Detection of Myocardial Viability with Positron Emission Tomography in a Patient with Ischemic

Case Presentation: David Weiss Discussion: Howard J. Eisen Guest Editor: Abass Alavi

Nuclear Medicine Division, Department ofRadiology and the Cardiovascular Section, Department of Medicine, Hospital ofthe University ofPennsylvania, Philadelphia, Pennsylvania

Physical exam revealed a blood pressure of 100/60 J NucI Med 1991; 32:130—135 and a regular pulse of 100. Sharp discs were present on fundiscopic exam with no arteriovenous nicking. Ca rotid artery pulseswere normal with no bruits, and no CASEPRESENTATION jugular venous distention was present. The lungs were clear to auscultation and percussion. Cardiac exam A 52-yr-old man became unresponsive while riding revealed a regular rate, a soft Il/VI systolic ejection in a van driven by his son in August 1989. The son murmur at the lower sternal border, and the presence stopped the van, found the patient to be without spon of an S4. No S3 was heard. Abdominal exam was taneous respirations or pulse, and started cardiopul remarkablefor slight hepatomegaly.The spleenwasnot monary resuscitation. He was aided by a passerby, but enlarged. No peripheral edema, cyanosis, or clubbing approximately 30—45mm elapsed before spontaneous was present. respirations returned. Enroute to a nearby hospital, the Electrocardiographic findings included sinus tachy patient was described as being cyanotic with a very cardia with evidence of right . Left weak pulse. In the emergency room, the patient was axis deviation was present and poor R-wave progression lethargic, and later combative, agitated, and confused. across the precordium was noted. No Q-waves, ST Premature ventricular contractions were noted and, segment, or T-wave abnormalities were present. therefore, a lidocaine infusion was started. Laboratory evaluation upon admission revealed a The patient had reportedly been in good health until creatine kinase of 18, LDH of 367, and glucose of 766. approximately 6 wk prior to admission when he had The arterial blood gases on a 100% rebreathing mask presented with slurred speech and personality changes. were as follows: pH 7.31, p02 of 186, and pCO2 of 28. Computed tomography of the head performed on Au Cardiac enzymes obtained following admission showed gust 24, 1989 revealed a hemorrhagic left parietal in no evidence of an acute . Chest farct, which wastreatedconservatively.The neurologic ifim revealed no evidence ofheart failure, with a mildly signs improved over a period of 3 wk with the only enlarged and somewhat globular appearing cardiac sil residual being a minimal expressive aphasia. Diabetes houette. A radionucide ventriculogram revealed a mellitus had also been discovered during this hospital markedly diminished left ventricular ejection fraction admission. of2O%, biventricular enlargement, apical akinesis, and His family history was significant in that his mother severe hypokinesis of the left ventricle. died at age 52 due to heart disease; a sister also had on August 24, 1989 confirmed a . The patient had a smoking significantly low left ventricular ejection fraction of history ofhalfa pack per week, but had quit 5 mo prior 20%. Biventricular enlargement was present along with to admission. A history ofalcohol abuse in the past was a probable intracardiac thrombus along the septal wall. reported, but recent use was denied. Heart valves were structurally normal. Hemodynamics assessed at cardiac catheterization ReceivedNov.2, 1990;acceptedNov.2, 1990. on August 28, 1989 were remarkable for an elevated For reprintscontact:HowardJ. Eisen,MD. CardiovascularSection, Hospitalof the thversity of PennSylvania,9 Gates Bldg., 3400 Spruce St., mean pulmonary capillary wedge pressure of3O mmHg, Philadelphia,PA19104. elevated right heart pressures consistent with pulmo

130 The Journal of Nuclear Medicine •Vol. 32 •No. 1 •January 1991 @ :@@@:‘

nary hypertension and a diminished cardiac output of 2.99 liters per minute. Cardiac index was 1.47 liters per minute per meter squared. The left ventricular end diastolic pressurewas elevated at 30 mmHg. The arte riovenous02 difference was markedly elevated at 11.3 U) ‘/ vol%. Left ventricular ejection fraction was estimated to be l0%—l5% with globally decreased left ventricular wall motion. Three-vesselcoronaryartery diseasewasdocumented with a 90% stenosis just proximal to the first acute marginal branch of the right coronary artery, a short, diffusely narrowed left main coronary artery, and a tight occlusionbetween the first septalbranch and the first diagonal branch of the left anterior descending (LAD) coronary artery. The LAD lesion appeared to be a total occlusion which had recanalized. A 90% stenosis of the first obtuse marginal branch of the circumflex

artery was present at the vessel origin, and a 50% .@)7B) segmental occlusion of the circumflex was noted dis FIGURE 1 tally. Stress and rest thallium scintigrams show an anterior and The impression at the time of the cardiac catheteri upper septal defect with no redistribution.Other regions of zation was that of severe three-vessel coronary artery the myocardiumshow thalliumuptake. disease with a low output state due to severe biventri cular failure. On the basis ofthese findings, the patient's heart disease was termed end-stage and he was not left ventricle with fixed defects in the anterior and upper considereda candidate for coronary artery bypasssur septal walls, most consistent with scar (Fig. 1). Radio gery. nuclide gated ventriculography done on the same day A tomographic thallium study was then performed demonstrated dilated ventricles, a left ventricular ejec following cardiac pacing on September 7, 1989. The tion fraction of 13%, and global left ventricular hypo patient's heart was paced to 87% of predicted maxi kinesis with akinetic septum and anteroapical walls. On mum. A large defect was present on the immediate the basis of these findings and the attendant intraoper images involving the septum, apex, and inferior wall. ative and perioperative risk of bypass grafting in this Dilatation of the left ventricle was noted on the imme setting, coronary artery bypass graft (CABG) surgery diate post-pacing images. The delayed study revealed was not considered prudent. However, metabolic im the defects to be largely fixed with only slight improve aging was considered to further define the viability of ment in a small portion of the anteroseptal wall. the myocardium. Electrophysiologic studies were performed but no Positron emission tomography (PET) of the heart could be induced. The patient was anti was performed utilizing 10.5 mCi of fluorine-18-la coagulated for the cardiac thrombus. The patient was beled-2-fluoro-2-deoxyglucose(FDG) with the patient transferred to the Hospital of the University of Penn in a fasting state. One hundred grams ofan oral glucose sylvania (HUP) on September 18, 1989 for possible solution was administered orally 1hr prior to injection. cardiac transplantation and placement of an automatic Reconstructed tomographic images revealed normal implantable cardiac defibrillator (AICD). uptake of FDG in both the inferoapical region and in The admitting diagnosis at HUP was dilated cardio the septum, suggesting myocardial viability or “hiber myopathy, most likely ischemic in nature, with proba nating―myocardium (Fig. 2). With this additional in ble associated malignant ventricular and formation, bypass grafting was undertaken with grafts an episode of sudden cardiac death. Admitting chest placedfrom the aorta to the LAD, first obtusemarginal film confirmed the presence of a mildly enlarged heart branch, and from the aorta to the first acute marginal, without evidence of congestive . Carotid second acute marginal, and the distal right coronary Doppler examination revealed no significant stenoses. artery. In addition, patches were inserted for the even Electrophysiologicstudies were repeated with the in tual placement of an AICD. duction of a monomorphic ventricular . Postoperative radionuclide gated ventriculography A stress-rest thallium study was performed on Sep was performed on October 6, 1989 and showed a tember 22, 1989 and the patient achieved 60% of marked improvement in left ventricular ejection frac maximal predicted heart rate with no ischemic electro tion to 36%. Septal and apical wall motion abnormali cardiographicfindings. Scintigraphy revealed a dilated ties persisted but were also substantially improved. Post

Detecting Myocardial Viability •Weiss et al 131 viability. Indirect assessments of viability have relied on global as well as regional left ventricular function and wall motion. Such assessments in the past have been made using contrast or radionuclide angiography or echocardiography. Left ventricular segments that were akinetic, dyskinetic, or severely hypokinetic were felt to be infarcted zones that had little myocardial viability. Exercise-stress tests with thallium-20 1 (201Tl) scintigraphy have provided an improved method of discriminating ischemic but viable myocardium from irreversibly damaged necrotic myocardium (1—3).It has become apparent from prior studies that regional yen tricular wall asynergy or dysnergy does not provide accurate evidence for myocardial viability and that Transaxialslices of PET scan with [18F]FDG.Note homoge dysnergic or asynergic ventricular wall may contain neous myocardialFDG uptake through most of the myocar both viable but functionally impaired and necrotic dium including the anterior wall and upper septum (location of myocardium. the thalliumdefects). Rozanski and colleagues showed that akinetic myo cardial regions with evidence of demonstrated operative course was unremarkable, and prior to dis by 201T1had improved wall motion with revasculariza charge, the patient returned to the operating room for tion after CABG (3). In contrast, akinetic regions with placement of an AICD generator. infarction defined as fixed thallium defects showed no A sternal wound infection diagnosed 4 wk after dis improvement following revascularization. Gibson and charge required hospitalization briefly for i.v. antibiot co-workersprospectivelystudied patients with exercise ics, but otherwise, the patient has recovered satisfactor thallium scintigraphy before and after CABG (4). Fixed ily. thallium defects with relatively higher thallium content (>50% of normal tissue thallium content) were more DISCUSSION likely to show less severe regional wall motion impair This case illustrates an important concern in clinical ment and were more likely to show normal thallium , the determination of myocardial viability. perfusion patterns after revascularization. It hasbecome The scenario described is not an uncommon one: severe apparent that fixed thallium defects at 4 hr after exercise left ventricular dysfunction and three-vessel coronary may still occur in myocardium that can recover func disease without definitive clinical or prior historical tion after revascularization, indicating that these fixed evidence of myocardial necrosis as would occur in defects are not infarcts. Berman and colleagues have myocardial infarction. The distinction between viable shown that defects which are fixed at 4 hr after exercise but functionally impaired myocardium and irreversibly often show reversibility at 24 hr in patients with myo damaged and necrotic myocardium is important be cardial infarction, indicating the presence of viable cause the clinical strategies and therapeutic options for myocardium that might not have been detected if only patients with severely compromised cardiac function 4 hr redistribution studies were done (5—6). Reinjection will vary depending on the relative extent of viable and with 1mCi of201Tlat 4 hr after exercise has been shown necrotic myocardium. As this case demonstrates, pa by Rocco and co-workers to demonstrate normal per tients with extensive, viable myocardial regions may fusion in 50% of segments with fixed thallium defects, benefit from restoration of coronary artery perfusion confirming the difficulty in distinguishing viable from with improvements in global and regional left ventric irreversibly damaged myocardium with 201Tlscintigra ular function. In contrast, patients with extensive myo phy with 4 hr redistribution studies alone ( 7). cardial necrosismay not benefit from revascularization Braunwald, Kloner, and Rahimtoola introduced the and may only have cardiac transplantation asan option. concept of “stunned―and “hibernating―myocardium Many patients with acute myocardial infarction re (8—11). Hibernating myocardium is believed to result ceive thrombolytic therapy and are left with large re from chronic hypoperfusion which is sufficient to main gions of myocardium subtended by coronary arteries tammyocardialviabilityandcellularintegritybutin with high-grade stenoses. The decision regarding coro sufficient to maintain normal myocardial contractility. nary artery revascularization is often dependent on the This situation may occur either regionally in the case determination of viable myocardium since this would of a patient with a single severe coronary artery occlu allow for selection of the patients most likely to benefit sion and inadequatecollateral circulation or globally in from these invasive procedures. a patient with severe three-vessel coronary artery dis There are several techniques for assessing myocardial ease. The latter circumstance can result in severely

132 The Journal of Nuclear Medicine •Vol. 32 •No. 1 •January 1991 depressed left ventricular function in patients without Vaghaiwalla-Mody et al. showed that patients with clinical or electrocardiographic evidence of myocardial idiopathic dilated (IDCM) could be infarction (10). This is referred to as ischemic cardio distinguished from those with ischemic cardiomy myopathy. Such patients have regions of necrotic myo opathies using PET with FDG to measure metabolism cardium and viable myocardium interspersed. Im and with nitrogen-l3-ammonia to measure flow (16). provement in left ventricular function and regional wall Patients with had more motion has been demonstrated in patients with signifi matched perfusion and metabolic defects indicative of cant coronary artery disease who undergo revasculari infarcts than patients with IDCM. zation (1 1). Hibernating myocardium should be distin The group at UCLA has reported the use of metabolic guished from “stunned―myocardium, which is func imaging with PET to detect viable myocardium in a tionally impaired but metabolically active and, hence, patient with severe congestive heart and triple-vessel is viable myocardium following an acute myocardial coronary artery disease failure referred for cardiac trans infarction. plantation (1 7). On the basis of PET imaging, which Distinguishing ischemic cardiomyopathy from di detected viable myocardium, the patient underwent lated cardiomyopathy is often difficult clinically. Deter CABG with improvement in left ventricular function mining the method of therapy for such patients may after revascularization. This clinical scenario is similar depend upon the documentation of significant regions to that of the patient in this case presentation. These of myocardial viability. Ischemic cardiomyopathy has two cases highlight a potential clinical use of cardiac interspersed regions of necrotic and viable myocar PET, namely to determine if patients with ischemic dium. If large regions of viable myocardium are dem cardiomyopathies are candidates for CABG as opposed onstrated, these patients may benefit from CABG as to cardiac transplantation. The clinical ramifications of opposed to cardiac transplantation, which is often the this would be to reserve donor organs, which are in only therapeutic option for patients with irreversibly critically short supply, for those who have no other depressed left ventricular function. options and enable those who would be candidates for Thallium-20l scintigraphy may often overestimate CABGto undergothislesscomplexprocedure. the extent of infarcted and hence irreversibly damaged Newer methods of assessing myocardial viability in myocardium. An alternative technique for assessing dude measurement of oxidative metabolism with PET myocardial viability is the detection of myocardial me and the tracer ‘‘C-labeledacetate (18—23).Brown and tabolism as the sine qua none ofviability. This has been co-workers at Washington University in St. Louis dem accomplished using PET with tracers ofmetabolic path onstrated that ‘‘Cclearance from isolated heart myo ways such as FDG and carbon-i 1- (‘‘C)acetate. Using cardium correlated with ‘‘C-CO2content in the coro PET, Brunken and co-workers have shown that myo nary sinus (18). These correlations were true for nor cardial regions with Q-waves electrocardiographically mal, ischemic, and hypoxic myocardium as well as have myocardial viability in 21 of 3 1 regions studied myocardium stressed at different workloads (18). Car (12). Tillisch et al. showed that the presence of myo bon-l 1-acetate turnover is also independent of substrate cardial viability documented by FDG uptake detected utilization (19). Using a canine preparation, Brown et by PET had an 85% predictive value for improvement al. showed that clearance of ‘‘Cradioactivity from the in regional wall motion following revascularization. heart correlated closely with myocardial oxygen con Conversely, absence of myocardial FDG uptake had a sumption and rate pressure product at a variety of negative predictive value of 92% for improvement in workloads (20). Carbon-i 1-acetate has been studied in regional myocardial function following revasculariza patients (21—23).This work has shown that myocardial tion (13). ‘‘C-acetate turnover can be measured with PET in Brunken et al. compared PET with FDG to 201'fl humans and that ‘‘C-acetateconsumption is perturbed scintigraphy in patients with persistent, fixed thallium in ischemicand infarcted myocardial regions.The util defects indicative ofscar (14). Of 142 segments studied ity of this tracer for assessingmyocardial viability and in 26 patients, 101 had fixed defects, 31 had partially for predicting improvement in left ventricular regional reversible defects, and 10 had completely reversible wall motion after intervention is unknown. defects by thallium scintigraphy. Of the 101 fixed de Bonow and colleagues have compared PET with fects, 47 had intact glucose metabolism as defined by FDG to thallium stress-rest studies with reinjection of PET with FDG, implying myocardial viability. Of the thaffium immediately after acquisition of redistribution partially reversible defects, 20 had glucose metabolism images (24). They showed that 201T1reinjection studies detected by PET. Tamaki and colleagues obtained sim were capable of demonstrating myocardial viability in ilar results in a study of 28 patients with prior myocar regions detected by PET with FDG but not detected by dial infarctions (15). Of 39 persistent defects noted, 15 conventional stress-thallium studies, which suggested showed enhanced glucose metabolism, indicating viable that reinjection ofthalhium at the time ofthe rest study myocardium. may enhance the utility of thallium scintigraphy for

DetectingMyocardialViability•Weisset al 133 detecting viable myocardium. This study was per REFERENCES formed in a relatively small group ofpatients, therefore, I. Pohost GM, Zir LM, Moore RH, McKusick KA, Guiney TE, studies with larger patient groups are required. Beller GA. Differentiation of transiently ischemic from in Several groups are studying magnetic resonance im farcted myocardium by serial imaging after a single dose of aging (MRI) as a technique for distinguishing viable thallium-20l. Circu!ation l977;55:294—302. from irreversibly damaged myocardium. Wendland and 2. Ritchie JL, Albro PC, CaldwellJH, Trobaugh GB, Hamilton OW.Thallium-201myocardialimaging:a comparisonof the colleagues have shown that MRI with a chelate of redistribution and rest images.J Nuc!Med l979;20:477—483. gadolinium, Gd-DTPA-BMA, was able to distinguish 3. Rozanski A, Berman DS, Gray R, Ctal. 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134 The Journal of Nuclear Medicine •Vol. 32 •No. 1 •January 1991 myocardial oxidative metabolism with carbon-l 1-acetate and 23. Ambrecht JJ, Buxton DB, Brunken RC, Phelps ME, Schelbert positron emission tomography despite altered patterns of HR. Regionalmyocardialoxygen consumptiondetermined substrate utilization. J Nuci Med 1989:30:187—193. noninvasively in humans with [I-' ‘C]acetateand dynamic 20. Brown M, Myears D, Bergmann S. Noninvasive assessment positron tomography. Circulation 1989;80:863—872. of canine myocardial oxidative metabolism with carbon-l I- 24. Bonow RO, Bacharach SL, Cuocolo A, Dilsizian V. Myocar acetate and positron emission tomography. JAm Coil Cardiol dial viability in coronary artery disease and left ventricular 1988:12:1054. dysfunction: thallium-201 reinjection vs. fluorodeoxyglucose 21. Henes C, Bergmann S. Walsh M, Sobel B, Geltman EM. [Abstract].Circulation l989;80:II—377. Assessment of myocardial oxidative reserve with positron 25. WendlandMF, SaeedM, TakeharaY, HigginsCB.Non-ionic emission tomography and carbon- 11-acetate. J Nuci Med Gd-DTPA-BMA has the potential to differentiate between 1989:30:1489—1499. reversible and irreversible myocardial injury [Abstract]. Cir 22. Walsh MN, Geltman EM, Brown MA, et al. Noninvasive culationl989;80:II—237. estimation of regional myocardial oxygen consumption by 26. PettigrewRI, BrownellA-L, HolmvangG, ci al. Iron oxide positron emission tomography with carbon- 11-acetate in pa MRIofmyocardialtissueblooddeliverypost-acuteinfarction: tients with myocardial infarction. J Nuci Med 1989:30:1798— comparison with quantitative PET [Abstract]. Circulation 1809. 1989;80:II—232.

(continuedfromp. 101) SELF-STUDY TEST Radiobiologyand RadiationProtection indications.Whereasthe IND-NDAprocessis intendedfor the medicinephysicianshould prescribethe smallestdosagethat will developmentof newcommercialpharmaceuticals,thereisocca yieldastudyresultofacceptablequality,basedonconsiderations sionallyadesiretostudyaradioactivedruginaverylimitednumber ofthesensitivityofthecountingorimagingequipmentbeingused ofpatientsstrictlyforthepurposeofobtainingfundamentalmetabol and the weight(and sometimesage) of the patient.Patient icor biochemicalinformation.TheFDAhasprovidedforthistype throughputshouldbe onlya minorconsideration.However,certain ofinvestigationinPart361ofTitle21oftheCodeofFederalRegula clinicalcircumstancesmightjustifya higherdose,e.g.,acritically tions.Becausethe informationobtainedfromthesestudieswill not illor unstablepatientinwhomcompletingtheexaminationfaster directlybenefitthepatientsbeingstudied,theFDAhasimposed would be of definite benefit to the patient. Thus, the maximum maximumlimitsonthepharmacologicdoseandabsorbedradiation dosageofaradiopharm@euticalistobedeterminedbythenuclear doses, which cannot be exceeded in such studies. medicinephysicianusinginformationonabsorbeddosefromthe Title10of theCodeof FederalRegulationscontainsallof the packageinsertandexercisinghisor herbestclinicaljudgment. regulationspublishedbytheU.S.NuclearRegulatoryCommission. Dosagessignificantlyabovethosesuggestedinthepackageinsert Part20 dealsstrictlywith radiationprotectionstandardsthatapply may be used, but the physician should be ready to defend the to radiationworkers,membersof the generalpublic,and the dosageas beingmedicallyjustifiedin eachspecificinstance. environment. Discussionsof exposure to patients in Part 20 are limitedto:(1)asectionthatexcludesaradiationworker'sdosedue to a medical procedure from being added to his occupational ITEM 3: ALARA PhIlosophy exposureand(2)asectionthatexcludespatientexcretafromthe ANSWER:D wastedisposal standards.Part35, which was extensivelyrevised A fundamentaltenetof radiationprotectionphilosophyisthatno in 1986,setsforththe regulationsthatcontrolthesafeuseof by personshouldbeexposedto radiationandradioactivematerials product radioactivematerialsor the associatedradiationsin the unlessthere is a demonstrablebenefitto that person in particular, clinical practice of medicine. The regulationsin Part 35 stipulate to societyin general,or to both.Thispostureis basedon the thetrainingandexperienceofphysicianswhomaybeauthorized conservativebutprudenthypothesisthatevensmallamountsof touseby-productmaterial,theradiopharmaceuticalsthatmaybe radiationhavethe potentialto causeirreparabledamage.The usedbyNRC.licensedphysicians,andotherrequirementsrelated balancingof benefitand risk resultsin the semiquantitative to qualityassurancerecord-keeping,etc.Part35 makesnomention relationship“benefit—riskratio,―butthebenefit—riskratiodoesnot of the maximum allowabledosage for any radiopharmaceutical. take into account the costs involvedin achieving reduced risk. In NCRPReportNo.70providesa detailedreviewofthe nuclear high-qualitymedical practice,the benefit—riskratio(withregardto medicineimagingprocessandthefactorsthatmustbeconsidered radiationexposure)isalwaysclearlygreaterthanonaBenefitsand inthede@gnofaradiopharmaceuticaloranewimagingprocedura risksaremuchmoredifficultto defineinotherinstances,suchas The report discussestypical valuesof absorbeddosesfrom theselectionofthesitefora low-levelradioactivewastedisposal currentlyusedradiopharmaceuticalsandcautionsthatthe ALARA facility.Inthesetypesofcases,thepeopleorinstitutionsaccruing conceptshouldbe appliedto administereddosagele@ls;however, thebenefitusuallyarenotthesamepeopleor communitieswho it doesnotofferanysuggestionsaboutmaximumadministered areexposedto the risk. dosages. The mandateto reduce risk regardlessof the magnitude of the Thereare no regulationsthat stipulatethe maximumdosage of costs (time,personnel,money)is embodied in the philosophy of aradiopharmaceuticalthataphysicianmayadministertoapatient. ALAP,or as /owas possible ALAP wasthe operating philosophy The FDA has a long-standingpolicy that the way a drug is ofradiationsafetyregulatoryagenciesuntilrecently.Althoughthere administeredto a patientis a medicaldecisionbestleftto the is nothinginherentlywrongwith attemptingto controlradiation judgmentofaqualifiedphysician.IntheFDA'sview,thispolicyhas exposurestoALAP@thereisapracticalproblem—howdowedefine alwaysappliedtoradiopharmaceuticalsaswellastononradioactive ALAPsothatweknowwhenwehaveaccomplishedit?Aregulatory pharmaceuticals.Incontrast,the NRCformerly restrictedthe use agency inspector may tell you that 15 mrems/monthis ALAP for of a radiopharmaceutical to the chemical form, route of a nuclearmedicinetechnologist,butyourexperiencemayhave administration,and dosagerangestipulatedinthe packageinsert; shownthat2OmremsfrnonthisALAPforyourclinic.Whosedefinftion thisrestrictionnolongerappearsinthecompleterevisionof Part should be accepted, and who willarbitratethese disputes?ALAP 35thatwaspublishedinOctober1986andtookeffectinApril1987. can be extendedto the point of requiringthat exposuresbe The FDA'spositionthat dosage levelsareto be determinedbythe essentiallyzero,becauseadditionalshieldingor otheralterations physiciannowappliesfullyto radiopharmaceuticals.A nuclear (continued on p. 189)

Detecting Myocardial Viability •Weiss et al 135