Mark W. Ketterer

Ischemic, Hemodynamic, and Neurohormonal Responses to Mental and Exercise Stress Experience From the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI)

BACKGROUND The pathophysiology of mental stress-induced myocardial ischemia, which occurs at lower heart rates than during physical stress, is not well understood. METHODS AND RESULTS The Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) evaluated the physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. Hemodynamic and neurohormonal responses to bicycle exercise, public speaking, and the Stroop test were measured by radionuclide ventriculography, ECG, and blood pressure and catecholamine monitoring. With mental stress, there were increases in heart rate, systolic blood pressure, cardiac output, and systemic vascular resistance that were correlated with increases in plasma epinephrine. During exercise, systemic vascular resistance fell, and there was no relationship between the hemodynamic changes and epinephrine levels. The fall in ejection fraction was greater with mental stress than exercise. During mental stress, the changes in ejection fraction were inversely correlated with the changes in systemic vascular resistance. Evidence for myocardial ischemia was present in 92% of patients during bicycle exercise and in 58% of patients during mental stress. Greater increases in plasma epinephrine and norepinephrine occurred with ischemia during exercise, and greater increases in systemic vascular resistance occurred with ischemia during mental stress. CONCLUSIONS Mental stress-induced myocardial ischemia is associated with a significant increase in systemic vascular resistance and a relatively minor increase in heart rate and rate-pressure product compared with ischemia induced by exercise. These hemodynamic responses to mental stress can be mediated by the adrenal secretion of epinephrine. The pathophysiological mechanism involved are important in the understanding of the etiology of myocardial ischemia and perhaps in the selection of appropriate anti-ischemic therapy.

Mental Stress-Induced Ischemia and All-Cause Mortality in Patients With Coronary Artery Disease Results From the Psychophysiological Investigations of Myocardial Ischemia Study

Background—Ischemia during laboratory mental stress tests has been linked to significantly higher rates of adverse cardiac events. Previous studies have not been designed to detect differences in mortality rates. Methods and Results—To determine whether mental stress–induced ischemia predicts death, we evaluated 196 patients from the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study who had documented coronary artery disease and exercise-induced ischemia. Participants underwent bicycle exercise and psychological stress testing with radionuclide imaging. Cardiac function data and psychological test results were collected. Vital status was ascertained by telephone and by querying Social Security records 3.5±0.4 years and 5.2±0.4 years later. Of the 17 participants who had died, new or worsened wall motion abnormalities during the speech test were present in 40% compared with 19% of survivors (P =0.04) and significantly predicted death (rate ratio=3.0; 95% CI, 1.04 to 8.36;P =0.04). Ejection fraction changes during the speech test were similar in patients who died and in survivors (P =0.9) and did not predict death even after adjusting for resting ejection fraction (P =0.63), which was similar in both groups (mean, 56.4 versus 59.7;P =0.24). Other indicators of ischemia during the speech test (ST-segment depression, chest pain) did not predict death, nor did psychological traits, hemodynamic responses to the speech test, or markers of the presence and severity of ischemia during daily life and exercise. Conclusions—In patients with coronary artery disease and exercise-induced ischemia, the presence of mental stress–induced ischemia predicts subsequent death.

Men deny and women cry, but who dies? Do the wages of ''denial'' include early ischemic coronary heart disease?

OBJECTIVES In this study patients with documented ischemic coronary heart disease (ICHD; prior MI or CAD per catheterization) were tested for the association of various measures of emotional distress with Age at Initial Diagnosis. METHODS The measures were chosen because of a published track record at predicting mortality in this population. Females were oversampled to achieve equivalent numbers of each sex (n=50), and thus equivalent statistical power. In a subset of patients (38 males and 32 females), Spouse/Friend Ketterer Stress Symptom Frequency Checklists (KSSFCs) were received. RESULTS Females reported more depression and anxiety than males. However, spouses or friends reported more anger for males. Denial (spouse/friend minus self-ratings) was greater in males for all three scales of the KSSFC (Anger, P=.005; Depression, P=.024; Anxiety, P=.001). Although females showed the same trend, self and spouse or friend ratings of distress were significantly associated with Age at Initial Diagnosis only in males. When split at the sample mean on the Spouse/Friend KSSFC AIAI (Anger) scale, Age at Initial Diagnosis occurred 14.2 years earlier in males. CONCLUSIONS Use of a significant other in assessing psychosocial/emotional distress in males may confer greater accuracy, and therefore predictive power for clinical endpoints.

Aid and Influence: Health-Promoting Exchanges of Older Married Partners

Dyadic exchanges of support and control were investigated in couples in which the husband was recently treated or assessed for heart disease. Each partner in 61 marital dyads (N = 122 participants) reported the frequency with which both social support and social control to promote a healthy lifestyle were provided to and received from one another. Multivariate findings demonstrated the influence of intrapersonal (or actor) and interpersonal (or partner) contributions of providing support and control to each spouse’s perception of receiving such exchanges from the other. These findings reveal that marital partners’ perspectives of receipt of health-related exchanges of support and control are associated not only with the behavior of the partner, but also with their own initiation of health-promoting exchanges on their partner’s behalf.

THE PSYCHOPHYSIOLOGICAL INVESTIGATIONS OF MYOCARDIAL ISCHEMIA (PIMI) STUDY: OBJECTIVE, METHODS, AND VARIABILITY OF MEASURES

Objective This study evaluated physiological, neuroendocrine, and psychological status and functioning of patients with coronary artery disease in order to clarify their role in the expression of symptoms during myocardial ischemia (MI), and to establish repeatability of responses to mental stress. Design and methods of the study are presented. Methods One hundred ninety-six coronary artery disease patients were examined during physical and mental stress tests in four hospitals. Eligibility criteria included narrowing of at least 50% in the diameter of at least one major coronary artery or verified history of myocardial infarction, and evidence of ischemia on an exercise treadmill test. Psychological, biochemical, and autonomic function data were obtained before, during, and after exposure to mental and exercise stressors during 2 or 3 half-days of testing. Ventricular function was assessed by radionuclide ventriculography, and daily ischemia by ambulatory electrocardiography. Sixty patients returned for a short-term mental stress repeatability study. Twenty-nine individuals presumed to be free of coronary disease were also examined to establish reference values for cardiac responses to mental stress. Results Study participants were 41 to 80 years of age; 83 (42%) had a history of MI, 6 (3%) of congestive heart failure, and 163 (83%) of chest pain; 170 (87%) were men; and 90 (46%) had ischemia accompanied by angina during exercise treadmill testing. Ischemia during ambulatory monitoring was found in 35 of 90 (39%) patients with and 48 of 106 (45%) patients without angina during exercise-provoked ischemia. Intraobserver variability of ejection fraction changes during bicycle exercise and two mental stress tests (Speech and Stroop) was good (kappa = 1.0, .90, and .76, respectively; percent agreement = 100, 97.5, and 93.8%, respectively). Variability of assessed wall motion abnormalities during bicycle exercise was better (kappa, agreement = 85%) than during Speech or Stroop kappa and .57, percent agreement = 70% and 82.5%, respectively). Conclusions Study design, quality control data, and baseline characteristics of patients enrolled for a clinical study of symptomatic and asymptomatic myocardial ischemia are described. Lower repeatability of reading wall motion abnormalities during mental stress than during exercise may be due to smaller effects on wall motion and lack of an indicator for peak mental stress.

Is aspirin, as used for antithrombosis, an emotion-modulating agent?

Antiplatelet substances, generally aspirin, have become widely used for secondary prevention of ischemic heart disease. Used in relatively small doses, it is generally assumed that aspirin has no psychoactive effect. The present study took advantage of a sample of 174 males undergoing coronary angiography to see if regular aspirin use as prophylactic therapy for ischemic heart disease was associated with one or more of a number of measures of emotional distress. Aspirin use was found to be associated with less depression and anxiety or worry, as reported by the patient and as perceived by a significant other. Despite a significant association of aspirin use with the presence of documented coronary artery disease, the association of aspirin use and diminished distress could not be accounted for by the previously observed high prevalence of depressed/anxious individuals among patients with negative or nominal results on angiography, or by a number of other demographic or clinical variables such as age and socioeconomic status. Although only correlational in nature, present results raise the question of whether aspirin may have a beneficial mood-modulating effect.

The big mush: psychometric measures are confounded and non-independent in their association with age at initial diagnosis of Ischaemic Coronary Heart Disease.

The present study uses early diagnosis of ischaemic coronary heart disease (ICHD) as a proxy for disease malignancy in testing the statistical strength of association, and uniqueness/confounding, of several psychometric scales that have previously been found to prospectively predict death in cardiac samples (Beck Depression Inventory, Crown–Crisp Phobic Anxiety Scale, Type D Scale & Ketterer Stress Symptom Frequency Checklist). Eighty-three patients (no. of females=35) with documented ICHD were assessed for traditional and psychometric risk factors. The psychometric risk factors were moderately to strongly intercorrelated, and strongly confounded in their relationship to age at initial diagnosis. In a stepwise multiple regression, only the AIAI (aggravation, irritation, anger and impatience) scale of the Ketterer Stress Symptom Frequency Checklist (KSSFC) survived as a predictor of age at initial diagnosis (P=0.016). In a subgroup of the sample for whom the Spouse/Friend Version of the KSSFC was received (n=58, or 70%), spouse/friend reported AIAI survived as the only predictor (P=0.010). While present results need replication in a prospective study of diagnosed ICHD patients for all important clinical outcomes, only one psychometric screening instrument may be necessary to identify patients in need of treatment.

Reproducibility of mental stress-induced myocardial ischemia in the psychophysiological investigations of myocardial ischemia (PIMI)

Objective Many patients with coronary artery disease (CAD) develop myocardial ischemia in response to mental stress. This has been documented both in the natural environment and in the laboratory. However, the reproducibility of laboratory mental stress-induced ischemia has not been investigated. Method Sixty patients with documented CAD and a positive exercise stress test discontinued cardiac medications and underwent two standardized mental stress tests (a timed Stroop Color-Word test and a public speaking task) in a nuclear cardiology laboratory (Visit 1), and repeated this procedure between 2 and 8 weeks later (Visit 2). Measurements of cardiovascular function and neurohormonal responses were obtained throughout testing, and mood state was assessed before and after testing. Results Sixty-eight percent of the 56 patients with detailed radionuclide data from both visits had consistent responses (ie, ischemia either present during both sessions or absent during both) to the Stroop task (kappa = .29, p = .03), 61% had consistent responses to the speech task (kappa = .20, p = .12), and 60% had consistent responses when ischemia was considered present if it occurred during either the Stroop test, the speech task, or both, and absent if it did not occur during either task (kappa = .22, p = .07). Hemodynamic and neuroendocrine responses to the tests were moderately reproducible. Conclusions We conclude that two popular laboratory tests for mental stress-induced myocardial ischemia are modestly reproducible. The relatively low reproducibility is probably influenced by uncertainties in detecting relatively small changes in wall motion, habituation of the patient to repeated exposure to psychological stressors, and physiological differences in threshold for ischemia on different days of testing.

Psychosocial and traditional risk factors in early ischaemic heart disease: cross-sectional correlates.

Background Psychosocial/emotional distress has been repeatedly found to be a correlate of the onset/aggravation of ischaemic heart disease. Methods Eighty-three patients (63 men and 20 women) with known coronary artery disease who entered an aggressive lifestyle modification programme were administered a clinical/demographic history and the Symptom Checklist 90 – Revised at baseline. Several measures of social isolation/alienation (shyness/self-consciousness, feeling lonely, feeling abused and overall) were derived from the the Symptom Checklist 90 – Revised. Results Univariate tests of the association of known cardiovascular risk factors and the Symptom Checklist 90 -Revised scales with age at initial diagnosis yielded several significant results for history of hypercholesterolaemia (P = 0.018), history of hypertension (P = 0.030), somatization (P = 0.007), obsessive-compulsive (P = 0.009), depression (P = 0.006), anxiety (P = 0.021), hostility (P = 0.003), paranoia (P = 0.050), psychoticism (P = 0.029), the Global Severity Index (P = 0.007), the Positive Symptom Distress Index (P = 0.005), the Positive Symptom Total Score (P = 0.003) and feeling abused (P = 0.037). Only history of hypertension, history of hypercholesterolaemia and the hostility scale (overall F= 6.08 and P = 0.0009) emerged as unique correlates of age at initial diagnosis in a multiple regression using only the significant univariate predictors. Conclusions Psychosocial factors are sufficiently confounded with one another that they lose their predictive value once one is entered in the equation. High scores on the hostility scale were associated with a 5.7 year differential in age at initial diagnosis. The younger a patient is at initial diagnosis, the more likely he/she is to have high levels of emotional distress.

SILENT VERSUS SYMPTOMATIC MYOCARDIAL ISCHEMIA : THE ROLE OF PSYCHOLOGICAL AND MEDICAL FACTORS

This study examined the relationship of psychological, cardiac, and general medical history factors to asymptomatic (silent) versus symptomatic myocardial ischemia among 102 patients who underwent treadmill exercise testing and had perfusion imaging indicative of ischemia. During exercise, 68 patients exhibited silent ischemia, and 34 experienced chest pain. Patients with silent ischemia rated higher than symptomatic patients on anger control, externally oriented thinking, and somatosensory amplification, but did not differ on depression or global alexithymia. Anger control and externally oriented thinking remained independent correlates in multivariate analysis, controlling for demographic and cardiac factors. Groups did not differ on general medical or cardiac variables. Thus, this study suggests that affective and cognitive factors, but not biomedical factors, are associated with silent, as opposed to symptomatic, ischemia during exercise testing.