Author + information
- Received August 21, 1998
- Revision received January 25, 1999
- Accepted February 15, 1999
- Published online June 1, 1999.
- David S Sheps, MD, MSPH, FACC∗,*,
- Robert P McMahon, PhD†,
- Kathleen C Light, PhD‡,
- William Maixner, PhD, DDS‡,
- Carl J Pepine, MD, FACC§,
- Jerome D Cohen, MD, FACC∥,
- A.David Goldberg, MD¶,
- Robert Bonsall, PhD#,
- Robert Carney, PhD#,
- Peter H Stone, MD, FACC∗∗,
- David Sheffield, PhD∗,
- Peter G Kaufmann, PhD††,
- the PIMI Investigators
- ↵*Reprint requests and correspondence: Dr. David S. Sheps, 2 Professional Park Drive, Suite 15, Johnson City, Tennessee 37604
The purpose of this study was to test whether cutaneous thermal pain thresholds are related to anginal pain perception.
Few ischemic episodes are associated with angina; symptoms have been related to pain perception thresholds.
A total of 196 patients with documented coronary artery disease underwent bicycle exercise testing and thermal pain testing. The Marstock test of cutaneous sensory perception was administered at baseline after 30 min of rest on two days and after exercise and mental stress. Resting hot pain thresholds (HPTs) were averaged for the two baseline visits and divided into two groups: 1) average HPT <41°C, and 2) average HPT ≥41°C, to be clearly indicative of abnormal hypersensitivity to noxious heat.
Patients with HPT <41°C had significantly shorter time to angina onset on exercise testing than patients with HPT ≥41°C (p < 0.04, log-rank test). Heart rates, systolic blood pressure and rate–pressure product at peak exercise were not different for the two groups. Resting plasma beta-endorphin levels were significantly higher in the HPT <41°C group (5.9 ± 3.7 pmol/liter vs. 4.7 ± 2.8 pmol/liter, p = 0.02). Using a Cox proportional hazards model, patients with HPT <41°C had an increased risk of angina (p = 0.03, rate ratio = 2.0). These differences persisted after adjustment for age, gender, depression, anxiety and history of diabetes or hypertension (p < 0.01).
Occurrence of angina and timing of angina onset on an exercise test are related to overall hot pain sensory perception. The mechanism of this relationship requires further study.
It is well documented that patients with coronary artery disease and inducible ischemia have a predominance of asymptomatic ischemia when episodes associated with angina are compared with the total ischemic burden (1–4). Why some ischemic episodes are associated with symptoms and others are not is poorly understood. Symptoms have been variously reported to be related to levels of circulating opioid peptides or pain perception thresholds, presence or absence of neurologic disease, personality variables and the physical or mental stressors associated with a particular ischemic episode (5–11). The Psychophysiological Investigations of Myocardial Ischemia (PIMI) study, a multicenter study of patients with documented coronary artery disease, has multiple objectives (12), including examination of the relations between symptoms associated with myocardial ischemia and somatic sensory threshold, autonomic reflexive control of the heart and beta-endorphin responses. Accordingly, the purpose of this report is to specifically examine the relationship between anginal symptoms during exercise or mental stress and objective indicators of cutaneous pain perception.
The PIMI study is a multicenter study of 196 patients with documented coronary artery disease who were evaluated during physical and mental stress testing in four clinical units. This study was approved by the human rights committees of each participating institution and written informed consent was obtained. Of the 196 PIMI patients, presence of coronary artery disease was established by angiography in 189 (96.4%) and by history of myocardial infarction documented by electrocardiograms (ECGs) or enzymes in seven (3.6%). Eligibility criteria and design of the PIMI study have been described (12). Briefly, the PIMI study evaluated physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. To be eligible for PIMI, all patients had to show ECG evidence of exercise-induced ischemia on an Asymptomatic Cardiac Ischemia Pilot Study protocol exercise treadmill test at a qualifying visit. The ECG criteria for ischemia included the following: 1) J point and ST 80 depression ≥0.1 mV/s; or 2) ST 80 depression ≥0.15 mV and ST-segment up-sloping >0.1 mV/s, as compared with the rest tracing (13). Patients were excluded if they had significant hypertension which could not be controlled safely on diuretics alone to allow discontinuation of beta-adrenergic blocking agents, calcium channel blocking agents and other cardiac medications, or evidence of neuropathy under detailed examination. Hemodynamic and neurohumoral responses to bicycle exercise and mental stress tasks (public speaking and the Stroop color word test) were measured by radionuclide ventriculography, ECG, blood pressure monitoring and catecholamine levels. Ambulatory electrocardiographic monitoring for 48 h was also performed. Patients were asked to press an event marker on the recorders during anginal episodes; however, very few such event indicators were noted during episodes of ST-segment depression. At the end of this period patients were also asked if they had had angina during the 48-h period.
The biochemical methods have been described in detail elsewhere (12). Briefly, plasma epinephrine and norepinephrine were measured by high performance liquid chromatography with electrochemical detection after extraction with alumina, and plasma beta-endorphin and cortisol were measured by radioimmunoassay using commercially available materials (Incstar Corporation, Stillwater, Minnesota).
Physical stress study visit
On the physical stress day, a maximal bicycle exercise tolerance test with radionuclide imaging was performed in addition to a series of psychological tests and examination of sensory thresholds. The sequence of procedures was designed to minimize distractions and discomfort from extraneous procedures or artificial elevations of neuroendocrine parameters. The patient was prepared and instrumented for 12-lead ECG, ambulatory ECG and automated blood pressure recording; after a 30-min rest period, blood was drawn for determinations of resting levels of neurohormones (epinephrine, norepinephrine, cortisol and beta-endorphin). The Marstock test of sensory perception (14)was administered to establish warm, cool, heat pain and cold pain perception thresholds. The bicycle exercise test was performed with workload increasing by 100 to 150 KPM in 3-min stages and radionuclide images recorded during the last 2 min of each stage. Twelve-lead ECGs, heart rate and blood pressure were recorded at 1-min intervals during the test, and ambulatory ECGs were recorded continuously. Blood specimens were drawn 1 min after beginning exercise, at peak exercise and 10 min after exercise. The Marstock procedure was repeated after exercise and before drawing postexercise blood specimens.
Mental stress study visit
Procedures during Visit 1 mental stress day followed a pattern similar to that of Visit 1 physical stress day, except that two 5-min mental stress tests (Stroop color word test and speech) were substituted for the bicycle exercise test. The data collection protocols for mental and exercise stress were designed very similarly to facilitate comparison between responses to these two procedures, although it was not possible to define “peak” stress for mental stress as one can for exercise testing. For the speech task, patients were to speak for 5 min on an assigned topic while being observed and “evaluated” by laboratory staff. The patient was instructed to role play confronting a nursing home administrator about negligent care of a relative. The Stroop color word test was administered by computer on a video monitor after a short practice. The pace at which words were displayed was automatically adjusted to a level of difficulty designed to result in 60% correct responses.
Blood specimens for neurohormones were drawn 1 min after beginning each mental stress task, at the end of each task and 10 min after completing the second task. Blood pressure and heart rate were automatically recorded 30 s after beginning each mental stress test and each minute thereafter. Table 1shows the biochemical analyses and sample collection schedule for neurohormones during the exercise and mental stress testing.
Sensory perception testing
Results from the Marstock test of cutaneous sensory perception were obtained at baseline after the 30-min rest on two days and after exercise and mental stress. Perception thresholds were determined for warmth, coolness, hot pain and cold pain using a thermal probe applied to the skin overlying the zygomatic arch of the face. Resting hot pain thresholds were averaged for the physical and mental stress visits. Care was taken to stabilize the performance of the Marstock procedure across clinical sites. Measures taken included central training of staff, use of a computer algorithm for administering the stimuli and site visits to each clinical unit where an experienced investigator reviewed performance. Careful review of recorded outputs from the Marstock procedure from each site was also performed.
Patients were divided into two groups: 1) average hot pain threshold <41°C; and 2) average hot pain threshold ≥41°C. Previous data in normal subjects have shown hot pain threshold <41°C to be indicative of abnormal hypersensitivity to noxious heat (15). Patient characteristics were compared between subgroups with chi-square tests or Fisher exact test for categorical variables and Wilcoxon tests (16)for continuous measures. Comparisons of time to angina between patients with and without hot pain thresholds <41°C were performed using survival analysis methods to avoid confounding early termination of the test due to fatigue or other reasons with freedom from risk of angina (17). At each time point during the test, the probability of developing angina at that point is evaluated using all patients who have exercised that long in the denominator rather than those who will develop angina eventually. The cumulative probability of developing angina as exercise duration increased in each group was calculated using the Kaplan-Meier method (18)and compared using the log-rank tests (19). Comparisons of time to angina adjusted for other variables were performed using the Cox proportional hazards model (20).
Comparisons of mean differences in biochemical and hemodynamic measures at rest and during stress tests were adjusted using linear regression for age, gender and, for peak exercise measures, duration of exercise.
Patients were instructed to inform the investigators if and when they first experienced angina during exercise or mental stress testing. Time to onset of angina was determined. History of angina was assessed via Rose questionnaire collected as a subscale of the Anginal Syndrome Questionnaire, and by verbal debriefing after the 48-h ambulatory ECG.
Sensory perception testing
Patient characteristics by average resting hot pain threshold are shown in Table 2. Compared with patients with a higher hot pain threshold (≥41°C), there were more female subjects present in the lower hot pain threshold group, 33% versus 10%, p < 0.001. Other characteristics, including history of myocardial infarction, diabetes, hypertension and age, did not differ significantly between the two groups.
Kaplan-Meier estimates of the cumulative percentage of patients with angina by duration of bicycle exercise for patients with low hot pain threshold (<41°C) versus those with higher thresholds (≥41°C) are shown in Figure 1. Patients with a low hot pain threshold have a shorter time to onset of angina during exercise testing than patients with higher hot pain thresholds, p < 0.04. Using a Cox proportional hazards model, the differences in time to angina on the bicycle test were adjusted for gender, levels of depressed and anxious affect, and history of diabetes or hypertension. After adjustment, the angina failure rate ratio for patients with low versus high hot pain thresholds remained elevated (rate ratio = 1.7), but was not statistically significant (p = 0.10).
Cold pain thresholds were not related to the presence of angina during the exercise (mean ± standard deviation = 7.3 ± 12.9°C vs. 7.2 ± 12.2°C for angina vs. no angina, p > 0.10) and mental stress (mean ± standard deviation = 10.5 ± 13.3°C vs. 7.0 ± 12.4°C for angina vs. no angina, p > 0.10). Patients with low hot pain threshold also had shorter time to angina during treadmill test (failure rate ratio = 2.0, p = 0.02) than patients with hot pain thresholds ≥41°C, a difference which remained significant after adjusting for gender, levels of depressed and anxious affect and history of diabetes or hypertension, (p < 0.01) with a Cox proportional hazards model.
Occurrence of angina during three types of stress tests (Table 3)and during ambulatory ECG recording and by history during the past three months was slightly higher among patients with low hot pain threshold, although these differences were not statistically significant.
Correlation between biochemical measures and hot pain thresholds
Table 4shows biochemical measures by hot pain threshold, with and without adjustment for gender, clinical unit and duration of bicycle exercise test. After adjustment for gender, resting measurements on both physical and mental stress days were higher in patients with lower hot pain thresholds (<41°C) compared with patients with higher hot pain thresholds (≥41°C) for beta-endorphin (p = 0.01 and p = 0.02, respectively) and epinephrine (p = 0.02 and p = 0.07, respectively). Adjusted estimates of differences by hot pain threshold in the magnitude of beta-endorphin and epinephrine responses to exercise and mental stress were not statistically significant. Patients with lower hot pain thresholds had higher resting cortisol levels on mental stress day (adjusted p = 0.03) but not on physical stress day, and had significantly smaller increases in cortisol in response to exercise than did patients with higher hot pain thresholds (both p < 0.05). Norepinephrine levels at rest or in response to stress did not vary by hot pain threshold.
Hemodynamic responses to mental stress (Table 5)and bicycle exercise (Table 6)were examined by hot pain threshold. On mental stress day (Table 5)resting systolic blood pressure was markedly higher (adjusted difference 11.6 mm Hg, p < 0.009) and change in systolic blood pressure during mental stress was marginally lower (adjusted difference −7.5 mm Hg, p = 0.06) among patients with lower hot pain thresholds versus those without. No significant differences in heart rate and blood pressure at angina onset were observed on bicycle exercise day or on qualifying treadmill test between patients with versus without lower hot pain thresholds.
Relationships between time to onset of angina and ischemia
The relationships among hot pain threshold, ischemia and angina were explored with analyses of times to ≥1 min ST depression and angina, and their difference in the two patient groups during treadmill testing. Patients with lower hot pain thresholds had earlier onset of ST depression (mean difference = 1.5 min, p = 0.003) than those with higher pain thresholds. Among patients reporting angina on the exercise treadmill test, we subtracted time to onset at ≥1 mm ST-segment depression from time to angina. On average, in patients with higher pain thresholds, reported angina onset coincided with onset of ≥1 mm ST-segment depression, but in patients with low hot pain thresholds, reported angina onset occurred 2 min before onset of ≥1 mm ST-segment depression (p = 0.03).
The important findings of this study can be summarized as follows. Patients with lower cutaneous hot pain thresholds have shorter times to onset of angina than patients with a higher hot pain threshold, if angina occurred. This was due to both a shorter time to the onset of ischemia and to the perception of angina (anginal latency period) after ischemia. These patients also had higher levels of resting neurohormones, including beta-endorphin, cortisol and epinephrine, and had hemodynamic measurements (heart rate and blood pressure) suggestive of a state of arousal of the hypothalamic–pituitary–adrenal (HPA) axis at rest, which has been reported to be associated with decreased perception of sensory stimuli and a tendency toward diminished responsivity to stressors (21–35). These findings were associated with earlier onset of angina during exercise and a nonsignificant tendency toward differences in clinical occurrence of angina by history during the various stressors and as reported during ambulatory ECG monitoring. This suggests that time to onset of angina during an exercise test may be a more sensitive marker of susceptibility to angina than reporting of presence versus absence of angina during daily life.
Relation between pain threshold and clinical symptoms
The results of this study are both interesting and provocative. First, there appears to be a relationship between hot pain threshold, as measured by a thermal probe device, and time of onset of angina during exercise. This finding suggests a correlation between sensitivity to exercise-induced anginal pain and cutaneous thermal pain threshold. Previous work has been somewhat contradictory in this area. Work by Droste and Roskamm and others showed a correlation between pain thresholds and symptoms with patients with silent ischemia showing higher pain thresholds than patients with painful ischemia (28–31), but other published work did not show such a correlation (32). Furthermore, in the current study, the low hot pain threshold group also has a higher resting plasma beta-endorphin level and a tendency toward a diminished change with stress compared with other patients, suggesting some abnormality of the HPA axis. Ordinarily, one would expect higher resting plasma beta-endorphins to be associated with a decreased sensitivity to pain; however, patients who have low thermal thresholds and angina may have a dysfunctional HPA axis as well as an altered relationship between plasma levels of beta-endorphin and pain perception (23–25).
Potential role of the opioid system
Many mechanisms have been postulated to explain altered pain perception in patients with coronary artery disease (33). The potential role of the opioid system and the significance of plasma opioid levels in mediating cutaneous pain perception and angina are controversial. Several authors have demonstrated positive correlations between plasma opioid levels and cutaneous pain perception indices or reported pain (36); others have not found such a relationship. Reported differences may be due to many factors, including differences in patient populations, assay techniques and experimental protocol (32,34,35).
Pain, as a type of stressful stimulus, can stimulate beta-endorphin release. The beta-endorphin response to repeated episodes of angina may cause persistent elevation of beta-endorphin levels in patients due to a hyperfunctioning HPA axis. Sustained elevation of endogenous opioids may result in down-regulation of opioid receptors, thereby altering the expected relationship between plasma levels of beta-endorphin and cutaneous thermal pain perception. The elevation in beta-endorphin levels observed in our patients with lower pain thresholds at baseline might be expected had they had repeated episodes of pain during daily life. Against this hypothesis is the failure to find differences in recent history of angina by the Rose questionnaire or debriefing after the ambulatory ECG monitoring utilized in our study. However, symptomatic patients may show a great variation in beta-endorphin levels to each stressful stimulus; patients with symptoms during percutaneous transluminal coronary angioplasty have been shown to have a reduction in beta-endorphin during the procedure, whereas patients with silent ischemia showed less variation (36). Patients who have chronic overstimulation of the opioid system and a higher baseline beta-endorphin level may also have a dysfunctional response of their opioid system to stress. It has also been shown in laboratory animals that repetitive nociceptive stimuli can modify gene expression of opioid peptides (37).
The abnormalities in the opioid system as shown in our studies cannot be viewed as entirely causal of the differences in the anginal pain experience in our patients. This is because it is well known that there are multiple pain regulatory systems (9,33,35)and that there may be synergism between the various systems. Abnormalities in serotonin may have been responsible for some of our findings, although we did not directly test this. Catecholamines can also modify perception of pain and were altered in our patients, as previously described. Recently, the central processing of afferent pain messages from the heart in determining silent versus painful myocardial ischemia have also been implicated (38,39). Using positron emission tomography, Rosen et al. (39)found that patients with silent ischemia had greater activation of the frontal cortex than patients with angina during dobutamine infusion. Thus, abnormal central processing of afferent pain messages may be causally related to silent ischemia.
Regardless of the exact mechanisms involved, earlier onset of ischemia and a shorter latency period between ischemia and pain perception both contributed to our findings. Hot pain thresholds <41°C were present in about 14% of PIMI patients, not all of whom reported angina during testing or daily life. Differences in disease severity may also explain these findings, but we could not examine this possibility, as PIMI did not collect current angiographic data on patients when they were enrolled. These abnormalities in sensory pain perception, and associated differences in neurohormone levels, may be linked to differences in perception of cardiac pain in this small subset of patients with coronary artery disease. These abnormalities in perception were present in a few patients studied and in a greater proportion of women than men, consistent with previous studies (21,22). The significance of this finding for differences in anginal perception within a given patient over time, or among most cardiac patients, should be investigated.
☆ The Psychophysiological Investigations of Myocardial Ischemia (PIMI) was supported by contracts HV 18114, HV 18119–HV 18121 and HV 28127 from the National Heart, Lung, and Blood Institute. Support for electrocardiogram data collection was provided in part by Applied Cardiac Systems, Laguna Hills, California; Marquette Electronics, Milwaukee, Wisconsin; Quinton Instruments, Seattle, Washington, and Mortara Instruments, Milwaukee, Wisconsin. Dinamap equipment was provided by Critikon, Inc., a Johnson and Johnson Company. Michael Eddy, University of Pittsburgh, and Richard Lutz, University of North Carolina provided Stroop Test software. Dr. Kathleen Light provided role play scenarios for the speech task. Some centers had partial support from General Clinical Research Center grants. A list of participating centers and investigators appears in Kaufmann et al. (1998) (12). The opinions and assertions contained herein are those of the authors and should not be construed as representing positions or policies of the National Heart, Lung, and Blood Institute or the U.S. Department of Health and Human Services.
- Psychophysiological Investigations of Myocardial Ischemia
- Received August 21, 1998.
- Revision received January 25, 1999.
- Accepted February 15, 1999.
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