EDITORIAL

Is it possible for myocardial perfusion imaging toavoid missing any patients with high-risk coronarydisease?

Mark I. Travin, MDa,b

See related article on p. 521

A major goal of noninvasive cardiac imaging is toidentify all patients at high risk of a serious cardiacevent. The clinical utility of a particular testing modalitytherefore depends on the confidence one has in the test’sability to exclude high-risk disease. Stress single photonemission computed tomography (SPECT) radionuclidemyocardial perfusion imaging (MPI) has been shown tobe excellent in this regard, as patients with a studyinterpreted as showing no evidence of abnormal myocar-dial perfusion have a likelihood of myocardial infarctionor cardiac death of approximately 0.6% per year.1 Assuch an event rate is less than the statistical risk ofpursuing an invasive management course, it is deemedappropriate to treat such patients medically, with perhapsperforming repeat testing at appropriate intervals de-pending on the clinical situation.2

Nevertheless, a 0.6% risk means that 6 out of 1000patients with a perfusion imaging study interpreted asnormal, in terms of perfusion, will have a serious,possibly fatal event over the following year, and the riskis higher—9 out of 1000—in patients who have hadpharmacologic stress.3 For a busy nuclear cardiologylaboratory that tests thousands of patients per year, thisadds up to many events in patients with normal perfusiontests. Although often such a catastrophic event is a resultof plaque rupture at the site of non–flow-limiting coro-nary atherosclerosis, in which case SPECT MPI wouldgenerally not be able to detect an abnormality in thevulnerable artery, in other cases a severe stenosis in oneor sometimes all 3 major coronary vessels is simply notdetected by SPECT MPI.4

FACTORS MASKING HIGH-RISK DISEASE

There are a variety of potential reasons for SPECTnuclear imaging missing high-risk disease. Methodologicproblems can play a role. If an exercising patient doesnot achieve an adequate heart rate; if, in the setting ofvasodilator pharmacologic testing, the patient, unbe-knownst to the staff, ingested caffeine or took aminoph-ylline before testing; or if the patient has taken antian-ginal medications, there may be insufficient coronaryvasodilatation to detect significant disease.5-8 Carefullaboratory protocols and procedures should minimizesuch a scenario.

Various image artifacts, such as patient motionduring image acquisition and soft-tissue attenuation, canalso impair detection of coronary artery disease (CAD).For example, in men diaphragmatic attenuation of theinferior wall may mask detection of a left anteriordescending (LAD) perfusion defect in the anteriorwall.9,10 Skillful image acquisition and use of variousmethods to overcome attenuation artifacts can reduce butnot eliminate these situations.

Another potential cause of perfusion imaging miss-ing serious disease is the plateauing, at high flow rates, ofmyocardial uptake of the perfusion tracers most com-monly used for stress imaging. Such leveling off of traceruptake can theoretically mask blood flow reserve differ-ences, particularly if vasodilator stress is used.11 Newperfusion tracers are needed to address this importantlimitation of perfusion imaging.

Finally, limitations of SPECT resolution, attributedin part to current collimation techniques, can hide de-fects, particularly in persons with small hearts.12 Newreconstruction techniques and new camera technologyare under investigation to address this problem.13,14

However, there is increasing understanding that inthe setting of multivessel disease, balanced ischemia mayresult in missing a patient who has high-risk coronarydisease. Current techniques of SPECT image interpreta-tion are unable to assess absolute blood flow. Detectionof perfusion defects with SPECT imaging requires thatone or several myocardial regions have relatively re-duced blood flow compared with other areas of themyocardium. If blood flow is uniformly decreased, such

From the Department of Nuclear Medicine, Montefiore Medical Cen-ter,a and Albert Einstein College of Medicine,b Bronx, NY.

Reprint requests: Mark I. Travin, MD, Department of Nuclear Medi-cine, Montefiore Medical Center, 111 E 210th St, Bronx, NY10467-2490.

J Nucl Cardiol 2007;14:492-6.1071-3581/$32.00Copyright © 2007 by the American Society of Nuclear Cardiology.doi:10.1016/j.nuclcard.2007.06.110

492

as may occur in the setting of CAD involving all majorvascular territories, there may in some cases be no visualevidence of abnormal myocardial perfusion or, moreoften, only the most severely perfused area will bedetected.15-17 Given that the amount of disease is oftencrucial in deciding who would benefit from coronaryrevascularization, such underestimation of disease extentis a major limitation of SPECT that needs to be over-come.

DIFFICULTY IDENTIFYING LEFT MAIN DISEASE

One particular type of high-risk CAD that has beenfound difficult to detect with SPECT MPI is a significantleft main (LM) stenosis, particularly if disease is isolatedto this vessel only.18 From the early days of perfusionimaging, it has been known that a typical LM perfusionpattern—that is, defects in both the LAD and leftcircumflex vascular territories—is only rarely observedin patients with an LM stenosis,19,20 surprising in that theLM artery can provide up to 75% of myocardial bloodflow.21 Yet, identification of patients with an LM steno-sis is crucial, as patient survival is greatly improved withbypass surgery.22-25

To improve detection of an LM stenosis and otherhigh-risk CAD, various ancillary test parameters havebeen investigated as supplements to radiotracer perfusionpatterns. Imaging findings such as abnormal tracer wash-out or increased lung uptake when thallium 201 is used,19,26

transient ischemic dilatation (TID),27,28 and electrocardiog-raphy (ECG)–gated SPECT functional data,29 as well asnon-imaging parameters such as hemodynamic response tostress and ischemic ECG findings,30-32 have all been shownto enhance detection of high-risk disease when the perfu-sion pattern is normal or low risk. Hachamovitch et al33

have shown that supplementing perfusion findings withother variables is extremely effective in risk-stratifyingpatients.

In accord with this approach, the article by Bermanet al34 in the current issue of the Journal queried adatabase of 1864 consecutive patients who had bothstress radionuclide MPI and coronary angiographywithin 3 months to identify 101 patients with LMstenosis significant enough for referral to revasculariza-tion, and they investigated combinations of image andstress parameters that could prospectively have noninva-sively identified these patients. In terms of isolatedperfusion pattern findings, only 56% of patients hadmoderately to severely abnormal scans, and most ofthese patients had both LM and 3-vessel disease. Forpatients who had LM with LAD and left circumflexdisease, moderately to severely abnormal perfusion pat-terns were present in only 43%. Of LM patients, 13%

had normal perfusion by visual analysis. To be sure, sucha low rate of LM detection is not acceptable.

However, the article under discussion showed thatthe incorporation of additional findings—low ejectionfraction (EF), perfusion defects in multiple territories,abnormally increased lung uptake (of technetium 99msestamibi), a regional wall motion abnormality, or TID,where the patient needed only one of these parameters—allowed identification of 83% of these LM diseasepatients, again with the identification of high-risk anat-omy being best in patients with both LM and 3-vesseldisease.

There are at least two concerns with these results.First, although incorporation of high-risk non-perfusionfindings improved identification of patients with LMdisease, there still remained a significant number ofpatients with high-risk, potentially life-threatening dis-ease who would have been missed if they had not beenreferred for catheterization. Of 101 LM patients, 17 werenot identified as being at moderate or high risk. Close toone fourth (22%) of patients with a combination of LMand right coronary artery stenosis were not identified.Although the 17 patients who were not identified by theset criteria did have some image or stress abnormality (amild perfusion defect, an equivocal defect, or one of theother non-perfusion abnormalities), under typical cir-cumstances, they would have been considered at lowerrisk and thus not appropriate for catheterization based ontest results alone. We do not know from the reported datawhat led the providers to refer these patients for cathe-terization.

However, more of a problem in terms of using thearticle’s findings to guide patient management is thatthere was likely a large subset of the original 1864patients who, by the study criteria, would have beenclassified as being at increased risk who either did notundergo catheterization and would not have been foundto have LM disease or who did undergo catheterizationand did not have a significant LM stenosis. The studyresults raise the following question: Should every patientwith a mildly abnormal perfusion pattern and one of thenon-perfusion risk findings described in the article un-dergo cardiac catheterization? A recent study by Emmettet al35 showed, for example, that in the presence of leftventricular hypertrophy and diabetes, patients with TIDfrequently do not have high-risk coronary disease. Al-though many investigators would consider their reported45% incidence of extensive CAD to be justification forcatheterization, with the larger number of variablesdescribed in the article under discussion here, the per-centage with high-risk disease would likely be muchlower. It is not clear what threshold of potential high-riskanatomy (which is not the same as the risk of a cardiacevent) would justify catheterization. The same group has

Journal of Nuclear Cardiology Travin 493Volume 14, Number 4;492-6 Missing high-risk patients with myocardial perfusion imaging

recently published data showing SPECT image ischemiaand EF thresholds that can be used to identify patientswho will have a survival advantage with revasculariza-tion,36,37 but these thresholds will still, of course, missmany individual patients with high-risk anatomy whowill have a serious cardiac event.

CAN WE DO BETTER?

Are there potential alternative ways of using nuclearperfusion imaging that can avoid missing individualpatients who have high-risk CAD without also subjectinglarge numbers of patients to unnecessary catheteriza-tions? As indicated at the beginning of this discussion,careful attention to patient preparation, skillful imageacquisition and processing, development of better perfu-sion tracers, and advances in camera and processingtechnology will lessen SPECT image underestimation ofCAD.

Yet, an important aspect of radionuclide MPI thatneeds further development and wider use is imagequantitation. A major strength of nuclear imaging is thatit is inherently quantitative. In the previously cited studyby Ragosta et al,17 SPECT perfusion visually appearednormal in numerous territories that had abnormalfractional flow reserve. Positron emission tomography(PET) perfusion imaging shows promise in being ableto noninvasively measure such fractional flow reserveabnormalities. Gould and colleagues38,39 have shownthat by use of exacting technical standards, quantita-tive analysis of rubidium 82 and nitrogen 13 ammoniaPET images can detect subtle, subclinical changes incoronary flow reserve, allowing detection of earlydisease. Yoshinaga et al40 showed that in territoriesperfused by stenotic coronary arteries, quantitation ofcoronary flow reserve with oxygen 15–labeled wateroften shows abnormalities not appreciated by visual analy-sis of Tc-99m tetrofosmin SPECT images. Finally, there arereports that measurement of coronary flow reserve withRb-82 PET can improve identification of multivessel dis-ease in situations where balanced ischemia produces visu-ally homogeneous perfusion images.41,42 At the same time,work is progressing on the complicated measurement ofabsolute blood flow with Rb-82 perfusion PET that couldprovide further accuracy in the detection of high-riskanatomy.43

Another potential advantage of PET is the ability toacquire images almost immediately after tracer injection,allowing ECG-gated functional data to be acquired whilethe patient is still under stress (when a long-acting stressagent such as dipyridamole is used) and comparing anactual stress EF with a rest EF. Dorbala et al44 recentlydemonstrated that with Rb-82 perfusion PET, a de-

creased stress EF compared with a rest EF increased theability to detect multivessel disease.

IS THERE A ROLE FOR HYBRID IMAGING?

Computed tomography angiography (CTA) is par-ticularly useful for excluding high-risk anatomy becauseof a high negative predictive value.45 Combining CTAwith SPECT or with PET has the potential to provide acomprehensive anatomic and physiologic assessment ofall patients and should never miss high-risk coronarydisease, including life-threatening congenital anoma-lies.46,47 At the same time, routinely performing hybridimaging on all patients with potential high-risk disease isfraught with problems, including the radiation and con-trast risks related to hybrid imaging and costs, as well asthe current lack of data showing how to best manage allof the various CAD anatomic/physiologic combinationsthat would be seen. The proper clinical use of hybridCTA/radionuclide perfusion imaging remains to beworked out.

CONCLUSIONS

As powerful as standard stress SPECT radionuclideMPI is in diagnosing CAD, risk-stratifying patients, andguiding effective management in large cohorts, it still toooften misses high-risk disease in individual patients.Whereas incorporation of non–perfusion pattern findingscan help identify more patients at risk for a catastrophiccardiac event, such techniques still do not identify allpatients, and they too often misidentify patients who do nothave such disease. Better methods are needed to rectify thisimportant limitation of radionuclide MPI, and advances intechnology have much promise in this regard.

Acknowledgment

The author has indicated he has no financial conflicts ofinterest.

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