Martha N. Ballenger

Production of Arrhythmias by Elevated Carboxyhemoglobin in Patients with Coronary Artery Disease

OBJECTIVE To assess the effects of exposure to 4% and 6% carboxyhemoglobin on ventricular arrhythmias in patients with coronary artery disease. DESIGN Randomized, double-blind, crossover design. SETTING Exercise laboratory with an environmentally controlled exposure. PATIENTS Forty-one nonsmokers with documented coronary artery disease. INTERVENTION On day 1, a training session with no exposure, the baseline carboxyhemoglobin level was measured, and a supine bicycle exercise test was done. On days 2 to 4, patients were exposed to room air, 100 ppm carbon monoxide (target, 4% carboxyhemoglobin) or 200 ppm carbon monoxide (target, 6% carboxyhemoglobin), and they then did supine bicycle exercise with radionuclide ventriculography. Ambulatory electrocardiogram recordings were made during the 4 consecutive days to determine the frequency of ventricular premature depolarization (VPD) at various intervals. MEASUREMENTS AND MAIN RESULTS The frequency of single VPD/h was significantly greater on the 6% carboxyhemoglobin day than on the room air day during the exercise period (167.72 +/- 37.99 for 6% carboxyhemoglobin compared with 127.32 +/- 28.22 for room air, P = 0.03). During exercise, the frequency of multiple VPD/h was greater on the 6% carboxyhemoglobin day compared with room air (9.59 +/- 3.70 on the 6% carboxyhemoglobin compared with 3.18 +/- 1.67 on room air, P = 0.02). Patients who developed increased single VPD during exercise on the 6% carboxyhemoglobin day were significantly older than those who had no increased arrhythmia, whereas patients who developed complex arrhythmias were also older and, in addition, exercised longer and had a higher peak workload during exercise. CONCLUSION The number and complexity of ventricular arrhythmias increases significantly during exercise after carbon monoxide exposure producing 6% carboxyhemoglobin compared with room air but not after exposure producing 4% carboxyhemoglobin.

Relation between systemic hypertension and pain perception.

To test the hypothesis that hypertension diminishes pain perception, a study was made that evaluated the relation between arterial blood pressure and thermal pain perception in human subjects. The average mean arterial pressure in all 20 men studied (10 hypertensive, 10 normotensive) proved to be significantly related to both thermal pain threshold (p = 0.05) and tolerance (p = 0.003). The difference between normotensive and hypertensive groups in baseline and posttest plasma levels of beta endorphin was also significant (p = 0.02) and indicated an interaction between endogenous opioids and blood pressure. Other recent studies of hypertension in relation to hypalgesia were also reviewed. An increased pain threshold was found in hypertensive versus normotensive rats. In cats, electrical stimulation of vagal afferent nerves (cardiopulmonary baroreceptors) suppresses nociceptive responses, and both pharmacologic elevation of blood pressure and vascular volume expansion produce antinociception. Together with preliminary findings in human studies, these results indicate an interaction between pain-controlling and cardiovascular regulatory functions that is probably mediated by the baroreceptor system.

Psychophysical responses to a speech stressor: Correlation of plasma beta-endorphin levels at rest and after psychological stress with thermally measured pain threshold in patients with coronary artery disease

OBJECTIVES We tested the hypothesis that psychological stress alters plasma levels of opioid peptides and that these plasma levels are related to pain perception in patients with coronary artery disease. BACKGROUND Public speaking psychological stress has previously been shown to be associated with silent ischemia. METHODS After instrumentation and a 30-min rest period, venous blood samples for beta-endorphin were obtained before and immediately after psychological stress in 20 patients with coronary artery disease. Pain threshold was then assessed using a thermal probe technique at baseline and immediately after stress. Patients gave three brief speeches lasting a total of 15 min about real-life hassle situations. RESULTS Psychological stress significantly increases plasma beta-endorphin levels (4.3 +/- 0.9 pmol/liter [mean +/- SE] at rest to 8.3 +/- 2 pmol/liter after stress, p < 0.05). There was a significant positive correlation between pain threshold and beta-endorphin levels after stress (r = 0.577, p = 0.008). This significant positive correlation was still present while rest blood pressure and change in blood pressure during stress were controlled for by analysis of covariance techniques. CONCLUSIONS In patients with coronary artery disease and exercise-induced ischemia, public speaking produces psychological stress manifested by increased cardiovascular reactivity and causes an increase in plasma beta-endorphin levels that is significantly correlated with pain thresholds. These findings may explain the predominance of silent ischemia during psychological stress in patients with coronary artery disease.

Beta-endorphin response to exercise and mental stress in patients with ischemic heart disease

UNLABELLED We compared symptomatic, hemodynamic and opioid responses of heart disease patients to exercise testing and a stressful public speaking task. Plasma beta-endorphins were measured at rest and immediately post stress. Nineteen of 50 patients had angina during exercise; 31 had asymptomatic ischemia. No patient had angina during the speech, but two had ECG changes and 39% had radionuclide changes indicating ischemia. Patients with asymptomatic ischemia on exercise had a significantly greater beta-endorphin response than those with angina. Public speaking elicited a significantly larger beta-endorphin increase relative to change in double product (an index of stress) than did exercise. CONCLUSIONS (1) Patients with silent vs painful ischemia experience a greater beta-endorphin response to exercise. (2) beta-endorphin response to a speech stressor is greater than to exercise when controlled for an index of stress. (3) Increased beta-endorphin response to a speech stressor may partially explain the predominance of silent ischemia during psychological stress.

Myocardial ischemia during daily activities the importance of increased myocardial oxygen demand

The role of increased myocardial oxygen demand in the pathophysiology of myocardial ischemia occurring during daily activities was evaluated in 50 patients with coronary artery disease and exercise-induced ST segment depression. Each patient underwent ambulatory electrocardiographic (ECG) monitoring for ST segment shifts during normal daily activities and symptom-limited bicycle exercise testing with continuous ECG monitoring. All 50 patients had ST depression greater than or equal to 0.1 mV during exercise. A total of 241 episodes of ST depression were noted in the ambulatory setting in 31 patients; only 6% of these were accompanied by angina pectoris. Significant (0.1 mV) ST depression during ambulatory monitoring was preceded by a mean increase in heart rate of 27 +/- 12 beats/min. Patients with ischemia during daily activities developed ST depression earlier during exercise (7.9 +/- 4.4 vs. 14.2 +/- 6.4 min, p less than 0.001) and tended to have significant ECG changes at a lower exercise heart rate and rate-pressure product than did those without ST depression during ambulatory monitoring. In the 31 patients with ischemia during daily activities, the mean heart rate associated with ST depression in the ambulatory setting was closely correlated with the heart rate precipitating ECG changes during exercise testing (r = 0.74, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased heart rate response to laboratory-induced mental stress predicts frequency and duration of daily life ambulatory myocardial ischemia in patients with coronary artery disease

This study assessed the relation between hemodynamic data during a standardized mental stressor and ambulatory ischemia to determine if laboratory-induced responses could predict the magnitude of daily life ischemia. Forty-two men and 11 women, aged 46 to 79 years (mean 61), with coronary artery disease and exercise-induced ischemia were studied. All patients underwent 24- to 48-hour ambulatory electrocardiographic (ECG) monitoring (mean 43 +/- 0.8 hours) and laboratory-induced mental stress using a public speaking task. Hemodynamic data were obtained at rest and every minute during mental stress. Thirty-three of 53 patients (62%) had at least 1 ischemic episode during ECG monitoring. In patients who had ambulatory ischemia, there was a mean number of 7.9 +/- 1.8 episodes (mean total duration 79.2 +/- 24.1 minutes/48 hours). Significant positive correlations were found for peak heart rate and changes in heart rate during mental stress and ambulatory ischemia (r = 0.353 to 0.462, p < 0.05) in patients who had ambulatory ischemia. There was no correlation between systolic blood pressure during mental stress and ambulatory ischemia. Results of this study demonstrate that heart rate response during laboratory-induced mental stress correlates with magnitude of ischemia on ambulatory ECG monitoring in patients with coronary artery disease.

The Relationship Between Plasma p-Endorphin, Opioid Receptor Activity, and Silent Myocardial Ischemia

ObjectiveTo investigate the role of the opioid system in the pathophysiology of silent ischemia through opiate antagonism with naloxone, and to determine the reproducibility of resting and postexercise β-endorphin levels in predominantly asymptomatic patients with coronary artery disease. DesignRandomized, double-blind, placebo-controlled crossover trial. SettingA University hospital referral center. PatientsTen patients with prior evidence of silent exercise-induced ischemia were studied. InterventionAn infusion of saline placebo or naloxone at two dose regimens of 0.015 mg/kg or 0.15 mg/kg before supine exercise testing during three separate occasions for each patient. Outcome MeasuresPlasma β-endorphin was measured at rest, immediately after exercise, and 5 min poststress. Timing and severity of angina and exercise hemodynamics were also determined. ResultsSeven of 10 patients reported no angina, whereas the other three experienced angina with placebo and after administration of naloxone at both doses. The severity and duration of angina was consistently noted to decrease in these patients after naloxone administration, especially after low-dose naloxone relative to placebo. There were no apparent correlations between β-endorphin levels and the characteristics of angina in these three patients, nor between β-endorphin and hemodynamic responses in all patients in the study. Conclusions(a) naloxone failed to precipitate angina in this population of patients with silent ischemia; (b) naloxone appears to exert an analgesic effect at low doses; and (c) a variability of 5 pM at rest and 13 pM after exercise might be expected in predominantly asymptomatic patients due to random variation, which is comparable with results found in normal subjects.

A comparison of amplitude-modulated and frequency-modulated ambulatory monitoring systems

To compare the results of monitoring for ischemia with amplitude-modulated (AM) and frequency-modulated (FM) ambulatory recorders, 22 patients with coronary artery disease were monitored during exercise and during 24 to 48 hours of daily activities. Simultaneous recordings were obtained with Oxford Medilog 4000-II and Medilog MR-35 systems from the same 2 bipolar leads. Each potential ischemic episode was interpreted blindly by 2 investigators. Significant ST depression was strictly defined as greater than or equal to 1 mm of horizontal or down-sloping ST depression persisting for 0.06 second beyond the J point and lasting greater than or equal to 1 minute. Of 82 episodes reviewed, 63 (77%) were either positive (37) or negative (26) for ischemia by both systems. However, 17 episodes were interpreted as positive on AM tracings but negative on FM tracings; the converse was true for only 2 episodes (p less than 0.01). For episodes read as positive with both systems, there were close correlations between recorders for duration (r = 0.80) and magnitude (r = 0.90) of ST depression. Because of the greater number of positive AM events, however, the mean total duration of ST depression for patients with ischemia during daily activities was greater on AM than on FM recordings (74 +/- 77 vs 39 +/- 42 minutes, p less than 0.10). Discrepancies between AM and FM tracings were invariably due to small differences in ST-segment morphology or in the magnitude of ST-segment depression. In summary, AM monitors generate complexes similar in appearance to those produced by FM devices in most instances.(ABSTRACT TRUNCATED AT 250 WORDS)