2. Palmer MR. Bergstrom M, Pate BD. Beddoes MP. Noise distribution due to emission 9. Lange K, Carson R. EM reconstruction algorithms for emission and transmission and transmission statistics in positron emission tomography. IEEE Trans NucÃSci tomography. J Comput Assist Tomog 1984;8:306-316. 1986:33:439-442. 10. Ollinger JM. Reconstruction-reprojection processing of transmission scans and the 3. Uahlbom M. Hoffman EJ. Problems in signal-to-noise ratio for attenuation correction variance of PET images. IEEE Trans Med Imag 1992:39:1122-1125. in high resolution PET. IEEE Trans NucÃSci 1987:34:288-293. 11. Yu D-C. Huang S-C. Study of reprojection methods in terms of their resolution loss 4. Huang SC. Carson RE. Phelps ME. Hoffman EJ, Scheiben HR. KühlDE. A boundary and sampling errors. IEEE Trans NucÃSci I993;40:l 174-1177. method for attenuation correction in positron computed tomography. J NucÃMed 1981:22:627-637. 12. Alpert NM, Chesler DA, Correia JA, et al. Estimation of the local statistical noise in emission computed tomography. IEEE Trans Med Imag 1982:1:142-146. 5. Xu EZ, Mullani NA. Gould KL, Anderson WL. A segmented attenuation correction for PET. J NucÃMed 1991:32:161-165. 13. Huesman RH. A new fast algorithm for the evaluation of regions of interest and 6. Meikle SR, Dahlbom M. Cherry SR. Attenuation correction using count-limited statistical uncertainty in computed tomography. Phys Med Biol 1984;29:543-552. transmission data in positron emission tomography. J NucÃMed 1993:34:143-150. 14. Kendall Sir M, Stuart A, The advanced theory of statistics. New York: Macmillan: 7. Abramowitz M, Stegun 1A. Handbook of mathematical junctions. New York: Dover 1979:52-53. Publications; 1968. 15. Freedman NMT, Bacharach SL. Carson RE, Price JC. and Dilsizian V. Effect of 8. Shcpp LA. Vardi Y. Maximum likelihood reconstruction for emission tomography. smoothing during transmission processing on quantitative cardiac PET. J NucÃMed IEEE Tram Med Imag I982;l:l 13-122. 1996: in press.
NUCLEAR CARDIOLOGY: CURRENT PERSPECTIVE Myocardial Viability: Unresolved Issues
Abdulmassih S. Iskandrian The Philadelphia Heart Institute, Presbyterian Medical Center, Philadelphia, Pennsylvania
nation (6,20). A recent study (21 ), however, raised doubt about Key Words: myocardial viability assessment; PET; SPECT; MRI; the reliability of determining absolute rates of myocardial two-dimensional echocardiography glucose uptake using the glucose tracer analog lsF-deoxy- J NucÃMed 1996; 37:794-797 fluoroglucose (21 ). The presence of redistribution (reversible defect) on rest-redistribution thallium imaging is also consistent Jlhe determination or assessment of myocardial viability has, with hypoperfusion and reduced resting flow (5,16,17) in viable over the past decade, captured the imagination and interest of myocardium. The recovery of regional dysfunction in such many investigators in basic and clinical research using state-of- segments after coronary revascularization is also consistent the-art technologies such as PET, SPECT, MRI and two- with hibernation. On the other hand, the presence of redistribu dimensional echocardiography (2-DE) (1-12). The emphasis in tion on stress images or the presence of mild fixed thallium these studies has been to determine the absolute and compara defects, mild fixed sestamibi defects or improvement in wall tive accuracy of these techniques (1-3 ). There are recent studies motion during inotropic stimulation (such as dobutamine) do addressing the evaluation of the effect of viability assessment not fulfill the same criteria for hibernating myocardium because on patient outcome (13-17). The use of biochemical agents and it may be that mild fixed perfusion defects represent viable other imaging methods in viability assessment is complex with myocardium but are not markers of hibernating myocardium many unresolved issues (Table 1) to be considered in the design (8,9,17). A good example is subendocardial infarction with and implementation of clinical protocols and in routine patient admixture of scar and normal myocardium in the infarcìzone. care. The subepicardial myocardium is viable but does not have to be hibernating and this zone may very well respond to inotropic DEFINITION stimulation. If LV dysfunction is due to hibernation, it poten The issue of myocardial viability is most important in the tially may recover after coronary revascularization while such presence of left ventricular (LV) dysfunction. Viable myocar recovery may not be expected if the dysfunction is due to dium may be normal, hibernating or stunned while nonviable subendocardial scarring. This may explain the reason why myocardium represents scar (1-3). Thus, hibernating myocar improvement in wall motion on echocardiography with dobut dium is viable but viable myocardium is not necessarily amine has not been a specific marker of recovery of LV hibernating. Hibernation refers to systolic LV dysfunction in the function after revascularization (22). presence of hypoperfusion that recovers after coronary revas- A similar issue may be raised with perfusion imaging. For cularization (1,2,18). It may represent a downregulation of example, Figure 1 depicts the resting myocardial perfusion on a contractile function in response to reduced resting myocardial radionuclide tomogram; area 1 is a region with normal tracer blood flow. Stunned myocardium refers to systolic LV dysfunc uptake; area 2 is a region with mild fixed defect; area 3 is a tion that persists after an ischemie episode despite restoration of region with severe fixed defect and area 4 is a region with flow (19). The distinction between viability and hibernation is important to the understanding of differences between various TABLE 1 diagnostic methods that use different markers such as flow, List of Unresolved Issues in Myocardial Viability metabolism or function. The flow-metabolism mismatch pattern determined by PET (which reflects reduced resting flow but 1. Definition of viable myocardium preserved, albeit altered, metabolism) represents the main 2. Quantification of viable myocardium stream description of the pathophysiological changes in hiber 3. Correlation between perfusion and function 4. Patient selection 5. Time of follow-up assessment Received Jul. 10, 1995; revision accepted Oct. 8, 1995. For correspondence or reprints contact: Abdulmassih S. Iskandrian, MD, William 6. Completeness of revascularization Penn Synder III Professor of Medicine, Director, Cardiovascular Research Center, 7. Perioperative myocardial infarction Medical College of Pennsylvania and Hahnemann University, 230 Broad St., Philadel 8. Endpoints phia, PA 19102.
794 THE JOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 5 •May 1996 reversible defect. If reversibility is a marker of hibernation, then TABLE 2 only 1 of the 4 regions has hibernating myocardium (reversible Relation between Regional Myocardial Perfusion and Wall Motion defect implies reduced resting myocardial blood flow due to Item Perfusion Wall motion Issues to be considered severe coronary stenosis and viable myocardium). On the other hand, if normal uptake, mild fixed defect and reversible defect 1. Normal Normal NA are considered as markers of viable myocardium, then three of 2. Normal Abnormal Stunning, remodeling, relative the four regions contain viable myocardium. The question is: perfusion, malregistration, primary cardiomyopathy* which pattern determines the recovery of LV function in this patient? Based on the mismatch pattern by PET, the answer is 3. Abnormal Abnormal Hibernation ±scar and/or normal one region (1,2,6). myocardium 4. Abnormal Normal Malregistration, misinterpretation QUANTITATION (attenuation artifacts) Although it is feasible that a given myocardial region may be entirely hibernating or entirely scarred, more often than not "Concomitant primary cardiomyopathy and coronary artery disease. there is a mixture of normal, stunned, hibernating and scarred NA = not applicable. myocardium (1 ). The relative proportion of hibernating myo cardium to other abnormalities in a given segment will deter nuclide angiograms, which provide three-dimensional informa mine the extent of recovery of regional function after coronary tion, may be preferred to allow more precise segmental regis revascularization. Thus, in Figure 1, if area 4 is a region with tration (7). severe defect that is completely reversible, it may be more important than if it is a mild defect that is partially reversible PATIENT SELECTION because, in the first example, there is more hibernating myo Many of the published studies involve patients with mild-to- moderate LV dysfunction (4,13-16,22). The selection bias may cardium. Similarly, the total extent of hibernation in the LV myocardium will determine the extent of recovery of global LV explain why the various diagnostic techniques provide compa function measured as ejection fraction (EF). The mere presence rable accuracy in predicting recovery of LV function after of hibernation is not in itself a justification for coronary revascularization (Fig. 2). It is possible that, as LV dysfunction revascularization. With SPECT, problems related to attenua becomes more severe, the accuracy of these techniques diverge. tion, scatter and partial volume effect may make quantitative Myocardial viability assessment is most important in patients assessment of hibernating myocardium less reliable than PET. with severe LV dysfunction who have no disabling angina but have congestive heart failure because if angina exists that alone CORRELATION BETWEEN PERFUSION AND FUNCTION may guide therapy. The prognosis of patients with coronary Table 2 lists the relationship between regional LV function artery disease, severe LV dysfunction and congestive heart and perfusion. A normal perfusion is possible in a region with failure is poor with medical therapy. Coronary revascularization wall motion abnormality because of stunning, remodeling, in selected patients (with viable myocardium) has resulted in malregistration (segments are not comparable), concomitant improvement in EF, symptoms and survival (5-7, 12-17). In primary cardiomyopathy and coronary artery disease or because the United States, there are over 3 million patients with the normal perfusion is relative and not absolute. Abnormal congestive heart failure and over 70% of these patients have perfusion may exist in a region with normal wall motion because of malregistration or because of misinterpretation of the perfusion pattern (attenuation artifact rather than true VIABILITY ASSESSMENTS abnormality). Also, it is difficult to compare data from three- (PET, Thallium, Mibi, 2DE) dimensional perfusion images (by SPECT) to two-dimensional (planar) radionuclide angiography. In the future, SPECT radio-
Radionuclide Perfusion Tomogram
>50 30 20 LVEF(%)
FIGURE 2. Schematic and arbitrary presentation of predictive accuracy of various methods to assess myocardial viability. In patients with normal LVEF, all methods should at least theoretically be 100% accurate. In patients with mild LV dysfunction, the accuracy of these methods is within a narrow range. It is possible that the accuracy will differ in patients with more severe LV FIGURE 1. Schematic presentation of a resting201T1tomogram showing four dysfunction. There are no sufficient data to draw firm conclusions as to which regions with different tracer distribution: area 1 (anterior) shows normal line represents which test modality. Conceivably, we will never know the uptake and clearance; area 2 (lateral) shows mild fixed defect; area 3 (inferior) accuracy in patients with EF < 10%. 2-DE = two-dimensional echocardi- shows severe fixed defect and area 4 (septal) shows reversible defect. ography.
MYOCARDIALVIABILITY•ISKANDRIAN 795 coronary artery disease (23). Aggressive medical therapy in medications for angina pectoris or congestive heart failure, but cluding the use of angiotensin-converting enzyme inhibitors it may not be a reliable endpoint for viability assessment increases longevity by 6-12 mo at the most and the limited because improvement in exercise tolerance may occur without number of donors and the expense of transplantation would improvement in EF. Moreover, in some patients, angina pecto suggest that many patients may be potential candidates for ris, rather than fatigue or dyspnea, may be the limiting symptom viability assessment to determine if coronary revascularization before coronary revascularization (/). improves LV function and the functional status (24). It is important that the method for measuring changes in EF Recent data in patients with acute myocardial infarction be reliable and reproducible (28). The ideal utility of viability suggest gradual improvement of LV function and perfusion studies will be the ability to predict postrevascularization EF pattern after 6 mo; inclusion of these patients in clinical trials based on preoperative EF, extent of hibernation and coronary may therefore alter the conclusion drawn from viability studies anatomy (Fig. 3). The ultimate goal is to have postrevascular (25). ization EF above 30%-35%—which means that, in a patient with an EF of 10%-20%, more hibernating myocardium should TIME OF FOLLOW-UP ASSESSMENT be present than in a patient with an EF of 20%-30% to warrant The optimal time to reassess LV function after revascular revascularization. The 30%-35% cutoff is based on studies ization has yet to be determined. Most of the studies provide showing that patients with an EF lower than 30%-35% have a data at 8-12 wk (4,6,12). It is possible that recovery, in some poor prognosis (29-31). The effect of LV dilation on the patients, may occur at 6-12 mo but, obviously, longer fol changes in EF is a subject that needs to be addressed carefully low-up may be associated with problems of restenosis after because it is quite conceivable that marked LV dilation io".y angioplasty or graft occlusion after bypass grafting. It may prevent recovery of LV function, despite the presence of viable therefore be important to have serial measurements after coro myocardium (1,4). The precise degree of dilation beyond which nary revascularization. recovery is least likely cannot be answered from existing data.
COMPLETENESS OF REVASCULARIZATION AND CONCLUSION PERIOPERATIVE EVENTS The complexity of issues raised by the different imaging Assuming that viability assessment is accurate, the recovery patterns and other factors that determine recovery of function of LV function will depend on completeness of revasculariza after coronary revascularization, irrespective of perfusion pat tion, lack of perioperative myocardial infarction and continued tern, may explain the relative lack of substantiation in the patency of grafts (or angioplasty site). Incomplete revascular literature about specific perfusion patterns and specific patho- ization, (for example because of poor distal runoff) especially to physiology. These, and other issues not related to perfusion the culprit area, may be an important reason for discordance pattern, are relevant to future clinical protocols in viability between preoperative assessment and postoperative recovery. assessment using any of the diagnostic modalities because they In the study by Tamaki et al. (72), 30% of the patients were are generic and deal with defining viable myocardium and the excluded from intent to treat analysis because of incomplete endpoint after coronary revascularization. The concept of re revascularization. Repeat coronary angiography after revascu versing LV dysfunction and improving survival is a novel one, larization may not be practical in either routine patient care or but implementation of prospective studies to test this hypothesis a clinical research protocol. Another difficult problem is the is at best a difficult one. For ethical and moral reasons, occurrence of perioperative myocardial infarction. Chaitman randomization is not possible (e.g., randomization of a patient and Jaffe highlighted the problems of diagnosing acute myo with clear evidence of extensive hibernation to medical therapy cardial infarction in the perioperative period because conven tional criteria of symptoms, electrocardiographic changes and 100-1 enzyme changes are not very reliable (26). Thus, despite correct -100 preoperative assessment of viability, postoperative improve ment may not be realized due to perioperative infarction. What I criteria should be used to detect perioperative infarction? è Worsening of wall motion abnormality, a decrease in LVEF, ED 60 infarct-avid imaging (using newer imaging agents), new perfu sion defects or newer methods of enzymatic analysis (subforms 50 of creatine kinase MB, cardiac troponins and myoglobin) are & possible answers (7,17,27). oI 40 e ENDPOINTS £ 30 What endpoints should be used to determine the outcome after coronary revascularization? From the patients' viewpoint, 20 improvement in symptoms is far more important than improve ment in wall motion abnormality or EF! Yet, from a scientific 10 standpoint, improvement in regional wall motion abnormality and EF are objective and more reliable. Ideally, improvement in O EF should be associated with improvement in symptoms and predicted EF survival. The best primary endpoint appears to be improvement (by scan) in EF while the secondary endpoints include improvement in symptoms and survival. Although wall motion improvement is FIGURE 3. Schematic presentation of ideal situation in which the radionu- clide image predicts the degree of improvement of EF after coronary useful for segmental analysis it may have limited significance revascularization, if there is no perioperative myocardial infarction and on symptoms, EF and prognosis. Improvement in exercise complete revascularization was feasible (Patient 1). In Patient 2, the scan performance has been used in assessing the efficacy of many correctly predicted no improvement.
796 THEJOURNALOFNUCLEARMEDICINE•Vol. 37 •No. 5 •May 1996 or a clear evidence of extensive scarring to coronary revascu- 15. Lucignani G, Paolini G, Landoni C, et al. Presurgical identification of hibernating myocardium by combined use of technetium-99m-hexakis 2-methoxyisobutylisonitrile larization). Careful consideration of the issues raised above single-photon emission tomography and fluorine-18 fluoro-2-deoxy-D-glucose may, however, be helpful in patient care and study design. The positron emission tomography in patients with coronary artery disease. Etir J NucÃMed relatively high cost involved in the management of patients with 1992;I9:874-881. 16. Gioia G, Powers J, Russell J, Cassel D, Heo J, Iskandrian AS. Prognostic value of congestive heart failure suggests the need of a large trial in this rest-redistribution SPECT thallium imaging in patients with coronary artery disease group of patients. and ischemie cardiomegaly. Am J Cardiol 1995:75:759-762. 17. Ragosta M, Beller GA, Watson DD, Kaul S, Gimple LW. Quantitative planar REFERENCES rest-redistribution 2("T1 imaging in detection of myocardial viability and prediction of 1. Scheiben HR, Buxton D. Insights into coronary artery disease gained from metabolic improvement in left ventricular function after coronary bypass surgery in patients with imaging. Circulation 1988;78:496-505. severely depressed left ventricular function. Circulation 1993:87:1630-1641. 2. Scheiben HR. Merits and limitations of radionuclide approaches to viability and future 18. Rahimtoola SH. The hibernating myocardium. Am Heart J 1989;! 17:211-221. developments. J NucÃCardio] 1994;l:S86-S96. 19. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventric 3. Iskandrian AS. Van der Wall EE. When is myocardial viability a clinical relevant ular dysfunction. Circulation 1982:66:1146-1149. issue? In: Iskandrian AS, Van der Wall EE, eds. Myocardial viability: detection and 20. Opie LH. Effects of regional ischemia on metabolism of glucose and fatty acids: clinical relevance. Amsterdam: Kluwer; 1994:179-193. relative rates of aerobic and anaerobic energy production during myocardial infarction 4. Iskandrian AS, Powers J, Cave V. Wasserleben V. Cassel D. Heo J. Assessment of and comparison with effects of anoxia. Ore Res 1976;38(suppl I):l-52-I-74. myocardial viability by dynamic tomographic 123I-iodophenylpentadecanoic acid 21. Hariharan R, Bray M. Granim R. Doenst T. Goodwin GW, Taegtmeyer H. Funda imaging. Comparison to rest-redistribution thaIIium-201 imaging. J NucÃCardiol mental limitations of 1!*F-2-deoxy-2-fluoro-D-glucose for assessing myocardial glu I995;2:101-109. cose uptake. Circulation 1995:91:2435-2444. 5. Iskandrian AS, Hakki A-H, Kane SA, Goel IP, Mundth ED, Segal BL. Rest and redistribution thalltum-201 myocardial scintigraphy to predict improvement in left 22. Afridi I. Kleinman NS. Raizer AE. Zoghbi WA. Dobutamine echocardiography in ventricular function after coronary arterial bypass grafting. Am J Cardiol 1983;51: myocardial hibernation: optimal dose and accuracy in predicting recovery of ventric 1312-1316. ular function after coronary angioplasty. Circulation 1995:91:663-670. 6. Ttllisch J, Brunken R, Marshall R, Schwaiger M, Mandelkern M, Phelps M, Scheiben 23. Redfield MM, Gersh BJ, Bailey KR, Ballard DJ, Rodehefter RJ. Natural history of HR. Reversibility of cardiac wall motion abnormalities predicted by positron tomog idiopathic dilated cardiomyopathy: effect of referral bias and secular trend. J Am Coll raphy. N EnglJ Med 1986:314:884-888. Cardio/ 1993:22:1921-1926. 7. Udelson J, Coleman P, Metherall J, et al. Predicting recovery of severe regional 24. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular dysfunction. Circulation 1994;89:2552-256I. ventricular ejection fractions and congestive heart failure. N Engl J Med 199I;325: 8. Dilsizian V, Rocco T, Freedman N, Leon M, Bonow R. Enhanced detection of 293-302. ischemie but viable myocardium by the reinjection of thallium after stress-redistribu 25. Galli M, Marcassa C. Bolli R, et al. Spontaneous delayed recovery of perfusion and tion imaging. N Engl J Med 1990:323:141-146. contraction after the first five weeks after anterior infarction: evidence for the presence 9. Smart SC. Sawada SG, Ryan T, et al. Low dose dobutamine echocardiography detects of hibernating myocardium in the infarcted area. Circulation 1994:90:1386-1392. reversible dysfunction after thrombolytic therapy of acute myocardial infarction. 26. Chaitman BR. Jaffe AS. What is the true perioperative myocardial infarction rate? Circulation 1993:88:405-415. Does anyone know for sure? The need for clarification. Circulation 1995:91:1609- 10. Baer FM, Voth E, Schneider CA. Theissen P, Schicha H. Sechtem U. Comparison of 1610. low-dose dobutamine-gradient echo magnetic resonance imaging and positron emis 27. Puleo PR, Meyer D, Wathen C, et al. Use of rapid assay of subforms of creatine kinase sion tomography with F-18 fluorodeoxyglucose in patients with chronic coronary MB to diagnose or rule out acute myocardial infarction. N Engl J Med 1994:331:561- artery disease: A functional and morphological approach to the detection of residual myocardial viability. Circulation 1995;91:1006-1015. 566. 11. Zimmerman R, Mall G, Rauch B, et al. Residuai thaIIium-201 activity in irreversible 28. Ghods M, Pancholy S, Cave V, Cassel B, Heo J. Iskandrian AS. Serial changes in left ventricular function after coronary artery bypass: implications in viability assessment. defects as a marker of myocardial viability: clinicopathological study. Circulation Am Heart J 1995:129:20-23. 1995;91:1016-1021. 12. Tamaki N, Kawamoto M, Tadamura E, et al. Prediction of reversible ischemia after 29. Lee KL. Pryor DB. Pieper KS, et al. Prognostic value of radionuclide angiography in revascularization: perfusion and metabolic studies with positron emission tomography. medically treated patients with coronary artery disease: a comparison with clinical and Circulation 1995;91:1697-1705. catheterization variables. Circulation 1990:82:1705-1717. 13. Eitzman D, Al-Aouar Z, Kanter H. et al. Clinical outcome of patients with advanced 30. Iskandrian AS. Hakki AH. Goel IP, Mundth ED, Kane-Marsch SA, Schenck CL. The coronary artery disease after viability studies with positron emission tomography. J Am use of rest and exercise radionuclide ventriculography in risk stratification in patients Coll Cardiol 1992:20:559-565. with suspected coronary artery disease. Am Heart J 1985:110:864-872. 14. Di Carli MF, Davidson M, Little R, et al. Value of metabolic imaging with positron 31. CASS Principal Investigators and Associates. Coronary Artery Surgery Study (CASS); emission tomography for evaluating prognosis in patients with coronary artery disease a randomized trial of coronary artery bypass surgery: survival data. Circulation and left ventricular dysfunction. Am J Cardiol 1994:73:527-533. 1983:68:939-950.
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