This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blumenthal, J. A. Articles by O'Connor, C. Search for Related Content PubMed PubMed Citation Articles by Blumenthal, J. A. Articles by O'Connor, C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Stress

(Circulation. 1995;92:2102-2108.)
© 1995 American Heart Association, Inc.

Articles

Mental Stress–Induced Ischemia in the Laboratory and Ambulatory Ischemia During Daily Life

Association and Hemodynamic Features

James A. Blumenthal, PhD; Wei Jiang, MD; Robert A. Waugh, MD; David J. Frid, MD; James J. Morris, MD; R. Edward Coleman, MD; Michael Hanson, MD; Michael Babyak, PhD; Elizabeth T. Thyrum, PhD; David S. Krantz, PhD; Christopher O'Connor, MD

From the Department of Psychiatry and Behavioral Sciences (J.A.B., W.J., M.B., E.T.T.), the Department of Medicine (R.A.W., D.J.F., J.J.M., C.O.), and the Department of Radiology (R.E.C., M.H.), Duke University Medical Center, Durham, NC; and the Department of Medical and Clinical Psychology (D.S.K.), Uniformed Services University of the Health Sciences, Bethesda, Md.

Correspondence to Dr James Blumenthal, Box 3119, Division of Behavioral Medicine, Duke University Medical Center, Durham, NC 27710.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background The purpose of this study was to determine the correspondence of mental stress–induced ischemia in the laboratory with ambulatory ischemia and to assess the relationship between hemodynamic responses to mental stress and the occurrence of ischemia. Although exercise testing is usually used to elicit myocardial ischemia, ischemia during daily life usually occurs at relatively low heart rates and in the absence of strenuous physical exercise. Mental stress has been shown to trigger ischemic events in the laboratory at lower heart rates but at blood pressures comparable to exercise. We therefore compared the extent to which mental stress and exercise testing identify patients who develop ischemia out of hospital.

Methods and Results One hundred thirty-two patients with documented coronary disease and recent evidence of exercise-induced myocardial ischemia underwent 48-hour ambulatory monitoring and radionuclide ventriculography during exercise and mental stress testing. Patients who displayed mental stress–induced ischemia in the laboratory were more likely to exhibit ischemia during daily life (P<.021). Furthermore, patients who exhibited ischemia during ambulatory monitoring displayed larger diastolic blood pressure (P<.006), heart rate (P<.039), and rate-pressure product responses (P<.018) during mental stress.

Conclusions Among patients with prior positive exercise stress tests, mental stress–induced ischemia, defined by new wall motion abnormalities, predicts daily ischemia independent of exercise-induced ischemia. Exaggerated hemodynamic responses during mental stress testing also identify individuals who are more likely to exhibit myocardial ischemia during daily life and mental stress.

Key Words: ischemia • stress • hemodynamics

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Recent ambulatory ECG monitoring studies have shown that myocardial ischemia during daily life occurs frequently and that the majority of episodes are painless. Episodes often occur at relatively low heart rates—below those that are induced during exercise stress testing.^{1 2} In addition, ambulatory ischemia frequently occurs in the absence of strenuous physical exercise and during periods of mental arousal.^{3 4 5 6 7}

Laboratory studies also have demonstrated that in a substantial subset of coronary artery disease patients, myocardial ischemia can be reliably triggered by mental arousal and mental stressors.^{8 9 10 11 12 13} Like ambulatory ischemia, mental stress–induced ischemia is usually silent and occurs at relatively low heart rates primarily in the subgroup of patients with positive exercise tests. The similarities of mental stress–induced ischemia and ambulatory ischemia prompted us to investigate the relationship between laboratory-induced myocardial ischemia and ambulatory ischemia in patients with coronary artery disease. Although mental stress ischemia occurs at lower heart rates than exercise ischemia, arterial blood pressure elevations can be substantial.^{8 14} Thus, hemodynamic determinants of myocardial demand may play a role in low heart rate–related ischemia with mental stress.

The present study assessed the relationship of ischemia in response to mental stress and exercise testing in the laboratory, defined either by RNV or ECG, to ischemia measured by ambulatory ECG monitoring. Because the mechanisms of mental stress and exercise ischemia may be different, we also compared the pattern of hemodynamic responses in the laboratory during exercise and mental stress and assessed whether hemodynamic responses elicited in the laboratory were predictive of ischemia in the laboratory or during daily life.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Subjects
One hundred thirty-two patients (117 men, 15 women), age 36 to 74 years (mean age, 58.5±8.4 years) with documented coronary disease (by prior myocardial infarction, coronary artery bypass graft surgery, coronary angioplasty, and/or 75% stenosis in at least one of the major coronary arteries) and recent (1 year) evidence of exercise-induced ischemia, were studied. Sixty-four (48%) subjects had a prior MI, 45 (34%) had CABG, and 41 (31%) had a history of PTCA. Patients with cardiomyopathy, valvular heart disease, congestive heart failure, severe cardiac arrhythmias, left bundle-branch block, Wolff-Parkinson-White syndrome, resting blood pressure >200/120 mm Hg, left ventricular ejection fraction <30%, or left main coronary artery stenosis 50% were excluded. This study was approved by the Institutional Review Board at Duke University Medical Center, and informed consent was obtained from all subjects before their participation.

Ambulatory ECG Monitoring
Patients were withdrawn from ß-blockers, calcium channel blockers, and long-acting nitrates at least 48 hours before testing; one patient with exercise-induced ischemia on medications was not withdrawn. All patients were instrumented between 9 and 11 AM. An AM, tape-based, three-channel Holter ECG recorder (Zymed Inc) was used for ambulatory ischemic monitoring after careful skin preparation, postural testing, and calibration. Modified V₂, V₅, and aVF leads were selected for detecting ST segment variation.

ST segment analysis was performed on the Marquette series 8000 laser Holter system (Marquette Electronic Inc). Tapes were read at 500 times real time, and ECG data were digitized. Episodes of ST segment depression were examined by a cardiologist after all QRS complexes were classified. Myocardial ischemia was defined as horizontal or downsloping ST segment depression of 1 mm (0.1 mV) for 1 minute compared with baseline. The termination of an ischemic episode was determined at the time the ST segment depression returned to 0.9 mm (0.09 mV) of the baseline for 1 minute. If the ST segments became redepressed within 1 minute for 1 additional minute, the episodes were bridged as one. Ischemic burden was quantified as the area under the curve, ie, the magnitude of ST segment depression from the isoelectric line multiplied by duration of the ischemic episode. ST segment depression associated with ventricular tachycardia or frequent ventricular beats were excluded from analysis. Consensus was obtained for each ECG reading from two cardiologists who were blinded to the patient's identity and clinical data.

Mental and Exercise Stress Testing
On a separate day, while patients were still off anti-ischemic medications, they underwent a series of laboratory challenges and exercise stress testing using bicycle ergometry.

Mental Stress Testing
After a 40-minute calibration-rest period, subjects were asked to complete a series of mental stress tasks. (1) Mental arithmetic—Patients were asked to perform a series of serial additions, with encouragement to perform calculations as quickly as possible. (2) Public speaking—Patients were asked to give a speech on a current event topic to an audience of observers after 1 minute of preparation. Subjects were told that their speech would be evaluated. (3) Mirror trace—Subjects were asked to outline a star from its reflection in a mirror as quickly as possible. (4) Reading—Subjects read an easy-to-read and neutral passage selected from Reader's Digest or North Carolina Wildlife magazine. (5) Type A structured interview—Patients underwent a standard videotaped interview to assess type A behavior.¹⁵ The type A interview typically lasts 20 minutes, although the RNV acquisition was obtained for only 2 minutes after the question dealing with anger, which usually occurred after 1 to 2 minutes after the start of the interview (eg, "When you get angry or upset, do people around you know about it?"). Exercise was given last for all patients. Each task lasted 3 minutes (except for the type A interview), with a 6-minute rest period between each stressor.

Exercise Testing
After the series of mental stressors and after a 20-minute rest period, patients exercised on a cycle ergometer in the upright position at a beginning level of 25 W. Exercise workload was increased by 25 W every 2 minutes. Exercise was terminated when the following occurred: (1) 90% of the patient's predicted maximal heart rate was reached; (2) moderate to severe chest pain; (3) ST segment depression of 2 mm from baseline; (4) blood pressure decreased by 20 mm Hg; (5) malignant ventricular arrhythmia; or (6) dyspnea or severe fatigue.

Physiological Measures
Hemodynamic Measures
A standard 12-lead ECG was recorded with a Quinton Electrocardiograph (Quinton Electronics) at 1-minute intervals during the rest period, mental stress testing, and exercise testing. Heart rate was determined from the ECG. Blood pressure was measured every minute with an automatic oscillometric blood pressure monitor (Quinton Electronics). Hemodynamic responses—systolic and diastolic blood pressures, heart rate, and rate-pressure product—were obtained by subtracting the initial baseline level from the mean level recorded during each task.

Radionuclide Ventriculography
R wave–synchronized, multiple-gated equilibrium RNV with PARAGON PBR software (Medasys Inc) was performed at 20 frames per cycle with the use of a mobile gamma camera (Siemens Gamma-Sonics Inc) equipped with a 0.25-in sodium iodide crystal and an all-purpose collimator. Images were obtained after the labeling of autologous red blood cells with ^99mTc pertechnetate by the in vivo technique.¹⁶ Imaging acquisitions were obtained during the last 2 minutes of the rest period, the first 2 minutes of each stressor (except for the interview, which was keyed to a question dealing with anger), and at peak exercise with the camera positioned in the best septal–left anterior oblique view. LVEF was obtained using the software of the PBR system. Segmental wall motion of the left ventricle (high and low posterolateral, inferoapical, and septal walls) was later assessed visually through the observation of a continuous-loop video display of the images after filtering algorithms were applied. Wall motion was rated by a consensus of experienced physicians, all of whom were blinded to image-related activities (that is, which task was being viewed). Segmental wall motion ratings were assigned the following values: 1, normal; 2, mild hypokinesis; 3, severe hypokinesis; 4, mild akinesis; 5, severe akinesis; 6, mild dyskinesis; and 7, severe dyskinesis. A mild wall motion abnormality involved 50% of the wall being evaluated, whereas a severe wall motion abnormality involved >50% of the wall. Laboratory-induced myocardial ischemia was defined as a change of 1 (on the 1 to 7 scale) from baseline for any of the four wall segments. Previous studies have found this technique to be reliable and valid.¹⁷ To determine the reliability of our consensus ratings, we performed two independent consensus ratings on a random sample of 42 subjects. The intraclass correlation used for repeated-measures reliability estimates¹⁸ was .93, confirming the reliability of our RNV consensus ratings.

Data Analysis
We compared the relationship of ambulatory and Holter ischemia using ² analyses. To assess patterns of hemodynamic responses, we performed a repeated-measures ANCOVA, with task as a within-subjects factor and ischemia group (presence or absence of ischemia by Holter or laboratory mental stress) as the between-subjects factor. Separate analyses were performed for the ischemia group defined by ambulatory and laboratory ischemia. Age, baseline (resting) hemodynamic levels, and resting LVEF were used as covariates in all analyses. A two-tailed probability level of .05 was adopted as significant for all analyses.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Laboratory Ischemia During Mental Stress and Exercise
New WMA were observed in 45 of 132 patients (34%) during mental stress testing and in 65 patients (49%) during exercise. Of the 45 patients who had WMA during mental stress, 33 (73%) exhibited WMA with exercise. Of the 65 patients who had WMA during exercise, 33 (51%) exhibited WMA during mental stress. No patients had ECG evidence of ischemia during mental stress; 44 had ECG evidence of ischemia with exercise.

Table 1 shows the frequency of mental stress–induced WMA associated with each task. The mirror trace task elicited the most ischemic events; the speech task, mirror trace task, and type A interview together identified 45 (100%) of patients with mental stress–induced ischemia.

View this table: [in this window] [in a new window]   Table 1. Number of Subjects Exhibiting Ischemia by Mental Stress Task

Ambulatory Ischemia
Fifty-eight patients (44%) exhibited ECG myocardial ischemia during 48 hours of ambulatory monitoring. Fig 1 displays the number of Holter ischemic events that were observed for the entire sample. Patients with Holter ischemia had a mean 7.1 ischemic episodes (SD=9.67); the mode and median were 1 and 3 episodes, respectively.

View larger version (17K): [in this window] [in a new window]   Figure 1. Bar graph shows distribution of patients with ambulatory myocardial ischemia.

Clinical Characteristics of Patients With Ambulatory and Mental Stress–Induced Ischemia
Patients with and without TMI assessed during ambulatory monitoring did not differ significantly with age, cardiac history, medication, angiographic evidence of coronary artery disease, or resting left ventricular function (Table 2). There were no differences in demographic or clinical characteristics of patients with and without mental stress–induced TMI (Table 2).

View this table: [in this window] [in a new window]   Table 2. Demographic and Clinical Characteristics of Sample

Relationship Between Laboratory and Ambulatory Ischemia
A comparison of mental stress–induced ischemia and ambulatory ischemia revealed that patients with the former were more likely to exhibit ischemia during daily life (²(1)=5.31, P<.021 [Fig 2]).

View larger version (30K): [in this window] [in a new window]   Figure 2. Bar graph shows relationship of ischemia during mental stress testing (assessed by WMA) to ambulatory ECG ischemia. "Positive" indicates presence of ischemia; "negative" indicates absence of ischemia.

Of the 58 patients who exhibited ambulatory ischemia, 26 (45%) displayed WMA during mental stress testing; only 19 (26%) of the 74 patients who did not exhibit ambulatory ischemia displayed WMA. Interestingly, exercise-induced ischemia, defined by the presence of new or worsening WMA, was unrelated to ambulatory ischemia (P<.157). Patients who had ECG evidence of exercise-induced ischemia, however, were more likely to display ambulatory ischemia (P<.02). Although the relation of ambulatory to exercise ischemia as measured by ECG and to mental stress as measured by WMA was similar in magnitude, they were not redundant. A logistic regression model was estimated in which exercise ECG ischemia and mental stress WMA were entered in hierarchical fashion as predictors of ambulatory ischemia. The addition of mental stress wall motion scores to the equation with only exercise ECG ischemia yielded a significant increment in the model's predictive power (-2 log L change, 7.801; 1 df; P<.05), indicating that mental stress ischemia was uniquely associated with ambulatory ischemia over and above exercise ECG ischemia. The relative risk associated with ECG exercise ischemia was 3.65 (P<.001) and for mental stress WMA ischemia was 2.98 (P<.007).

Relationship Between Hemodynamic Responses and Mental Stress–Induced Ischemia
Analyses of systolic and diastolic blood pressures, heart rate, and double product revealed different magnitudes of hemodynamic response among the different stressors (P<.0001). The largest hemodynamic responses were produced by the public speaking task. Fig 3 shows that patients who exhibited ischemia during the mental stress testing displayed larger systolic blood pressure (P<.003) and rate-pressure product responses (P<.03) across the series of mental stressors than patients who did not exhibit ischemia. Heart rate responses were not different between the two groups (P<.63). For diastolic blood pressure responses, there was a group by task interaction (P<.028), with ischemic patients displaying larger responses than nonischemic patients during public speaking.

View larger version (32K): [in this window] [in a new window]   Figure 3. Bar graphs show cardiovascular responses during mental stress testing for systolic blood pressure (SBP, upper left), rate-pressure product (RPP, upper right), diastolic blood pressure (DBP, lower left), and heart rate (HR, lower right). Patients with and without mental stress ischemia (determined by radionuclide ventriculography) are plotted separately. BPM indicates beats per minute.

Relationship Between Hemodynamic Responses and Ambulatory Ischemia
Fig 4 shows that patients who exhibited ischemia during Holter monitoring displayed larger diastolic blood pressure (P<.006), heart rate (P<.039), rate-pressure product (P<.018), and a trend toward larger systolic blood pressure responses (P<.074) than those who did not exhibit ischemia.

View larger version (30K): [in this window] [in a new window]   Figure 4. Bar graphs show cardiovascular responses during mental stress testing for systolic blood pressure (upper left), rate-pressure product (upper right), diastolic blood pressure (lower left), and heart rate (lower right). Patients with and without ambulatory (Holter) ischemia are plotted separately. See Fig 3 abbreviations and definitions.

Because the data were not normally distributed and there was a wide range in the number of ischemic events (0 to 45) and the total ischemic burden (0 to 3515 mV/min), we compared ischemic activity among high and low diastolic blood pressure reactors using the Wilcoxon rank sum test. High diastolic blood pressure responders were associated with more ischemic episodes (P<.022) and a greater ischemic burden (P<.0379) compared with low diastolic blood pressure responders.

Comparison of Hemodynamic Responses During Exercise and Mental Stress
Responses during exercise and mental stress were compared with the use of the public speaking task, which was associated with the largest hemodynamic responses. Compared with exercise, public speaking was associated with less significant increases in heart rate (M_diff=48.7±1.8 beats per minute [bpm]; P<.0001), systolic blood pressure (M_diff=23.7±2.6 mm Hg; P<.0001), and rate-pressure product (M_diff=12 557±531 mm Hgxbpm; P<.0001) and greater increases in diastolic blood pressure (M_diff=4.5±1.3 mm Hg, P<.0006). Comparison of the hemodynamic responses between ischemic and nonischemic patients revealed that ischemic patients had larger responses to the speech stress relative to exercise in diastolic blood pressure (P<.035), systolic blood pressure (P<.0003), rate-pressure product (P<.006), and heart rate (P<.044).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This study demonstrates that patients who develop myocardial ischemia in response to mental stress are more likely to display ischemia out of hospital than those who do not. Radionuclide WMA during laboratory mental stress were found to be a better predictor of ambulatory ischemia than radionuclide WMA during exercise testing in this group of patients who had a history of positive exercise testing. Although the presence of new or worsening WMA during exercise testing was not related significantly to ambulatory ECG ischemia, ischemia during exercise testing, defined by ECG changes, was related to ambulatory ischemia. However, WMA induced by mental stress were associated with ambulatory ischemia independent of ECG exercise ischemia.

The RNV technique was better able to identify patients who exhibited ambulatory ECG ischemia than the ECG during mental stress testing (no patients exhibited ECG ischemia during mental stress). It is possible that the laboratory mental stress ischemic episodes were less severe and shorter in duration and were more easily detected by RNV than ECG. Ischemia detected by RNV may represent a more subtle form of ischemia that is not readily detected by ECG. Perhaps only in the more severe episodes triggered by exercise was the ECG able to detect ischemia in the laboratory. Because most ambulatory ischemic events occur at relatively low heart rates and during rest or light physical activities,^{1 2} it is not surprising that exercise is not as strongly related to ambulatory ischemia compared with mental stress. Indeed, mental stress testing may reproduce more closely the fluctuations of myocardial oxygen supply and demand that accompany daily life.

Our results are supported by recent findings by Gottdiener et al,¹³ who reported that mental stress–induced ischemia, determined by wall motion abnormalities measured by two-dimensional echocardiography, was associated with increased ambulatory ischemia during sedentary activities in a sample of 19 cardiac patients. Although our data confirm their findings in a larger patient sample using RNV rather than two-dimensional echocardiography and controlling for baseline LVEF, Gottdiener et al found only mental stress to be predictive of ischemia during sedentary activities. It is possible that this study lacked adequate power, or perhaps the subjects differed in their level of physical fitness, which has been shown to be inversely related to ischemic activity.¹⁹

Results of this study also suggest that patients who exhibit myocardial ischemia during mental stress testing and daily life respond with increased hemodynamic responses to laboratory mental stress. Because measurement of hemodynamic responses during ambulatory monitoring was not performed, we are unable to attribute ambulatory ischemia to exaggerated hemodynamic responses during daily life. However, patients with mental stress–induced ischemia display greater systolic blood pressure and rate-pressure product increases and larger diastolic blood pressure responses during public speaking, and patients who display ambulatory myocardial ischemia exhibit higher diastolic blood pressure, heart rate, and rate-pressure product increases during mental stress testing. Although increased hemodynamic responses could be a consequence rather than cause of myocardial ischemia, this possibility is unlikely for several reasons. First, the observed hemodynamic changes coincided with the onset of the mental stressor and were either maintained or declined very gradually over the 2-minute interval during which the ventriculographic measures were acquired. Ischemia-provoked hemodynamic responses might have been expected to increase further rather than be steady or slowly decline. Furthermore, because few of the mental stress–induced ischemic events were associated with anginal pain, it also is unlikely that symptom-mediated autonomic changes served to enhance hemodynamic responses.

These results are consistent with several other studies that have examined the relationship between the propensity toward increased hemodynamic responses and mental stress–induced ischemia in the laboratory.^{8 14 20} Systolic blood pressure is an important determinant of myocardial oxygen demand in patients with easily inducible myocardial ischemia. However, the occurrence of myocardial ischemia at low heart rates during ambulatory monitoring suggests that factors which decrease myocardial blood flow also may contribute to the development of myocardial ischemia. This possibility is supported by coronary angiographic studies that demonstrate paradoxical coronary vasoconstriction in response to environmental stimuli that can trigger ischemia.^{21 22 23}

The finding that heightened diastolic blood pressure responses distinguish patients with from those without myocardial ischemia both in the laboratory and ambulatory settings also is consistent with the hypothesis that reduced blood supply may be operative. It has been postulated that vasoconstriction (inferred from heightened diastolic blood pressure) may also occur in the coronary arteries or coronary microcirculation, resulting in reduced blood flow to the myocardium.²⁴ This hypothesis is supported by the recent observation that higher levels of diastolic blood pressure (at comparable ejection fraction falls) occurred during mental stress relative to exercise testing.²⁵

We noted that ischemic patients' hemodynamic responses during public speaking stress were associated with higher diastolic blood pressure responses but lower heart rate and rate-pressure product responses compared with responses during exercise. This pattern suggests a different pathophysiology for mental stress ischemia compared with exercise-induced ischemia and is consistent with a recent report indicating that mental stress–induced left ventricular dysfunction was accompanied by a smaller increase in rate-pressure product compared with exercise.²⁶

Clinical Significance
Because mental stress–induced ischemia is more likely to be associated with ambulatory ischemia than exercise-induced ischemia, mental stress testing may help to identify patients at risk for exhibiting transient myocardial ischemia during daily life. Determining the susceptibility of individuals to mental stress–induced ischemia may be helpful in guiding therapeutic efforts to reduce myocardial damage. Attenuation of hemodynamic responses to mental stress by pharmacological or behavioral therapies might be one approach to reduce ischemic activity. Animal studies have shown that surgically lowering heart rate may retard progression of coronary atherosclerosis,²⁷ and administration of ß-adrenergic blockade also slows disease progression, possibly by reducing hemodynamic responses.²⁸ Exercise training also attenuates cardiovascular and neuroendocrine responses to mental stress in humans without myocardial ischemia.²⁹ Furthermore, recent studies have shown that exercise may reduce ischemia in cardiac patients during daily life³⁰ as well as exercise stress testing.³¹ Thus, attenuation of hemodynamic responses to mental stress may potentially reduce ischemic activity.

	Selected Abbreviations and Acronyms

 

CABG = coronary artery bypass grafting LVEF = left ventricular ejection fraction MI = myocardial infarction PTCA = percutaneous transluminal coronary angioplasty RNV = radionuclide ventriculography TMI = transient myocardial ischemia WMA = wall motion abnormality (abnormalities)

	Acknowledgments

 
This study was supported by grants HL-43028, HL-49572, and HL-47337 from the National Institutes of Health. We would like to express our thanks to Dr David Thurber of Kaiser Permanente for assistance in subject recruitment, Ken McKee for technical support, and Lisa Flora for administrative assistance. We also are grateful to Marquette Electronics, who provided us with technical assistance.

Received August 15, 1994; revision received April 26, 1995; accepted May 16, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Deanfield JE, Maseri A, Selwyn AP, Ribeiro P, Chierchia S, Krikler S, Morgan M. Myocardial ischemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet. 1983;2:753-758. [Medline] [Order article via Infotrieve]
   
2. Schang SJ, Pepine CJ. Transient asymptomatic ST-segment depression during daily activity. Am J Cardiol. 1977;39:396-402.[Medline] [Order article via Infotrieve]
   
3. Barry J, Selwyn AP, Nabel EG, Rocco MB, Mead K, Campbell S, Rebecca G. Frequency of ST-segment depression produced by mental stress in stable angina pectoris from coronary artery disease. Am J Cardiol. 1988;61:989-993. [Medline] [Order article via Infotrieve]
   
4. Cecchi A, Dovellini E, Marchi F, Pucci P, Santoro G, Fazzini P. Silent myocardial ischemia during ambulatory electrocardiographic monitoring in patients with effort angina. J Am Coll Cardiol. 1983;1:934-939. [Abstract]
   
5. Freeman L, Nixon P, Sallabank P, Reavely D. Psychological stress and silent myocardial ischemia. Am Heart J. 1987;114:477-482. [Medline] [Order article via Infotrieve]
   
6. Hedges S, Krantz D, Contrada R, Rozanski A. Development of a diary for use with ambulatory monitoring of mood, activity, and physiological function. J Psychopathol Behav Assess. 1990;12:203-217.
   
7. Barry J, Selwyn AP, Nabel EG, Rocco MB, Mead K, Campbell S, Rebecca G. Frequency of ST-segment depression produced by mental stress in stable angina pectoris from coronary artery disease. Am J Cardiol. 1988;61:989-993.
   
8. Rozanski A, Bairey CN, Krantz DS, Friedman J, Resser K, Morell M, Hilton-Chalfen S, Hestrin L, Bietendorf J, Berman DS. Mental stress and the induction of myocardial ischemia in patients with coronary artery disease. N Engl J Med. 1988;318:1005-1011. [Abstract]
   
9. Deanfield JE, Shea M, Kensett M. Silent ischemia due to mental stress. Lancet. 1984;2:1001-1005. [Medline] [Order article via Infotrieve]
   
10. Tavazzi L, Bosimini E, Giubbini R, Galli M, Mazzeuro G. Silent ischemia during mental stress: scintigraphic evidence and electrocardiographic patterns. Adv Cardiol. 1990;37:53-66. [Medline] [Order article via Infotrieve]
    
11. Burg MM, Jain D, Soufer R, Kerns RD, Zaret BL. Role of behavioral and psychological factors in mental stress-induced silent left ventricular dysfunction in coronary artery disease. J Am Coll Cardiol. 1993;22:440-448. [Abstract]
    
12. Modena MG, Corghi F, Fantini G, Mattioli G. Echocardiographic monitoring of mental stress test in ischemic heart disease. Clin Cardiol. 1989;12:21-24. [Medline] [Order article via Infotrieve]
    
13. Gottdiener JS, Krantz DS, Howell RH, Hecht G, Klein J, Falconer JJ, Rozanski A. Induction of silent myocardial ischemia with mental stress testing: relationship to the triggers of ischemia during daily life activities and to ischemic functional severity. J Am Coll Cardiol. 1994;24:1645-1651. [Abstract]
    
14. Krantz DS, Helmers KF, Bairey CN, Nebel LE, Hedges SM, Rozanski A. Cardiovascular reactivity and mental stress-induced myocardial ischemia in patients with coronary artery disease. Psychosom Med. 1991;53:1-12. [Abstract/Free Full Text]
    
15. Blumenthal JA, Kamarck T. Assessment of the type A behavior pattern. In: Blumenthal JA, McKee DC, eds. Applications in Behavioral Medicine and Health Psychology: A Clinician's Source Book. Sarasota, Fla: Professional Resource Exchange; 1987:3-37.
    
16. Mettler FA, Guiberteau MJ. Cardiovascular system. In: Mettler FA, Guiberteau MJ, eds. Essentials of Nuclear Medicine Imaging. 2nd ed., Orlando, Fla: Grune & Stratton Inc; 1986:151-152.
    
17. Brady TJ, Thrall JH, Keyes JW Jr, Brymer JF, Walton JA, Pitt B. Segmental wall-motion analysis in the right anterior oblique projection: comparison of exercise equilibrium radionuclide ventriculography and exercise contrast ventriculography. J Nucl Med. 1980;21:617-621. [Abstract/Free Full Text]
    
18. Fleiss JL. The Design and Analysis of Clinical Experiments, New York, NY: John Wiley and Sons; 1986.
    
19. Jiang W, Trauner M, Waugh R, Frid D, Coleman RE, Hanson M, Phillips B, Morris J, O'Conner C, Blumenthal JA. Association of physical fitness is associated with transient myocardial ischemia in the laboratory during mental stress and during daily life. J Cardiopul Rehab. In press.
    
20. Specchia G, de Servi S, Falcone C, Gavazzi A, Angoli L, Bramulli E, Ardissino D, Mussini A. Mental arithmetic stress testing in patients with coronary artery disease. Am Heart J. 1984;108:56-63. [Medline] [Order article via Infotrieve]
    
21. Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. Dilation of normal and constriction of atherosclerotic arteries caused by the cold pressor test. Circulation. 1988;77:43-52. [Abstract/Free Full Text]
    
22. Yeung AC, Vekshtein VI, Krantz DK, Vita JA, Ryan TJ Jr, Ganz P, Selwyn AP. The effects of atherosclerosis on the vasomotor responses of coronary arteries to mental stress. N Engl J Med. 1991;28:1551-1556.
    
23. Rebecca G, Wagner R, Zebede T, D'Adamo A, Hanlon B, Sandor T, Ganz P, Selwyn A. Pathogenetic mechanisms causing transient myocardial ischemia with mental arousal in patients with coronary artery disease. Clin Res. 1986;34:338A. Abstract.
    
24. L'Abbate A, Simonetti I, Carpeggiani C, Michelassi C. Coronary dynamics and mental arithmetic stress in humans. Circulation. 1991;83(suppl II):II-94-II-99.
    
25. Legault SE, Breisblatt WM, Jennings JR, Manuck SB, Follansbee WP. Myocardial ischemia during mental stress testing: is the mechanism different from exercise-induced ischemia? Homeostasis. 1993;34:252-265.
    
26. Ironson G, Taylor CB, Boltwood M, Bartzokis T, Dennis C, Chesney M, Spitzer S, Segall GM. Effects of anger on left ventricular ejection fraction in coronary artery disease. Am J Cardiol. 1992;70:281-285. [Medline] [Order article via Infotrieve]
    
27. Beere PA, Glagov S, Zarsins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984;22:180-182.
    
28. Kaplan JR, Manuck SB, Adams MR, Weingand KW, Clarkson TB. Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet. Circulation. 1987;76:1364-1372. [Abstract/Free Full Text]
    
29. Blumenthal JA, Fredrikson M, Kuhn CM, Ulmer R, Walsh-Riddle M, Appelbaum M. Aerobic exercise reduces levels of cardiovascular and sympathoadrenal responses to mental stress in subjects without prior evidence of myocardial ischemia. Am J Cardiol. 1990;65:93-98. [Medline] [Order article via Infotrieve]
    
30. Todd IC, Ballantyne D. Effect of exercise training on the total ischaemic burden: an assessment by 24 hour ambulatory electrographic monitoring. Br Heart J. 1992;68:560-566.
    
31. Schuler G, Schlierf G, Wirth A, Mautner HP, Scheurlen H, Thumm M, Roth H, Schwarz F, Kohlmeier M, Mehmel HC, Kubler W. Low fat diet and regular, supervised physical exercise in patients with symptomatic coronary artery disease: reduction of stress-induced myocardial ischemia. Circulation. 1988;77:172-181.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				M. Hassan, K. M. York, H. Li, Q. Li, Y. Gong, T. Y. Langaee, R. B. Fillingim, J. A. Johnson, and D. S. Sheps Association of {beta}1-Adrenergic Receptor Genetic Polymorphism With Mental Stress-Induced Myocardial Ischemia in Patients With Coronary Artery Disease Arch Intern Med, April 14, 2008; 168(7): 763 - 770. [Abstract] [Full Text] [PDF]

				S. D. Holmes, D. S. Krantz, W. J. Kop, A. Del Negro, P. Karasik, and J. S. Gottdiener Mental Stress Hemodynamic Responses and Myocardial Ischemia: Does Left Ventricular Dysfunction Alter These Relationships? Psychosom Med, July 1, 2007; 69(6): 495 - 500. [Abstract] [Full Text] [PDF]

				T. Hizume, K. Morikawa, A. Takaki, K. Abe, K. Sunagawa, M. Amano, K. Kaibuchi, C. Kubo, and H. Shimokawa Sustained Elevation of Serum Cortisol Level Causes Sensitization of Coronary Vasoconstricting Responses in Pigs In Vivo: A Possible Link Between Stress and Coronary Vasospasm Circ. Res., September 29, 2006; 99(7): 767 - 775. [Abstract] [Full Text] [PDF]

				S. Ramachandruni, R. B. Fillingim, S. P. McGorray, C. M. Schmalfuss, G. R. Cooper, R. S. Schofield, and D. S. Sheps Mental Stress Provokes Ischemia in Coronary Artery Disease Subjects Without Exercise- or Adenosine-Induced Ischemia J. Am. Coll. Cardiol., March 7, 2006; 47(5): 987 - 991. [Abstract] [Full Text] [PDF]

				P. Taggart, P. Sutton, C. Redfern, V. N. Batchvarov, K. Hnatkova, M. Malik, U. James, and A. Joseph The Effect of Mental Stress on the Non-Dipolar Components of the T Wave: Modulation by Hypnosis Psychosom Med, May 1, 2005; 67(3): 376 - 383. [Abstract] [Full Text] [PDF]

				J. A. Blumenthal, A. Sherwood, M. A. Babyak, L. L. Watkins, R. Waugh, A. Georgiades, S. L. Bacon, J. Hayano, R. E. Coleman, and A. Hinderliter Effects of Exercise and Stress Management Training on Markers of Cardiovascular Risk in Patients With Ischemic Heart Disease: A Randomized Controlled Trial JAMA, April 6, 2005; 293(13): 1626 - 1634. [Abstract] [Full Text] [PDF]

				L. MONTEBUGNOLI, D. SERVIDIO, R. A. MIATON, and C. PRATI Heart rate variability: A sensitive parameter for detecting abnormal cardiocirculatory changes during a stressful dental procedure J Am Dent Assoc, December 1, 2004; 135(12): 1718 - 1723. [Abstract] [Full Text] [PDF]

				M. M. Burg, R. Lampert, T. Joska, W. Batsford, and D. Jain Psychological Traits and Emotion-Triggering of ICD Shock-Terminated Arrhythmias Psychosom Med, November 1, 2004; 66(6): 898 - 902. [Abstract] [Full Text] [PDF]

				A. Sherwood, J. W. Hughes, C. Kuhn, and A. L. Hinderliter Hostility Is Related to Blunted {beta}-Adrenergic Receptor Responsiveness Among Middle-Aged Women Psychosom Med, July 1, 2004; 66(4): 507 - 513. [Abstract] [Full Text] [PDF]

				W. J. Kop, D. S. Krantz, B. D. Nearing, J. S. Gottdiener, J. F. Quigley, M. O'Callahan, A. A. DelNegro, T. D. Friehling, P. Karasik, S. Suchday, et al. Effects of Acute Mental Stress and Exercise on T-Wave Alternans in Patients With Implantable Cardioverter Defibrillators and Controls Circulation, April 20, 2004; 109(15): 1864 - 1869. [Abstract] [Full Text] [PDF]

				P.C Strike and A Steptoe Systematic review of mental stress-induced myocardial ischaemia Eur. Heart J., April 2, 2003; 24(8): 690 - 703. [Full Text] [PDF]

				W. J. Kop, R. J. Verdino, J. S. Gottdiener, S. T. O'Leary, C. N. Bairey Merz, and D. S. Krantz Changes in heart rate and heart rate variability before ambulatory ischemic events J. Am. Coll. Cardiol., September 1, 2001; 38(3): 742 - 749. [Abstract] [Full Text] [PDF]

				A. Michalsen and G. Dobos Acute stress and ventricular arrhythmias Eur. Heart J., April 2, 2001; 22(8): 712 - 712. [PDF]

				W. J. Kop, D. S. Krantz, R. H. Howell, M. A. Ferguson, V. Papademetriou, D. Lu, J. J. Popma, J. F. Quigley, M. Vernalis, and J. S. Gottdiener Effects of mental stress on coronary epicardial vasomotion and flow velocity in coronary artery disease: relationship with hemodynamic stress responses J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1359 - 1366. [Abstract] [Full Text] [PDF]

				J. Denollet, J. Vaes, and D. L. Brutsaert Inadequate Response to Treatment in Coronary Heart Disease : Adverse Effects of Type D Personality and Younger Age on 5-Year Prognosis and Quality of Life Circulation, August 8, 2000; 102(6): 630 - 635. [Abstract] [Full Text] [PDF]

				J. A. Blumenthal, A. Sherwood, E. C. D. Gullette, M. Babyak, R. Waugh, A. Georgiades, L. W. Craighead, D. Tweedy, M. Feinglos, M. Appelbaum, et al. Exercise and Weight Loss Reduce Blood Pressure in Men and Women With Mild Hypertension: Effects on Cardiovascular, Metabolic, and Hemodynamic Functioning Arch Intern Med, July 10, 2000; 160(13): 1947 - 1958. [Abstract] [Full Text] [PDF]

				H. Hemingway, M. Shipley, P. Macfarlane, and M. Marmot Impact of socioeconomic status on coronary mortality in people with symptoms, electrocardiographic abnormalities, both or neither: the original Whitehall study 25 year follow up J Epidemiol Community Health, July 1, 2000; 54(7): 510 - 516. [Abstract] [Full Text]

				D. S. Krantz, D. S. Sheps, R. M. Carney, and B. H. Natelson Effects of Mental Stress in Patients With Coronary Artery Disease: Evidence and Clinical Implications JAMA, April 12, 2000; 283(14): 1800 - 1802. [Full Text] [PDF]

				G. A. Beller and B. L. Zaret Contributions of Nuclear Cardiology to Diagnosis and Prognosis of Patients With Coronary Artery Disease Circulation, March 28, 2000; 101(12): 1465 - 1478. [Full Text] [PDF]

				R. Lampert, D. Jain, M. M. Burg, W. P. Batsford, and C. A. McPherson Destabilizing Effects of Mental Stress on Ventricular Arrhythmias in Patients With Implantable Cardioverter-Defibrillators Circulation, January 18, 2000; 101(2): 158 - 164. [Abstract] [Full Text] [PDF]

				L. L. Watkins, J. A. Blumenthal, P. R. Kowey, H. Z. Brandspiegel, R. A. Marinchak, and S. J. Rials Worried to Death? • Response Circulation, September 14, 1999; 100 (11): 1250 - 1252. [Full Text] [PDF]

				D. S. Sheps, R. P. McMahon, K. C. Light, W. Maixner, C. J. Pepine, J. D. Cohen, A. D. Goldberg, R. Bonsall, R. Carney, P. H. Stone, et al. Low hot pain threshold predicts shorter time to exercise-induced angina: results from the psychophysiological investigations of myocardial ischemia (PIMI) study J. Am. Coll. Cardiol., June 1, 1999; 33(7): 1855 - 1862. [Abstract] [Full Text] [PDF]

				P. H. Stone, D. S. Krantz, R. P. McMahon, A. D. Goldberg, L. C. Becker, B. R. Chaitman, H. A. Taylor, J. D. Cohen, K. E. Freedland, B. D. Bertolet, et al. Relationship among mental stress-induced ischemia and ischemia during daily life and during exercise: the Psychophysiologic Investigations of Myocardial Ischemia (PIMI) Study J. Am. Coll. Cardiol., May 1, 1999; 33(6): 1476 - 1484. [Abstract] [Full Text] [PDF]