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J Am Coll Cardiol, 2006; 47:987-991, doi:10.1016/j.jacc.2005.10.051 (Published online 8 February 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Mental Stress Provokes Ischemia in Coronary Artery Disease Subjects Without Exercise- or Adenosine-Induced Ischemia

Srikanth Ramachandruni, MD*, Roger B. Fillingim, PhD*,{dagger}, Susan P. McGorray, PhD*, Carsten M. Schmalfuss, MD*,{dagger}, Gary R. Cooper, MD*,{dagger}, Richard S. Schofield, MD*,{dagger} and David S. Sheps, MD, MSPH*,{dagger},*

* University of Florida, Gainesville, Florida
{dagger} Malcom Randall Veterans Administration Medical Center, Gainesville, Florida

Manuscript received May 25, 2005; revised manuscript received August 8, 2005, accepted October 17, 2005.

* Reprint requests and correspondence: Dr. David S. Sheps, Division of Cardiovascular Medicine, University of Florida, 1601 Archer Road, Gainesville, Florida 32608. (Email: shepsds{at}medicine.ufl.edu).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 Conclusions
 References
 
OBJECTIVES: The purpose of this study was to investigate the possibility that some patients with coronary artery disease (CAD) but negative exercise or chemical stress test results might have mental stress-induced ischemia. The study population consisted solely of those with negative test results.

BACKGROUND: Mental stress-induced ischemia has been reported in 20% to 70% of CAD subjects with exercise-induced ischemia. Because mechanisms of exercise and mental stress-induced ischemia may differ, we studied whether mental stress would produce ischemia in a proportion of subjects with CAD who have no inducible ischemia with exercise or pharmacologic tests.

METHODS: Twenty-one subjects (14 men, 7 women) with a mean age of 67 years and with a documented history of CAD were studied. All subjects had a recent negative nuclear stress test result (exercise or chemical). Subjects completed a speaking task involving role playing a difficult interpersonal situation. A total of 30 mCi 99mTc-sestamibi was injected at one minute into the speech, and imaging was started 40 min later. A resting image obtained within one week was compared with the stress image. Images were analyzed for number and severity of perfusion defects. The summed difference score based on the difference between summed stress and rest scores was calculated. Severity was assessed using a semiquantitative scoring method from zero to four.

RESULTS: Six of 21 (29%) subjects demonstrated reversible ischemia (summed difference score ≥3) with mental stress. No subject had chest pain or electrocardiographic changes during the stressor. Mean systolic and diastolic blood pressure and heart rate all increased between resting and times of peak stress.

CONCLUSIONS: Mental stress may produce ischemia in some subjects with CAD and negative exercise or chemical nuclear stress test results.

Abbreviations and Acronyms
  CAD = coronary artery disease
  MSI = mental stress ischemia

Several investigators have reported that mental stress causes ischemia in a subgroup of coronary artery disease (CAD) subjects with exercise-induced ischemia (1–5). In fact, all previous studies except for one recently published (6) required a positive exercise test result as an entry criterion.

The purpose of this study was to investigate the possibility that some patients with CAD but negative exercise or chemical stress test results might have mental stress-induced ischemia. The study population consisted solely of those with negative test results.

Laboratory-induced mental stress ischemia (MSI) has been linked to an adverse prognosis, with significantly higher rates of subsequent fatal and nonfatal cardiac events (7–10). Epidemiologic studies have found that many acute myocardial infarctions are precipitated by stressful events (11).


   Methods
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 Abstract
 Methods
Results
 Discussion
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 References
 
Subject population.   This study was approved by the Committee for the Protection of the Rights of Human Subjects at the University of Florida, Gainesville, and the Malcom Randall Veterans Affairs Medical Center in Gainesville. Written informed consent was obtained. Twenty-one subjects had a negative nuclear exercise or chemical stress test result within the previous six months. All subjects had either: 1) angiographically proven narrowing of at least one major coronary artery of >50% or a history of percutaneous intervention or coronary artery bypass graft, or 2) previous myocardial infarction (at least six months prior) documented by significant elevation of serum isoenzyme of creatine kinase with muscle subunits (CK-MB) (more than two times normal) and troponin I. Antianginal medications were tapered or discontinued one day before testing (Table 1).


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  		Table 1. Demographics and Subject Characteristics
 
Experimental protocol.   Resting study
A total of 30 mCi 99mTc-sestamibi was injected in all subjects after 30 min of quiet sitting. Hemodynamic measurements (heart rate, blood pressure, electrocardiogram) were taken at baseline and every 5 min of the rest period. Patients again rested for 30 to 45 min before the nuclear imaging.

Mental stress study
Mental stress testing was performed on a separate day within one week of the resting study. The rest and stress sequence was randomized. Subjects rested for 30 min as previously described. Baseline resting electrocardiographic measurements were obtained before mental stress. Mental stress was then induced using a public speaking task (role playing a real-life hassle scenario). Participants were given two minutes to prepare and 4 min to speak before several research personnel. At 1 min into the speech, 30 mCi of 99m-Tc sestamibi was injected. Hemodynamic and electrocardiographic measurements were again taken every 1 min during mental stress and during 10 min of recovery. Thirty to 45 min after the mental stressor, participants underwent myocardial perfusion imaging (Fig. 1).


Figure 1
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  		Figure 1 Experimental time line.

 
Image analysis
Two experienced readers blinded to condition (rest or stress) analyzed the images. Interpretation of images followed the recommendations of the American Society of Nuclear Cardiology. Before interpretation, sources of error such as subject motion, attenuation, reconstruction artifacts, and low count density were sought. Image analysis was performed on QPS software (Cedars-Sinai Medical Center, ADAC Laboratories, Milpitas, California) with a 20-segment, 5-point model (0 = normal, 1 = mildly reduced uptake, 2 = moderately reduced uptake, 3 = severely reduced uptake, 4 = no uptake) (12). To verify the analysis performed by the experienced readers, we also used the built-in feature of the Cedars-Sinai QPS program to produce automated raw counts in a segmental grid. This display is not referenced to any normal standard.

Ischemia was defined as new or worsening perfusion defects with stress as compared with resting baseline images. A summed difference score based on the difference between summed stress score over the 20-segment model and summed rest score over the 20-segment model was calculated. Positive MSI was defined as a summed difference score of ≥3.

Statistical methods
Descriptive statistics and plots were used to characterize the data. A Wilcoxon signed rank test and paired t tests were used to test for changes in summed stress and rest scores, and hemodynamic (systolic blood pressure, diastolic blood pressure, heart rate) changes, respectively. Spearman correlation coefficients were used to examine relationships between summed difference scores and hemodynamic change variables. Characteristics of those with negative and positive MSI were compared using Fisher exact tests for categorical variables and two sample t tests for continuous variables. A p value of <0.05 was considered statistically significant.


   Results
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 Abstract
 Methods
 Results
Discussion
 Conclusions
 References
 
Twenty-one CAD subjects (14 men, 7 women) ranging in age from 52 to 80 years, participated in the study. The mean age was 67 (±7.6 standard deviation) years. Ninety-five percent of the subjects had evidence of CAD documented by previous coronary angiogram with significant (≥50% diameter narrowing) epicardial coronary stenoses and subsequent percutaneous coronary intervention or stent placements. One subject (5%) had a previous myocardial infarction. The mean left ventricular ejection fraction was 60%, with a range of 43% to 80%.

The experienced readers found that 6 of 21 (29%) subjects demonstrated reversible ischemia (summed difference score ≥3) with mental stress (Table 2). The summed difference score was 1.9 (±2.9) (mean ± standard deviation) in the overall subject population and 4.4 (±3) in subjects who had MSI. The mean number of new or worsening defects was 1.6 ± 2.4 in the overall patient population and 3.8 ± 2.3 in subjects who had one or more new or worsening perfusion defects. In each case, the automated quantitative analysis of the Cedars-Sinai raw counts/segmental grid polar maps confirmed the analysis of the experienced readers.


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  		Table 2. Hemodynamic Changes and Perfusion Results During Rest and Peak Mental Stress in Individual Subjects
 
Mental stress provoked significant blood pressure and heart rate responses (Table 2). There were no significant correlations between the magnitude of hemodynamic responses and mental stress perfusion defects. No subject had chest pain or electrocardiographic changes during the stressor.

Resting blood pressure, heart rate, demographic characteristics, and blood pressure reactivity at peak mental stress did not differ significantly between subjects with and without MSI (Table 3). All participants who had MSI were men, however, this finding has only borderline statistical significance (p = 0.06). Beta-blocker usage (p = 0.06) and angiotensin-converting enzyme inhibitor usage (p = 0.047) were borderline significantly higher in women.


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  		Table 3. Demographic Comparisons Between Positive and Negative Mental Stress Ischemia (MSI) Groups
 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
This study was specifically designed to test the hypothesis that a proportion of patients with CAD and a negative exercise or chemical stress test result would have mental stress-induced ischemia. The main finding is that 29% of our patient population did develop reversible perfusion defects induced by a laboratory mental stressor. The 95% confidence interval of this estimate (0.11 to 0.52) is rather wide because of the relatively small sample size. Nevertheless, it suggests that the study had adequate power to detect ischemia in the population.

The sample size was not adequately powered to analyze gender differences or perform subgroup analyses; however, the pattern of results suggested a higher prevalence of MSI in men. The angiotensin-converting enzyme inhibitor usage (p = 0.046) and beta-blocker usage (p = 0.06) were marginally higher in women. These results on gender should be viewed as hypothesis-generating in light of the power issue.

Our study identifies a new group of patients potentially at risk for mental stress ischemia. All previous studies except one (6) required CAD subjects with positive exercise test results as an entry criterion. Rozanski et al. (2) examined subjects with known CAD or with a high pretest probability of CAD. In their study, 21 of the 29 subjects (72%) had inducible wall motion abnormalities as detected by radionuclide ventriculography. They also found that public speaking was a more useful tool in inducing wall motion abnormalities than mental arithmetic. In the multicenter National Institutes of Health-sponsored Psychophysiological Investigations of Myocardial Ischemia (PIMI) study, 20% of subjects with CAD and a positive exercise test result had inducible wall motion abnormalities in response to a public speaking stressor (10).

Recently, we have shown that mental stress-induced myocardial ischemia using sestamibi single-photon emission computed tomography studies has good sensitivity, specificity, and reproducibility (3).

More recently, Akinboboye et al. (6) evaluated the prevalence of mental stress ischemia in CAD patients with left ventricular dysfunction using sestamibi SPECT imaging. They found a higher prevalence of mental stress ischemia in patients with severe left ventricular dysfunction than in those with normal left ventricular function (50% vs. 9%; p < 0.01) (6). In their study, a small group of patients (5 of 58) had negative exercise ischemia but positive mental stress ischemia test results.

Possible mechanisms.   Patients with CAD often show an exaggerated systemic response to stress. This can result in raised myocardial oxygen demand because of elevations in heart rate, blood pressure, and the rate of ventricular contraction (5). This may later lead to profound myocardial ischemia. This heightens the potential for lethal ventricular arrhythmia and sudden death (13).

Yeung et al. (14) have shown that mental stress can lead to a paradoxical arterial vasoconstriction in diseased coronary arteries. In another study, epicardial coronary vasoconstriction in response to mental stress was found to be directly related to stress-induced blood pressure increases (15).

Ischemia occurring in response to mental stress, in contrast to exercise stress, is associated with a less marked increase in heart rate and comparable or even larger blood pressure responses. The blood pressure changes may also occur quite suddenly during mental stress and are usually associated with increases in diastolic pressure, as opposed to no change or a decrease in diastolic blood pressure with exercise. Therefore, it is reasonable to hypothesize that mental stress and exercise may evoke differing hemodynamic responses and be associated with different types of ischemic responses (5,11,16,17).

Other mechanisms, such as endothelial dysfunction, coronary vasoconstriction, and/or impaired response of coronary microcirculation during the mental stressor, may also play a role in producing mental stress ischemia (15,16,18–22).

Regardless of the operative mechanism, the occurrence of mental stress-induced ischemia in CAD subjects without exercise- or adenosine-induced ischemia is a finding warranting continued study to determine a more precise estimate of its prevalence and whether or not it is associated with an adverse prognosis.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
Mental stress induces myocardial ischemia in some subjects with known CAD, without evidence of reversible ischemia induced by exercise or chemical stress. Mental stress also leads to significant hemodynamic responses in these subjects, but does not elicit symptoms of chest pain or electrocardiographic changes, which is consistent with results from previous studies. Further and larger-scale investigations are warranted to delineate the prognostic significance and underlying mechanisms of these findings.


   Acknowledgments
 
We gratefully acknowledge Judith Stewart’s assistance in manuscript preparation.


   Footnotes
 
This material is the result of work supported with resources and the use of facilities at the Malcolm Randall Department of Veterans Affairs Medical Center, Gainesville, Florida, and based on work supported in part by the National Institutes of Health Grants R01HL070265-01 and R01HL072059 and by Bristol-Myers Squibb.


   References
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 References
 

  1. Deanfield JE, Shea M, Kensett M, Horlock P, Wilson RA, de Landsheere CM, Selwyn AP. Silent myocardial ischaemia due to mental stress Lancet 1984;8410:1001-1005.
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  3. Kim CK, Bartholomew BA, Mastin ST, Taasan VC, Carson KM, Sheps DS. Detection and reproducibility of mental stress-induced myocardial ischemia with 99mTc-sestamibi SPECT in normal and coronary artery disease populations J Nucl Cardiol 2003;10:56-62.[CrossRef][ISI][Medline]
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  5. Goldberg AD, Becker LC, Bonsall R. Ischemic, hemodynamic, and neurohormonal responses to mental and exercise stress. Experience from the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) Circulation 1996;94:2402-2409.[Abstract/Free Full Text]
  6. Akinboboye O, Krantz DS, Kop WJ, et al. Comparison of mental stress-induced myocardial ischemia in coronary artery disease patients with versus without left ventricular dysfunction Am J Cardiol 2005;95:322-326.[CrossRef][ISI][Medline]
  7. Jiang W, Babyak M, Krantz DS, et al. Mental stress-induced myocardial ischemia and cardiac events JAMA 1996;275:1651-1656.[Abstract]
  8. Jain D, Burg M, Soufer R, Zaret BL. Prognostic implication of mental stress-induced silent left ventricular dysfunction in patients with stable angina pectoris Am J Cardiol 1995;76:31-35.[CrossRef][ISI][Medline]
  9. Krantz DS, Santiago HT, Kop WJ, Bairey Merz CN, Rozanski A, Gottdiener JS. Prognostic value of mental stress testing in coronary artery disease Am J Cardiol 1999;84:1292-1297.[CrossRef][ISI][Medline]
  10. Sheps DS, McMahon RP, Becker L, et al. Mental stress-induced ischemia and all-cause mortality in patients with coronary artery diseaseresults from the Psychophysiological Investigations of Myocardial Ischemia study. Circulation 2002;105:1780-1784.[Abstract/Free Full Text]
  11. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy Circulation 1999;99:2192-2217.[Abstract/Free Full Text]
  12. Hachamovitch R, Berman DS, Kiat H, et al. Exercise myocardial perfusion SPECT in patients without known coronary artery diseaseincremental prognostic value and use in risk stratification. Circulation 1996;93:905-914.[Abstract/Free Full Text]
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  14. Yeung AC, Vekshtein VI, Krantz DS, et al. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress N Engl J Med 1991;325:1551-1556.[Abstract]
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  16. Krantz DS, Sheps DS, Carney RM, Natelson BH. Effects of mental stress in patients with coronary artery diseaseevidence and clinical implications. JAMA 2000;283:1800-1802.[Free Full Text]
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