variability of myocardial ischemic responses to mental versus exercise or adenosine stress in...

Variability of myocardial ischemic responses tomental versus exercise or adenosine stress inpatients with coronary artery diseaseMustafa Hassan, MD,a,b Kaki M. York, PhD,b Qin Li, MS,c

Dorian G. Lucey, BA, NCT,a,b Roger B. Fillingim, PhD,d andDavid S. Sheps, MD, MSPHa,b

Background. Mental stress precipitates myocardial ischemia in a significant percentage ofcoronary artery disease (CAD) patients. Exercise or adenosine stresses produce differentphysiologic responses and cause myocardial ischemia via different mechanisms. Little is knownabout the comparative severity and location of myocardial ischemia provoked by these differentstressors. In this study we sought to compare the within-individual ischemic responses to mentalversus exercise or adenosine stress in a cohort of CAD patients.

Methods and Results. All patients underwent mental stress and either exercise or adenosinetesting within a 1-week period. Mental stress was induced via a public speaking task. Rest-stressmyocardial perfusion imaging was used with all testing protocols. Participants were 187 patients(65 women [35%]) with a documented history of CAD and a mean age of 64 � 9 years. Mentalstress–induced myocardial ischemia (MSIMI) was less prevalent and frequently of lessmagnitude than exercise- or adenosine-induced ischemia. Ischemia induced by exercise oradenosine testing did not accurately predict the development or the location of MSIMI. Theoverall concordance between these stressors for provoking ischemia was weak (percentagreement, 71%; � [� SE], 0.26 � 0.07). In a minority of patients (11%) mental stress provokedischemia in the absence of exercise- or adenosine-induced ischemia. Moreover, in patients whohad myocardial ischemia during both stressors, there were significant within-individualdifferences in the coronary artery distribution of the ischemic regions. MSIMI was more likelyto occur in a single-vessel distribution (86%) compared with exercise- or adenosine-inducedischemia (54%). The stressors had moderate agreement if the ischemic region was in the rightcoronary artery territory (percent agreement, 76%; �, 0.52 � 0.19) or the left anteriordescending coronary artery (percent agreement, 76%; �, 0.51 � 0.19) and significantly loweragreement in the left circumflex territory (percent agreement, 62%; �, 0.22 � 0.18).

Conclusions. Our findings indicate that mental and exercise or adenosine stresses provokedifferent myocardial ischemic responses. These observations suggest that exercise or adenosinetesting may not adequately assess the likelihood of occurrence or severity of MSIMI and thatdifferent mechanisms are operative in each condition. (J Nucl Cardiol 2008;15:518-25.)

Key Words: Psychological stress • exercise test • adenosine • myocardial ischemia

See related article on p. 491

Mentally stressful tasks can provoke transient myo-cardial ischemia in a significant proportion of patientswith coronary artery disease (CAD).1-4 Mental stress

testing in the laboratory is a simulation of daily lifestress.2,3 Several studies have shown that the develop-ment of myocardial ischemia in this setting predictsischemia during daily life, is a poor prognostic factor,and is linked to fatal and nonfatal cardiac events inpatients with CAD.2-8

From the Division of Cardiology, Department of Medicine,a Depart-ment of Epidemiology and Health Policy Research,c and Depart-ment of Community Dentistry and Behavioral Science, College ofDentistry,d University of Florida, and North Florida/South GeorgiaVA Healthcare System,b Gainesville, Fla.

This study was supported by grants HL 070265 and HL 072059 fromthe National Heart, Lung, and Blood Institute. This material is also theresult of work supported by resources and the use of facilities at theDepartment of Veterans Affairs Medical Center, Gainesville, Fla.

Received for publication Nov 27, 2007; final revision accepted April 1,2008.

Reprint requests: Mustafa Hassan, MD, Cardiology Research (151),VAMC, 1601 SW Archer Rd, Gainesville, FL 32608; [email protected].

1071-3581/$34.00Copyright © 2008 by the American Society of Nuclear Cardiology.doi:10.1016/j.nuclcard.2008.04.005

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Exercise or adenosine stress testing is commonlyused in clinical settings as a risk stratification tool inpatients with CAD. However, there is evidence that thesetesting modalities may not adequately assess the likeli-hood of risk related to mental stress.9-11 One studyreported that the addition of mental stress to exercisetesting improved the detection of myocardial ischemia.10

We recently reported that mental stress could provokeischemia in CAD patients with negative exercise oradenosine testing findings.9 If it is eventually proven thatthis category of patients is at increased risk for adverseevents, this will have significant implications for our currentmethods of risk stratification. Studying the variability ofresponses to mental and exercise or adenosine stress mayimprove our understanding of the pathophysiologic mech-anisms operative in these settings and may consequentlyhelp in improving our risk prediction strategies.

In this study we compared the variability of myo-cardial ischemic responses to mental versus exercise oradenosine stress in a cohort of CAD patients. We studiedthe within-individual concordance between these stressmodalities in provoking myocardial ischemia. We alsoexamined the variability in the regional distribution andmagnitude of ischemia in individuals in whom it devel-oped during both stress modalities.

METHODS

Study Design

The study protocol was approved by the University ofFlorida Institutional Review Board (Gainesville, Fla). Informedconsent was obtained from all participants. In random order, allpatients underwent mental stress and exercise or adenosine stresstesting on separate mornings within a 1-week period. None of theparticipants had any changes in their medications or clinical statusbetween the testing sessions. The tests were conducted after anovernight fast. �-Blockers, calcium channel blockers, and long-acting nitrates were withheld the nights before testing.

Subjects

Participants were recruited from outpatient clinics affili-ated with a university-based medical center. Eligibility criteriaincluded age greater than 18 years with a documented clinicaldiagnosis of CAD supported by (1) angiographic evidence ofgreater than 50% stenosis in 1 or more coronary arteries orprevious percutaneous intervention or coronary artery bypassgraft surgery; (2) previous myocardial infarction (MI) docu-mented by elevated troponin levels, Q-wave abnormalities onelectrocardiogram (ECG), or nonartifactual fixed perfusionabnormalities on nuclear scan; or (3) a positive radionuclidepharmacologic or exercise stress test. Patients were excluded ifthey had unstable angina or acute MI within the 2 monthsbefore enrollment, were pregnant, or weighed over 400 lb.

Mental Stress Procedure

Patients initially rested in a dark and quiet room for 30minutes while their heart rate (HR) and blood pressure weremeasured every 5 minutes by an ECG monitor and automaticoscillometric device (Dinamap; Critikon/GE Healthcare, Wauke-sha, Wis), respectively. Mental stress was then induced via apublic speaking task performed in front of a small audience, asin prior research.12 Participants were asked to speak on anassigned topic describing a stressful real-life event. They weregiven 2 minutes to prepare their speech and 3 minutes to speak.They were told that their speech would be videotaped and laterrated by the research staff for content, quality, and duration.Hemodynamic measurements were obtained every minute dur-ing the preparation and the speech periods and at 1, 3, 5, and 10minutes into the recovery period. Systolic blood pressure (SBP)and HR were used to calculate the double product (DP) value(DP � SBP � HR).

Exercise or Adenosine Testing

After a 30-minute rest period, a symptom-limited exercisestress test was performed in a standard fashion according to theBruce protocol.13 Patients exercised to achieve at least 85% oftheir age-predicted target HR.13 Twelve-lead ECGs were ac-quired in the sitting and standing positions before exercise, at eachminute during exercise, at peak exertion, and at each minute intorecovery for 10 minutes or until exercise-induced ST-segmentchanges resolved. Blood pressure and HR were recorded at minute2 of each exercise stage and at minutes 1, 3, 5, and 10 of recovery.If the patient could not exercise, a standard 6-minute adenosinestress test was performed instead.14 Xanthine derivatives andcaffeine-containing products were discontinued 48 and 12 hoursbefore testing, respectively. Whenever possible, adjunctive low-level treadmill exercise was used.15

Myocardial Perfusion Imaging

Myocardial perfusion imaging with technetium 99m ses-tamibi was used. A standard 2-day imaging protocol wasconducted for all stress modalities. During the mental stressprocedure, the radioisotope injection was given at 1 minute intothe speech (with a total dose of 20-30 mCi, based on thepatient’s body weight). This timing is based on previous reportsthat maximal HR, blood pressure, and neurohormonal re-sponses to mental stress usually occur at the near onset of thestressful task, and ischemic abnormalities are induced relativelyrapidly during this process.1,16,17 The radioisotope injectionwas given at peak exertion during the exercise test and at 3minutes during the adenosine protocol. Exercise was continuedfor at least 1 minute after the injection. Stress images wereacquired 30 to 60 minutes later via conventional methodol-ogy18 with single photon emission computed tomography(SPECT) (64 projections over a circular 180° orbit, with thegamma camera set at a 140-keV energy peak with a 20%window). A high-resolution collimator and 2-dimensional But-terworth filter were used, and transaxial tomograms werereconstructed by use of backprojections with a ramp filter.Resting images were obtained within 1 week of the stress test.

Journal of Nuclear Cardiology Hassan et al 519Volume 15, Number 4;518-25 Mental versus exercise or adenosine stress

We did not use an attenuation correction algorithm in thisstudy. However, we routinely used other well-accepted tech-niques to reduce the impact of attenuation artifacts such asprone imaging and walking instead of resting adenosine,whenever appropriate.18 The studies were interpreted by anexperienced nuclear cardiologist (D.S.S.) blinded to the condi-tion (mental vs exercise or adenosine). Another nuclear cardi-ologist performed a second reading of some randomly selectedstudies (n � 59). The agreement rate between the 2 readers was90%. Disagreements were resolved by consensus. Rest andstress images were visually compared for number and severityof perfusion defects by use of a 20-segment model. A scoringmethod from 0 to 4 was used, with 0 being normal uptake and4 being no uptake.16 A summed difference score (SDS) wascalculated as the difference between summed stress and restscores. Ischemia was defined as new or worsening perfusiondefects during mental, exercise, or adenosine stress as com-pared with the resting baseline images with an SDS of 4 orgreater. For the purpose of comparison in this study, the sameischemia definition was used for all testing protocols.

Standard criteria were used for assignment of vesselterritories.18,19 Each myocardial segment was assigned to oneof the coronary territories according to published guidelines.19

Specifically, segments 1, 2, 7, 8, 13, and 14 were assigned tothe left anterior descending coronary artery (LAD); segments 3,4, 9, 10, 15, and 16 to the right coronary artery (RCA); andsegments 5, 6, 11, 12, 17, and 18 to the left circumflex coronaryartery (LCX). Segments in the apical cap (19 and 20) wereconsidered watershed areas, and no vessel territory was as-signed to them.19 Involvement of a coronary territory wasconcluded when at least 2 adjacent segments within thedistribution of that artery showed reversible perfusion defects.This criterion is intended to account for potential overlap in thedistribution of the 3 coronary territories.

Statistical Analysis

Results were expressed as mean � SD for continuousvariables and frequencies and percentages for categorical vari-ables. Stress hemodynamic responses were calculated as thedifference between the peak stress and baseline resting mea-surements. For continuous variables, statistical differencesbetween groups were determined by use of the Student t test fornormally distributed data and Mann-Whitney U test for non-normally distributed data. Differences between categoricalvariables were determined by use of �2 analyses. Statisticalsignificance was considered as P � .05. On the basis of thepublished evidence that exercise stress testing and adenosinestress testing are highly concordant in provoking myocardialischemia,20-22 these modalities were grouped together andcompared with mental stress testing. Within individuals, thevariability of myocardial ischemic responses to mental versusexercise or adenosine stress (ischemia defined as SDS �4 onperfusion imaging) was examined by use of � statistics.23 Thisprocedure is preferred over the simple percent agreement becauseit measures the extent to which the agreement between the 2testing modalities exceeds the level to be expected based onchance alone. We report it here as � � its SE. A value of 1 denotesperfect agreement and 0 denotes no agreement beyond chance.

RESULTS

Patient Characteristics and Baseline Data

A total of 187 patients were studied; 65 of these(35%) were women. The mean age was 64 � 9 years.The majority of patients (88%) were white, whereas 7%were black. All participants had CAD. Of the patients,65% satisfied entry criteria based on abnormal coronaryangiograms, 35% had a history of coronary artery bypassgraft surgery, 19% had prior MI, and 63% had a historyof anginal symptoms. Other comorbid medical condi-tions included diabetes (32%), hypertension (78%), hy-perlipidemia (89%), and past or current smoking (72%).Demographic and clinical characteristics of the studypopulation are described in Table 1. All patients under-went mental stress testing. Of the patients, 90 (48%)underwent exercise stress and 97 (52%) received anadenosine infusion protocol.

Hemodynamic Responses

Mental stress induced significant changes in SBP,diastolic blood pressure (DBP), HR, and DP comparedwith the resting condition. The mean increase in thesevalues from rest to stress was 43 � 19 mm Hg for SBP;28 � 11 mm Hg for DBP; 19 � 12 beats/min for HR;and 5,762 � 2,976 for DP (P � .001). Within individ-uals, exercise induced higher increases in HR and DP

Table 1. Clinical and demographic characteristics ofstudy sample

Mean age (y) 64 � 9Women 65 (35%)Ethnicity

White 162 (88%)Black 12 (7%)

Previous MI 35 (19%)Previous CABG 65 (35%)Previous PCI 81 (43%)Past or current smoking 134 (72%)Hypertension 146 (78%)Diabetes 59 (32%)History of angina 117 (63%)Hyperlipidemia 167 (89%)�-Blockers 146 (78%)ACEI 102 (55%)Calcium channel blockers 40 (21%)Mean LVEF (%) 55 � 13Body mass index 30 � 6

Values are expressed as mean � SD or number (%).CABG, Coronary artery bypass graft surgery; PCI, percutaneouscoronary intervention; ACEI, angiotensin-converting enzyme inhib-itor; LVEF, left ventricular ejection fraction.

520 Hassan et al Journal of Nuclear CardiologyMental versus exercise or adenosine stress July/August 2008

and lesser increases in SBP and DBP compared withmental stress (all P � .001). The mean exercise-inducedincreases were 68 � 15 beats/min for HR; 13,281 �3,641 for DP; 30 � 20 mm Hg for SBP; and 11 � 10 mmHg for DBP. Adenosine induced smaller increases inSBP (8 � 15 mm Hg), DBP (5 � 10 mm Hg), HR (24 �15 beats/min), and DP (4,006 � 2,584) compared withthe exercise or mental tests (all P � .001). ECG changesof ischemia (�1 mm of ST depression) occurred in 23patients (12%) during exercise or adenosine testing. Suchchanges were very rare during mental stress (3 patients[2%]). Hemodynamic responses to the 3 stress testingmodalities are shown in Table 2.

Myocardial Ischemia

Mental stress–induced myocardial ischemia (MSIMI)was less prevalent (35 patients [19%]) than exercise- oradenosine-induced ischemia (62 patients [33%]). MSIMIoccurred at a lower DP value (6,100 � 2,561) comparedwith exercise- or adenosine-induced ischemia (8,109 �5,306). Ischemia developed during both mental and exer-cise or adenosine stress in 21 patients (exercise testing wasused in 8/21 patients). Among those 21 patients, there wasa trend toward increased severity of ischemia (measured bySDS) with exercise or adenosine compared with mentalstress (mean SDS for exercise or adenosine of 7.5 � 2.5

compared with 6.2 � 2.0 for mental stress [P � .11]).MSIMI occurred in 14 patients (11%) with negative exer-cise or adenosine ischemia. The overall concordance be-tween the 2 testing modalities was weak (percent agree-ment, 71%; � [� SE], 0.26 � 0.07). A 2 � 2 table for thebinary ischemia outcome by the stress modalities is shownin Table 3. When adenosine and exercise were separatelycompared with mental stress, similar concordance rateswere observed (percent agreement and � values of 71% and0.31 � 0.09 for adenosine and 70% and 0.20 � 0.11 for

Table 2. Hemodynamic and ischemic variables by stress testing modality

VariableMental stress

(n � 187)Exercise stress

(n � 90)Adenosine stress

(n � 97)

Mean SBP (mm Hg)Rest 120 � 18 137 � 19 142 � 22Stress 163 � 26 167 � 21 150 � 23Difference 43 � 19 30 � 20 8 � 15

Mean DBP (mm Hg)Rest 65 � 9 75 � 9 78 � 11Stress 93 � 13 86 � 11 83 � 12Difference 28 � 11 11 � 10 5 � 10

Mean HR (beats/min)Rest 60 � 10 63 � 12 64 � 11Stress 79 � 16 131 � 14 88 � 16Difference 19 � 12 68 � 15 24 � 15

Mean DP 7,219 � 1,604 8,608 � 1,812 9,100 � 2,117RestStress 12,982 � 3,629 21,901 � 3,677 13,107 � 3,064Difference 5,762 � 2,976 13,281 � 3,641 4,006 � 2,584

No. (%) with myocardial ischemia* 35 (19%) 26 (29%) 36 (37%)Mean SDS† 1.5 � 2.4 2.3 � 2.8 2.9 � 3.4

*Myocardial ischemia was defined as an SDS of 4 or greater on radionuclide perfusion imaging.†This analysis included all patients with and without stress-induced ischemia.

Table 3. Two-by-two table showing agreementbetween mental and exercise or adenosine stresstesting in provoking myocardial ischemia

Exercise oradenosine stress

Mental stress

Ischemia(SDS >3)(n � 62)

Noischemia(n � 125)

Ischemia (SDS �3) (n � 35) 21 14No ischemia (n � 152) 41 111

In 21 patients ischemia developed during both stressors. Theoverall concordance between the 2 testing modalities was weak(percent agreement, 71%; � [� SE], 0.26 � 0.07).


exercise, respectively). Figure 1 shows perfusion images for3 patients in the study. Ischemia developed during bothmental and adenosine stress in patient A, ischemia devel-oped during exercise but not during mental stress in patientB, and ischemia developed during mental stress but notduring exercise stress in patient C.

We further compared the coronary artery distributionof the ischemic segments in the 21 patients in whomischemia developed during both stress procedures (mentalvs exercise or adenosine). MSIMI was more likely to occurin a single-vessel distribution (18/21 patients [86%]) com-pared with exercise- or adenosine-induced ischemia (11/21

patients [54%]). When individual vessels were compared,the concordance rate was moderate for segments in theRCA territory (percent agreement, 76%; �, 0.52 � 0.19)and LAD territory (percent agreement, 76%; �, 0.51 �0.19) and significantly lower for segments within the LCXterritory (percent agreement, 62%; �, 0.22 � 0.18). Thisinformation is detailed in Table 4.

DISCUSSION

Our findings in this study indicate that there is asignificant variability in ischemic responses to mental

Figure 1. Representative perfusion images from 3 participants in study. Patient A developedischemia during both mental and adenosine stress testing. Patient B developed ischemia duringexercise testing, but had no evidence of mental stress-induced ischemia. Patient C developedischemia with mental stress and had no evidence of exercise-induced ischemia.


versus exercise or adenosine stress. The overall concor-dance for provoking ischemia between these testingmodalities was weak (percent agreement, 71%; �, 0.26).In a minority of patients (11%) mental stress provokedischemia in the absence of exercise- or adenosine-induced ischemia. Moreover, among the patients whohad myocardial ischemia during both stressors, therewere significant differences in the coronary artery distri-bution of the ischemic regions. MSIMI was more likelyto occur in a single-vessel distribution. The stressors hadmoderate agreement if the ischemic segments were in theRCA or LAD territories and significantly lower agree-ment in the LCX territory. Collectively, these findingssuggest that exercise or adenosine stress testing does notaccurately predict the development or the location ofMSIMI.

Several mechanisms are operative in the develop-ment of myocardial ischemia during each of thesestressors. Sympathetic stimulation and parasympatheticwithdrawal seem to be involved with both exercise andmental stress.17,24 Rozanski et al17 and other authors1,24

suggested that the mechanisms underlying MSIMI seemto be related to the acute presentation of the stressorwhereas, for example, response to exercise is usuallygradual; a mentally challenging task provides a sudden

stressor without a warm-up period. Adenosine, on theother hand, induces coronary vasodilatation via its effecton adenosine A2A receptors, creating flow disparitieswith increased blood flow to normal areas and reducedflow to areas distal to a significant coronary stenosis.14,18

The observed high disagreement rate between these testsfor inducing ischemia is most likely related to differ-ences in the types and intensity of the physiologicresponses provoked. Both epicardial coronary vasocon-striction and microvascular dysfunction of the coronaryarterial bed have been suggested as underlying mecha-nisms for MSIMI.25-27 These mechanisms may explainthe disagreement in the regional distribution of theischemic segments between mental and exercise oradenosine stress. Collectively, these observations sug-gest that MSIMI is a distinct clinical phenotype, differentfrom exercise- or adenosine-induced ischemia. If proven,this could have significant implications for our currentrisk stratification strategies.

Several studies have established the accuracy ofSPECT imaging with Tc-99m sestamibi in the regionaldiagnosis and coronary localization of CAD.28-30 It ispossible that the observed disagreements between thesetests could partially be explained by variability in inter-pretation of the imaging studies. However, this is un-likely to fully explain the observed differences. In ourstudy standardized image acquisition and interpretationprotocols were used for all testing modalities. Thestudies were interpreted by an experienced reader whowas blinded to the stress condition (D.S.S.).

The prevalence of MSIMI in this study was 19%;this is similar to the prevalence reported in the Psycho-physiological Investigations of Myocardial Ischemia(PIMI) study5 but somewhat lower than the rates re-ported in other studies.2,6,7 The ischemia detection meth-ods used in those studies were different. Whereas weused perfusion SPECT imaging, most previous studiesused radionuclide ventriculography. We have shown thatthe detection of MSIMI using SPECT imaging has goodsensitivity, specificity, and reproducibility.31 It is alsopossible that the lower rate of ischemia observed in thisstudy is due to differences in patients’ inclusion criteria.Specifically, our study did not require a positive exercisestress test or coronary stenosis beyond a certain severityfor inclusion whereas most of the previous studies did.The definition of MSIMI used in our protocol is new orworsening perfusion defects with an SDS of 4 or greater.To serve the comparative design of our study, we appliedthe same ischemia definition used for exercise or aden-osine stress testing. This may have also influenced thepercentage of patients with ischemia. However, knowingthat MSIMI is usually of less magnitude than exercise-induced ischemia, a lower definition threshold shouldprobably be used for the detection of MSIMI.

Table 4. Concordance in coronary distribution ofischemic segments between mental and exercise oradenosine stress testing

Coronaryterritory

Exercise oradenosine

stress

Mental stress

Absent Present

LAD Absent 6 2Present 3 10Percent agreement,

76%; � [� SE],0.51 � 0.19;P � .020

LCX Absent 10 1Present 7 3Percent agreement,

62%; � [� SE],0.22 � 0.18;P � .223

RCA Absent 9 2Present 3 7Percent agreement,

76%; � [� SE],0.52 � 0.19;P � .017

Included in this analysis are the 21 patients in whom ischemiadeveloped during both stress procedures.


In a small pilot study, Ramachandruni et al9 recentlyshowed that mental stress can provoke ischemia in CADpatients with negative exercise or adenosine tests. In thatstudy 6 of 21 subjects (29%) with negative exercise oradenosine ischemia showed reversible ischemia withmental stress. This percentage is higher than our currentfinding, which is most likely a result of the moreconservative ischemia definition used in our study. Thedesign of our current protocol eliminates confoundingfactors, as an intraindividual comparison approach wasused. The time proximity of the 2 tests was 1 week,which further strengthens the protocol.

LIMITATIONS

Arguably, many factors may be involved in theobserved variability reported in this study. Variabilitiesin image acquisition techniques, image interpretation,image quality, and attenuation artifacts may all accountfor some of the observed differences. Differences in thepotency of stressors used is another factor. There areestablished criteria for ensuring adequacy of exercisestress testing—that is, patients having achieved at least85% of their age-predicted HR.13 No such criterion hasyet been developed for mental stress testing. However, itis well documented that mental stress induced by apublic speaking task has good reliability and reproduc-ibility.31,32

The discordance in the ischemic response betweenthe 2 stress testing modalities could be due to the factthat MSIMI is usually of less magnitude than exercise-or adenosine-induced ischemia; however, this does notexplain the finding that MSIMI occurred in patientswith negative exercise or adenosine test findings.

One possible limitation pertains to the fact thatexercise and adenosine results were grouped togetherand compared with mental stress. This approach issupported by a large body of literature suggesting thatischemia induction by exercise and adenosine is highlyreproducible.20-22

CONCLUSION

Our findings in this study indicate that there ismarked variability in ischemic responses to exercise oradenosine versus mental stress testing. Whatever theunderlying mechanisms, it will be important to deter-mine whether mental stress testing provides additionalrisk prediction above and beyond the other traditionalrisk stratification tools in different categories of pa-tients.

Acknowledgment

The authors have indicated they have no financial conflictsof interest.

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variability of myocardial ischemic responses to mental versus exercise or adenosine stress in...

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