Heart International 2011; volume 6:e22

[Heart International 2011; 6:e22] [page 81]

Triple vessel coronary artery disease presenting as a markedly positivestress electrocardiographic test and a negative SPECT-TL scintigram:a case of balanced ischemiaEmad F. Aziz, Fahad Javed, Carlos L. Alviar, Eyal HerzogThe ACAP Program; St. Luke’s - Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA

Abstract

The presence of false negative nuclearstress test in the settings of positive electro-cardiographic changes is a very unusual phe-nomenon and is usually secondary to balancedischemia of the myocardial segments evaluat-ed by SPECT-TL. We present a case of an 81-year old post-menopausal female who present-ed to her primary care physician for evaluationof a 6-week dyspnea on exertion and wasreferred to our institution for exercise stresstest with Thallium SPECT with the objective ofruling out coronary artery disease and identi-fying possible areas of myocardial ischemia.The resting electrocardiogram was unremark-able and stress test evaluation was made. Thepatient was admitted to the cardiac care unitand coronary artery bypass grafting was suc-cessfully performed. The presence of falsenegative nuclear stress test in the settings ofpositive electrocardiographic changes is a veryunusual phenomenon and is usually second-ary to balanced ischemia of the myocardial

segments evaluated by SPECT-TL. Patientsundergoing stress tests with these character-istics should undergo careful evaluation and ahigh level of suspicion should be adopted forfurther diagnostic assessment of coronaryartery disease.

Introduction

Nuclear imaging with stress myocardial per-fusion techniques, mostly single-photon emis-sion computed tomography with radioisotopessuch as Thallium (SPECT-TL) and techniciam-99m, has become the preferred modality for thenon-invasive evaluation of ischemic heart dis-ease. This diagnostic method plays a particular-ly important role in the identification ofischemic territories and myocardial viabilityassessment.1 Its sensitivity (85-90%) has beenreported to be affected by different factors suchas lesion characteristics and exercise test per-formance.2 Reports of false negative myocardialperfusion scintigraphy tests have been welldescribed in the literature. They have beenassociated with different factors such as loca-tion of the lesions in the left circumflex arteryor bifurcation areas, lesions with mild athero-sclerotic burden producing non-obstructivecoronary heart disease, single vessel compro-mise, the use of antianginal agents prior to thetest or low levels of exercise leading to lowmyocardial oxygen consumption not sufficientto achieve diagnostic thresholds during stresstest evaluation.3 Similarly, some cases of falsenegative Thallium scans can be explained bythe use of certain agents such as caffeine orlow molecular weight heparin before the test.However, this has only been related to stresstests with dipyridamole and the most likelyexplanation is an interaction with the adeno-sine receptor antagonist.4,5

Cases of false negative ECG during exercisestress test in patients with coronary artery dis-ease later confirmed by positive nuclear stud-ies and coronary angiogram have often beendescribed. However, false negative SPECT-Tl

studies associated with balanced ischemia areless commonly seen and different theorieshave been proposed to explain this phenome-non. We present a case of a truly positive elec-trocardiographic stress test with a false nega-tive nuclear scan in a patient with multivesselcoronary artery disease, a very unusual phe-nomenon which is rarely seen and which hashad very few reports in the medical literature.

Case Report

We present a case of an 81-year old post-menopausal female with a past medical historyof hypertension and dyslipidemia, the lattermanaged with non-pharmacological treatment.Her outpatient pharmacological regimen con-sisted of mlodipine and hydrochlorothiazide forblood pressure control and aspirin for primarycardiovascular prevention. She presented toher primary care physician for evaluation of a6-week dyspnea on exertion and she wasreferred to our institution for exercise stresstest with Thallium SPECT with the objective ofruling out coronary artery disease and identify-ing possible areas of myocardial ischemia. Thepatient denied any other complaints includingchest pain, palpitations, fatigue, orthopnea,dizziness or cough. There were no other riskfactors for cardiovascular disease, such as his-tory of diabetes mellitus, known prior cardio-vascular events, smoking history or family his-tory of premature cardiovascular disease. Atpresentation the patient’s exercise tolerancewas minimal due to the shortness of breathdescribed above. The resting electrocardiogram was unre-

markable as shown in Figure 1. The patientpresented for stress test evaluation followingthe standard protocol for nuclear imagingestablished in our institution. This included aone-day test with rest/stress phases with 99m-sestamibi infusion followed by myocardial per-fusion imaging with SPECT. The stress proto-col followed for this case included exercisetreadmill and the heart rate achieved was 140

Correspondence: Emad F. Aziz, Coordinator ACAPProgram, St. Luke’s-Roosevelt Hospital Center,Columbia University College of Physicians &Surgeons, 1111 Amsterdam Avenue, New York,NY 10025, USA.E-mail: DrEAziz@Gmail.com; Eaziz@NYIT.Edu

Key words: false negative stress testing, balancedischemia.

Received for publication: 18 May 2011.Revision received: 5 September 2011.Accepted for publication: 25 October 2011.

This work is licensed under a Creative CommonsAttribution NonCommercial 3.0 License (CC BY-NC 3.0).

©Copyright E.F. Aziz et al., 2011Licensee PAGEPress, ItalyHeart International 2011; 6:e22doi:10.4081/hi.2011.e22

Case Reports

[page 82] [Heart International 2011; 6:e22]

beats per minute which was 101% of her max-imal predicted heart rate, with a maximalblood pressure of 160/90 mmHg during peakexercise. At that level of exercise, after approx-imately about 4 min the electrocardiogramshowed ST-segment depression of 2 mm inleads I, II, V5 and V6 with concomitant ST-seg-ment elevation of 1 mm in aVR; however, thepatient remained symptom free during theentire test (Figure 2). The patient’s calculatedDuke treadmill score (-10), carries a 64% prob-ability of significant CHD, a 47% probability ofsevere CHD and a 28% 5-year mortality.6-8 Theexercise protocol was, therefore, stopped andthe patient was taken to the nuclear laboratoryto complete SPECT imaging.Myocardial perfusion imaging was per-

formed both at rest and immediately after dis-continuation of the exercise treadmill phaseand standardized imaging integration software(Myovation™, General Electric HealthcareTechnologies, Milwaukee, Wisconsin, USA)was used to gate and reconstruct the planimet-ric images for results to be interpreted.Tomographic imaging of the different seg-ments and myocardial segments and wallswere completely normal and did not show anyapparent defects in perfusion in any territoryat rest or at stress (Figures 3A and B) with nosignificant wall motion abnormalities, no tran-sient ischemic dilatation and a left ventricularsystolic ejection fraction of 54%. However,given the markedly positive electrocardiogramduring peak exercise and the patient’s clinicalpresentation, she was taken to the cardiaccatheterization laboratory for angiographicevaluation. Cardiac catheterization showedtriple vessel coronary artery disease with 95%stenosis on the distal left main, 40% stenosisof the mid segment of the right coronaryartery, 75% stenosis of the mid segment of theleft anterior descending coronary artery and70% stenosis of the distal segment of the leftcircumflex coronary artery (Figure 4A and B).The patient was admitted to the cardiac careunit and coronary artery bypass grafting wassuccessfully performed.

Discussion

Exercise stress testing is a common screen-ing tool for the non-invasive evaluation ofpatients with suspected coronary heart dis-ease.8 In the last few decades, the combinationof electrocardiographic evaluation with imag-ing techniques such as echocardiography ornuclear scintigraphy has improved the diag-nostic accuracy of the stress test. The overallsensitivity and specificity of exercise ECG test-ing is approximately 65-68% and 72-77%respectively9-11 while Thallium SPECT providesa sensitivity of 81.9% with a specificity of

96.0% for the evaluation of the extension ofmyocardial ischemia based on comparisonsperformed with pathology specimens.12

False negative results in patients undergo-ing electrocardiographic stress test with exer-cise have been reported and they are often sec-ondary to submaximal exercise stress testing,mild to moderate stress-induced ischemia, sin-gle vessel coronary artery disease (CAD) andelectrical cancellation of the ischemic vectors.This last phenomenon, which has been associ-ated to multi-vessel disease, has been attrib-uted to a process called ischemic ST-segmentcounterpoise. This is basically the cancellationof the ischemic ST-segment vectors, secondaryto severe ischemia that is homogenously dis-tributed and that involves segments of themyocardium that are opposite to each other.13

This agrees with previous data showing thatThallium scans are more sensitive to detectmultivessel coronary artery disease than theexercise stress test, especially in patients witha prior history of myocardial infarction inwhich the distribution of the ischemic vectorsmight play a similar role.14 Similarly, it hasbeen reported that positive Thallium scans canidentify 75% of the patients with false negativeelectrocardigraphic exercise tests and 82% ofthe patients with positive ECG exercise tests.15

A study of 15 symptomatic patients demon-strated that myocardial perfusion imagingafter the combination of dipyridamole and lowlevel exercise can help to identify individualswith true ischemic segments with false nega-tive electrocardiographic stress test and non-diagnostic Thallium scans secondary to sub-

Figure 1. Baseline electrocardiography.

Figure 2. ST-segment depression in leads I, II, V5, V6 and ST-segment elevation in leadaVR.

Case Reports

[Heart International 2011; 6:e22] [page 83]

maximal exercise during the test.16

Our patient had markedly positive electro-cardiographic changes but a false negativeSPECT-TL. While she achieved adequate exer-cise levels during the stress test, factors suchas inadequate myocardial effort during peakexercise were unlikely to explain the negativenuclear study and despite having intermediatepre-test probability of CAD,17 she was found tohave severe disease. The literature reportssimilar cases with multi-vessel coronary dis-ease presenting as false negative scans andtrue positive electrocardiographic exercise testconfirmed by coronary angiogram.18-20 Theexact incidence of this phenomenon has notyet been accurately described and a clear etiol-ogy behind this process is not completelyunderstood. Despite this, the estimated fre-

quency of false negatives of SPECT-TL hasbeen reported to be around 11% and, accordingto some series, the ability of this phenomenonto correctly localize the ischemic region andcalculate the extent of myocardial involvementcan be as low as 20% in patients with triplevessel disease.21 In a recent sub-analysis of theJ-ACCESS study, 293 out of a total of 2,383patients undergoing exercise testing withmyocardial perfusion imaging were noted tohave ischemic electrocardiographic changeswith no reversible abnormalities.22

Our case represents this phenomenon cata-logued as balanced ischemia in which the radio-tracer uptake by the different myocardialregions becomes homogenously distributed sec-ondary to globalized hypoperfusion in all thesegments of the myocardium. The principle of

nuclear imaging techniques to detect ischemicareas is based on the fact that significant differ-ences, defined as 15-20%, in myocardial perfu-sion between different regions are identified asreversible defects within the cardiac musclewhen exposed to stress.23 The quantification ofthe radiotracer’s distribution could demonstrateglobal reduction in the uptake, but Thalliumassessment is based on relative differences inthe signal density between myocardial territo-ries. Therefore, the presence of uniformly dis-tributed ischemic burden in all the myocardialregions evaluated by SPECT-TL can lead to falsenegative results.24 In our case, the associatedSPECT-TL indicated homogeneous perfusion ofthe heart both at stress and rest phases withoutsignificant differences relative to the washoutor redistribution phases, and was interpreted asnormal.In general, a positive electrocardiographic

test with a negative TL in patients with sus-pected coronary artery disease in whom doubtsabout the diagnosis are raised usually requiresfurther evaluation with more invasive tech-niques. In our patient, despite the negative TLand because of case history and the stronglypositive ECG, the patient underwent cardiac

Figure 3. (A) Planar images-eCToolBox. (B) Planar images-MYOVATION.

Figure 4. (A) LAO caudal projection show-ing severe distal left main disease. (B) RAOcaudal projection showing severe distal leftmain disease.

A

A

B

B

Case Reports

[page 84] [Heart International 2011; 6:e22]

catheterization. This was also based on previ-ous studies demonstrating the prognosticvalue of ST changes during exercise stresstest. Colby et al. highlighted the importance ofcaution when interpretating the ST changesseen during exercise stress test. They foundthat the degree of exercise-induced ST depres-sion did not correlate with perfusion defects inthe exercise-induced Thallium-201. Arguably,this might not be true with ischemic ECGresponse to intravenous adenosine adminis-tration and normal perfusion on SPECT, as itwas shown that these patients, and particular-ly women, are at low risk of cardiovascularevents, even after long-term follow up.25

However, patients presenting with stronglypositive electrocardiographic changes duringexercise tests, especially at early stages of theBruce protocol with low levels of oxygen con-sumption (low Mets or low heart rate), warranta careful and more thorough evaluation forcoronary disease, even in the setting of nega-tive nuclear studies as they have been identi-fied to have a higher risk of myocardialischemia.26 Similarly, in terms of diagnosticand prognostic implications, vasodilator perfu-sion SPECT share similar characteristics withexercise stress testing.Another theory behind the presence of false

negative SPECT-TL with a truly positive elec-trocardiogram during peak exercise has beenproposed by Madias et al.19 These authors sug-gested that the cardiac apex is responsible forthe truly positive electrocardiographic changesin cases of global ischemia, like the one pre-sented here. They proposed that the apicalmyocardial wall segment, which is alsoischemic and able to generate ST segmentdeviations, is not cancelled by any vector com-ing from a muscular structure as there is notreally a myocardial segment opposite to theapex that could generate ischemic ST vectorscancelling the apical one. This issue might beperhaps overcome with the use of dipyri-damole Tl-201 gated myocardial perfusionimaging in order to detect the presence ofstunting myocardium by wall motion abnor-malities induced by ischemia, as proposed bysome authors.27,28

Conclusions

The presence of false negative nuclearstress test in the settings of positive electro-cardiographic changes is a very unusual phe-nomenon and is usually secondary to balancedischemia of the myocardial segments evaluat-ed by SPECT-TL. This is perhaps explained by aprocess in which the ischemic apical segmentis spared from electrocardigraphic vectors can-celling the ST segment changes. Patientsundergoing stress tests with these characteris-

tics should undergo careful evaluation and ahigh level of suspicion should be adopted forfurther diagnostic assessment of coronaryartery disease.

References

1. Marzullo P, et al. Imaging of myocardialviability: a head-to-head comparisonamong nuclear, echocardiographic, andangiographic techniques. Am J CardImaging 1993:7:143-51.

2. Fleischmann KE, et al. Exercise echocar-diography or exercise SPECT imaging? Ameta-analysis of diagnostic test perform-ance. JAMA 1998:280:913-20.

3. Fujimoto S, et al. Study of the predictorsand lesion characteristics of ischemicheart disease patients with false negativeresults in stress myocardial perfusion sin-gle-photon emission tomography. Circ J2006: 70:297-303.

4. Smits P, et al. False-negative dipyridamole-thallium-201 myocardial imaging after caf-feine infusion. J Nucl Med 1991:32:1538-41.

5. Hofman MS, et al. False-negative myocar-dial perfusion scintigraphy possibly as aresult of administration of low-molecular-weight heparin. Clin Nucl Med 2007:32:70-2.

6. Gulati M, et al. Prognostic value of theduke treadmill score in asymptomaticwomen. Am J Cardiol 2005:96:369-75.

7. Ho KT, et al. Long-term prognostic value ofDuke treadmill score and exercise thalli-um-201 imaging performed one to threeyears after percutaneous transluminalcoronary angioplasty. Am J Cardiol1999:84:1323-7.

8. Mark DB, et al. Exercise treadmill score forpredicting prognosis in coronary arterydisease. Ann Intern Med 1987:106:793-800.

9. Detrano R, et al. Exercise-induced ST seg-ment depression in the diagnosis of multi-vessel coronary disease: a meta analysis. JAm Coll Cardiol 1989: 14:1501-8.

10. Gianrossi R, et al. Exercise-induced STdepression in the diagnosis of coronaryartery disease. A meta-analysis. Circula-tion 1989:80:87-98.

11. Garber AM and Solomon NA. Cost-effec-tiveness of alternative test strategies forthe diagnosis of coronary artery disease.Ann Intern Med 1999:130:719-28.

12. Nagashima J, et al. [Evaluation of thalli-um-201 myocardial emission computedtomography based on a comparison withpostmortem findings]. Radioisotopes1986:35:631-5.

13. Madias JE, Mahjoub M, and Valance J. Theparadox of negative exercise stress

ECG/positive thallium scintigram. Ische-mic ST-segment counterpoise as theunderlying mechanism. J Electrocardiol1996:29:243-8.

14. Ahmadpour H, et al. Thallium 201 exercisescintigraphy for detection of multivesselcoronary artery disease after transmuralmyocardial infarction. J Natl Med Assoc1984:76:1193-200.

15. Hakki AH, et al. Implications of normalexercise electrocardiographic results inpatients with angiographically document-ed coronary artery disease. Correlationwith left ventricular function and myocar-dial perfusion. Am J Med 1983:75:439-44.

16. Verzijlbergen JF, et al. Inadequate exerciseleads to suboptimal imaging. Thallium-201myocardial perfusion imaging after dipyri-damole combined with low-level exerciseunmasks ischemia in symptomaticpatients with non-diagnostic thallium-201scans who exercise submaximally. J NuclMed 1991:32:2071-8.

17. Gibbons RJ, et al. ACC/AHA 2002 guidelineupdate for exercise testing: summary arti-cle: a report of the American College ofCardiology/American Heart AssociationTask Force on Practice Guidelines(Committee to Update the 1997 ExerciseTesting Guidelines). Circulation 2002:106:1883-92.

18. Madias JE. Falsely negative thallium-201scintigram associated with truly positiveexercise electrocardiogram: the case ofthe globally balanced myocardial ischemia.Cardiology 2006:105:22-4.

19. Madias JE, Knez P, and Win MT. True-posi-tive exercise electrocardiogram/false-neg-ative thallium-201 scintigram: a proposalof a mechanism for the paradox. ClinCardiol 2000:23:625-9.

20. Lesser JR, et al. Balanced myocardialischaemia: a case of "normal" stress Tc99sestamibi scan and diagnosis. Heart2005:91:e53.

21. Svane B, Bone D, and Holmgren A.Coronary angiography and thallium-201single photon emission computed tomog-raphy in multiple vessel coronary arterydisease. Acta Radiol 1990:31:325-32.

22. Takehana K, et al. Clinical significance ofischemic electrocardiographic changesduring stress myocardial perfusion imag-ing: sub-analysis of the J-ACCESS study.Ann Nucl Med 2010:24:215-24.

23. Aarnoudse WH, Botman KJ, and Pijls NH.False-negative myocardial scintigraphy inbalanced three-vessel disease, revealed bycoronary pressure measurement. Int JCardiovasc Intervent 2003:5:67-71.

24. Sharir T, et al. Identification of severe andextensive coronary artery disease by pos-texercise regional wall motion abnormali-ties in Tc-99m sestamibi gated single-pho-

Case Reports

[Heart International 2011; 6:e22] [page 85]

ton emission computed tomography. Am JCardiol 2000:86:1171-5.

25. Hage FG, Heo J, and Iskandrian AE.Adenosine-induced ST segment depres-sion with normal perfusion. Cardiol J2009:16:121-6.

26. Colby J, et al. Hemodynamic, angiographicand scintigraphic correlates of positive

exercise electrocardiograms: emphasis onstrongly positive exercise electrocardio-grams. J Am Coll Cardiol 1983:2:21-9.

27. Hung GU, Chen CP, and Yang KT.Incremental value of ischemic stunning onthe detection of severe and extensive coro-nary artery disease in dipyridamole Tl-201gated myocardial perfusion imaging. Int J

Cardiol 2005:105:108-10.

28. Kumar SP and Movahed A. Importance of

wall motion analysis in the diagnosis of

left main disease using stress nuclear

myocardial perfusion imaging. Int J

Cardiovasc Imaging 2003:19:219-24.