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

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.¹² In addition, ambulatory ischemia frequently occurs in the absence of strenuous physical exercise and during periods of mental arousal.³⁴⁵⁶⁷

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.^8910111213 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.⁸¹⁴ 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

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 β-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 χ² 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

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.

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.

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).

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 (χ²(1)=5.31, P<.021 [Fig 2]).

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.

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.

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 Hg×bpm; 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

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,¹² 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.⁸¹⁴²⁰ 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.²¹²²²³

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 β-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

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Footnotes