schwaiger M- et at. Measurement of regional myocardial blood flow with N-13 ammonia and posilan-emission tomeg . raphy in intact dogs . J Am Colt Cesdio11955 ;5:92-lop. 7 . Krwokupich 1. Heang SC. Phelps ME . MaeDorrdd NS, Shine KI . Dependence on "NH, myocardial extraction and ckaapce on flow and metabolism . Am J Physia11982:242:H536-42. 0. Schelben HR . WisenbergG, Phelps M E . et al. Noninvasive assessotent of coronary stenoses by myocardial imaging during pharmacobgie corenary vasodilalon . V1 . Detection of coronary artery disease in human beings with inuavenous N-13 ammonia and positron computed tomogra. phy . Am 1 Cordial 1982:49:1197-1207. 9. Tamaki N. Senda M . Yonekua Y, et al. Dynamic positron computed tunagrsphy of sbe heon with a high siuvhy posaran camera and nitrogen-13 ammonia. J Nod Med 198516:567-75 . 10. Kmokapich 1, Smith GT . Huang SC. et al . "N ammalia myocardial imaging at rest and with exemisc in normal volunteers : ilawatification of ahsolute myocardial perfusion with dynamic positron emission tanopaphy . Circulation 198: ;90 .1328-37 . 11 . Bellina CR, Parent O, Camici P, et al . Simuhanwus In vmuo and in rho validation ornhrogen-13amowniaforthn assessmentof regional myocardial blood flow. J Nod Med 1990;31:1335-43. 12 . Goad KL, Goldskin RA . Method NA. et al. Nmdnvasoe asacssnent of coronary ate- bymyocmdialpruPonionimmitingdaeinapkamacologie roomy vasodilatiort. Vlll . Clinical kacibddy of positron cardiac unit mg; without a eyetotan using generator-produced nabidium-82 . J Am Cull Cordial 1986:7 ;775-89. 13 . Denier LL, Gouts KL . Godslein RA, Kbkrside RL . Diagnosis of coamry artery disease by positron emission tomegnaphy. comparison m quandtetioe coronary artemrmaphy in 193 patients . Circulation 1989 ;79: 825-33. 14. Tillisch 1 . Betaken R, Marshall R, as aI . Reversibility of cardiac wallmotion abnonoalities predicted by positron lomngraphy . N Engi 1 Med 1986 ;314:984-8. 15, Banken R. TIIILSeh J . ScMvaiger M, el al . Ragiaeal perfuaioo. glucose metabolism, and wall motion in patients with chronic eleclroeardia . gmphie Q wave infarctions •, evidence for pertinence of viable tissue in me infarct regions by positron emission tomogaphy . Chculadon 1966 ; 73,51_63. 16, Armbrecht 11, Buxton DR, Schclbed HR . Validation of ht t Clacesate m a tracer for noninvasiveaasessmem of oxidative metabal61n with positron o gaphy in normal. ischemk, postischemk, and hyperemic canine myocardium,Circuation 1990 ;81 :1594-605 .
270
Editorial Comment Quantitative Determination of Regional Myocardial Blood Flow : Can It Be Accurately Measured Noninvasively?* DENNY D- WATSON, PHD, GEORGE A . BELLER, MD, FACC Charlorresvilie, Virginia
In the past decade significant advances have been made in our ability to assess noninvasively regional myocardial blood flow utilizing radionuclide imaging techniques . Conventional single photon myocardial perfusion imaging approaches with a gat:ima scintillation camera using either planar or SPECT methodology and tracers such as thallium-201 or technetium99m isonttriles permit evaluation of only relative alterations in regional flow under stress conditions or at rest . Absolute quatimdon of flow in mllmin per g has not been accomplished . The present study. In this issue of the Journal, Nienaber et al . (II describe a method far quamitation of regional myocardial blood flow after intravenous injection of nitrogen-13 (N-13) ammonia and rapid sequential imaging by dynamic positron emission tomography (PET). PET imaging permits tomographic reconstruction that reflects radietracer concentrations in the heart relatively unaffected by tissue attenuation (2) . N-13 ammonia (half-life 10 min) is cyclotronproduced aid after intravenous injection is extracted by the myocardium and metabolically trapped by the gtutamine synthetase reaction producing N-13-labeled gtutamine (3-7), Retention half-times of the N-13 atom in the myocardium range from 60 to 120 min, which is sufficient for acquisition of high quality tomographic images of the heart . Clinical imaging of relative myocardial blood flow with this tracer has successfully been accomplished employing exercise or pharmacologic stress (8,9). The capability and usefulness of PET with N-13 ammonia to quantitate absolute flow under stress conditions in the clinical setting has not yet been clearly demonstrated . The experimental work described in recent publications
awlaoals published in Jcwnnl ofCta A, vokox reatcl the views ofthe authors and do not aeceesadly 1ACC or the American Coleus orcardiology. Fmm The Division of Centiotaar, Department
f Cu 44.g, represent the slaws of
College
or Medicine, and the Division of Medical lmnging, Department of Radology, University or Virginia aeet Seknces Center. Charlottesville, Virginia . Address fonepdms- Gmrge A. Belkr, MU. Division ofCaruiology, Bos 151, University of Virginia HcJ1h Sciences Cmmr. Charlottesville. Virginia 22M.
olOOt by the Ae adcen Culk, of Csrdinloay
(10 .11) and in the current report by Nienaber et al . (1) is an important contribution in making progress toward clinical quantitative PET imaging. The main feature of this work is that tracer kinetic principles have been applied to develop quantitative measurements of regional flow . This is accomplished using an arterial sample to obtain an input function that is then combined with data from high temporal myocardial sampling to compute the index of myocardial blood flow . Two features of this approach are notable . First is the sampling of the arterial input function . After intravenous injection of any tracer, spreading of the tracer bolus, which occurs before it reaches the coronary artery, will affect the shape of the indicator-dilution curve sampled within the capillary bed so that sampling the myocardial tracer concentradon alone will not yield an accurate indication of regional myocardial flow. Nienaber et al . (l) use a simple but apparently adequate method to correct upstream bolus spreading . Concentrations of N-13 activity in blood were derived from a small region of interest located in the center of the left ventricular blood pool. A second narabtefeaatre oftllis work is the recognition of nonliner tracer extracrion as a funrifan of blood flaw. The extraction of N-I3 ammonia is observed to follow the model of Renkin and Crone, which predicts an exponential relation between blood now and tracer extrctfun . This model predicts progressively lower tracer extraction across a capillary membrane as the flow velocity through the capillary becomes greater. The regression equation inherent in the model permits direct conversion of observed net extractions of N- 13 ammonia to blood flow, which compensates for the flow-dependenl decrease in net extraction . The model is a general one that should apply to single photon tracers such as thallium-201 and the new technetium-99m perfusion agents, as well as to ammonia . Recognition and correction of the effect of flow dependency an extraction is necessary before tracer uptake can be accurately related to myocardial blood flow over a wide flow range using any extractable tracer . Clinical appltcabilly . Does this work presage general clinical utilization of PET? Although PET offers unique clinical capability, in this era of cost containment it is perhaps difficult to predict rapid growth of such a complex and expensive technology . It seems more likely that for the time being PET will continue as a primarily investigative tool . The study by Nienaber et al. (1) is a good example of methodology developed for PET, which can influence similar developments with other imaging modalities. For example, digital fluoroscopy oilers the potential to perform similar indicator dilution analyses . To similarly quantify myocardial blood flow might require the development of extractable contrast agents but the PET work could demonstrate the utility of such development. Contrast agents (microbubbles) used with eehocardiography have been detected in left ventricular myocardium after intravenous injection and similar methods could be used for analysis of contrast echo 0735-m097191153.50
JACC Vp1, 17. No. I January 1991 :210-1
WATSON AND SELLER EDITORIAL COMMENT
indicator-dilution data . Magnetic resonance imaging is now capable of detecting indicators in large vessels and myocardium using flash reconstruction techniques . Single photon radionuclide indicators offer similar possibilities than could become three-dimensional with the development of rapid SPECT imaging . Compared With PET, these alternatives offer formidable challenges and would require more development to be useful. However, an important role for PET may be to lead the way toward such advances . To what extent will improved quantitative regional myocardial bloodflow imaging be clinically useful? The amount of effort to be expended on developing regional myocardial flow quantitation might well depend on the clinical importance of having this capability. Will enhanced blood flow quantitation lead to improved detection of physiologically relevant coronary artery stenoses in patients with underlying coronary artery disease? Recent data (12,13) using PET and rubidium-82 for semiquantitative assessment of blood flow after dipyridamole stress are encouraging in this regard. However, it is still not clear whether stenoses detection rates utilizing PET methodology will be greatly superior to carefully performed quantitative single photon planar or SPECT imaging of regional myocardial perfusion . Will improved blood flow determination with corresponding regional myocardial metabolism measurements with PET prove to be the ultimate in vivo "gold standard - of myocardial viability? Significant progress has indeed been made in imaging of myocardial metabolism with PET employing fluorine-IS 2-deoxyglaense (14,15) and C-11 acetate (16). Thus, the work from research centers with PET capability will be of utmost importance in seeking answers to such questions regarding the clinical applicability of quantitative myocardial blood flow imaging .
References I . Member CA .amibO,Gumbhir5S.erat .Aquantitativeindouufrcgiaeal blood flow in canine myocardium derived noninvasisely with N-13 ammonia and dynamic positron emission tomogaphy . l Am Call Cardiol 1991 :17 :266-92. Schelbett HR. Current status and prospects of new radionuclides and
271
mmopsarmatenlicals Inn asrdiovareulur oaten medicine- Semis Null Med 1987 ;17:,45-SS . 3 . SubrlharnHR,PheipsME .HUangSC .Mat .N-13ammonuasaninduatue of myocardial blood flow. Circulation 1981 ;63:1259-72. a . aergman SR, Hack 5, Tewson T. e1 d. The dependence of accanalafwn of "NH, myocardium an melebalie factor., mid its implttations for quantitative assessmem of perfusion. Cinalatiao 1980x31 :34-43. S. Wisenberg G . Schetbees HR, Hofman RI, et a1 . In viva geantitatios of regional myocardial blood flow by posilmn-emisn!nn computed tomography. Circulation 1981 :63 :1248-58 . 6. Shah A . SchnBxrs MR. Schwaiger M- et at. Measurement of regional myocardial blood flow with N-13 ammonia and posilan-emission tomeg . raphy in intact dogs . J Am Colt Cesdio11955 ;5:92-lop. 7 . Krwokupich 1. Heang SC. Phelps ME . MaeDorrdd NS, Shine KI . Dependence on "NH, myocardial extraction and ckaapce on flow and metabolism . Am J Physia11982:242:H536-42. 0. Schelben HR . WisenbergG, Phelps M E . et al. Noninvasive assessotent of coronary stenoses by myocardial imaging during pharmacobgie corenary vasodilalon . V1 . Detection of coronary artery disease in human beings with inuavenous N-13 ammonia and positron computed tomogra. phy . Am 1 Cordial 1982:49:1197-1207. 9. Tamaki N. Senda M . Yonekua Y, et al. Dynamic positron computed tunagrsphy of sbe heon with a high siuvhy posaran camera and nitrogen-13 ammonia. J Nod Med 198516:567-75 . 10. Kmokapich 1, Smith GT . Huang SC. et al . "N ammalia myocardial imaging at rest and with exemisc in normal volunteers : ilawatification of ahsolute myocardial perfusion with dynamic positron emission tanopaphy . Circulation 198: ;90 .1328-37 . 11 . Bellina CR, Parent O, Camici P, et al . Simuhanwus In vmuo and in rho validation ornhrogen-13amowniaforthn assessmentof regional myocardial blood flow. J Nod Med 1990;31:1335-43. 12 . Goad KL, Goldskin RA . Method NA. et al. Nmdnvasoe asacssnent of coronary ate- bymyocmdialpruPonionimmitingdaeinapkamacologie roomy vasodilatiort. Vlll . Clinical kacibddy of positron cardiac unit mg; without a eyetotan using generator-produced nabidium-82 . J Am Cull Cordial 1986:7 ;775-89. 13 . Denier LL, Gouts KL . Godslein RA, Kbkrside RL . Diagnosis of coamry artery disease by positron emission tomegnaphy. comparison m quandtetioe coronary artemrmaphy in 193 patients . Circulation 1989 ;79: 825-33. 14. Tillisch 1 . Betaken R, Marshall R, as aI . Reversibility of cardiac wallmotion abnonoalities predicted by positron lomngraphy . N Engi 1 Med 1986 ;314:984-8. 15, Banken R. TIIILSeh J . ScMvaiger M, el al . Ragiaeal perfuaioo. glucose metabolism, and wall motion in patients with chronic eleclroeardia . gmphie Q wave infarctions •, evidence for pertinence of viable tissue in me infarct regions by positron emission tomogaphy . Chculadon 1966 ; 73,51_63. 16, Armbrecht 11, Buxton DR, Schclbed HR . Validation of ht t Clacesate m a tracer for noninvasiveaasessmem of oxidative metabal61n with positron o gaphy in normal. ischemk, postischemk, and hyperemic canine myocardium,Circuation 1990 ;81 :1594-605 .
