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ORIGINAL ARTICLE |
From the Department of Psychology (T.R., W.L.), University of British Columbia, Vancouver, British Columbia; Canada; the Division of Cardiology (R.F.D.), Ottawa Heart Institute, Ottawa, Ontario, Canada; and cooperating institutions of the Canadian Amlodipine/Atenolol Silent Ischemia Study.
Address reprint requests to: Thomas Rutledge, PhD, Behavioral Medicine Research Group, University of Pittsburgh, Bellefield Professional Bldg., 130 N. Bellefield Ave., Suite 520, Pittsburgh, PA 15260. Email: dr.tom{at}musclemail.com
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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METHODS: Eighty patients with known coronary disease and exercise-induced ischemia underwent treadmill exercise testing and 48-hour ambulatory electrocardiographic monitoring and completed a battery of standardized psychological tests assessing hostility, depression, and daily stress on four occasions during a 12-week pharmacological treatment study. After withdrawal of antiischemic drugs at baseline, patients returned for subsequent tests at 3-week intervals. During the second and third intervals, patients were prescribed one of two antiischemic medications, atenolol or amlodipine, or given a placebo. All patients were then placed on a combination treatment protocol for the 3 weeks before the final testing date.
RESULTS: The combination treatment produced highly significant benefits across all measured cardiac variables (20.3% improvement in exercise performance, 13% reduction in reported angina, 64.0% reduction in the frequency of ischemic episodes; for all, p < .01). However, results showed that high baseline levels of daily stress were associated with reliably smaller treatment effects on measures of ischemia frequency and treadmill exercise time and with a significantly greater likelihood of reporting angina after treatment (r = -0.24, -0.25, and -0.33, respectively; p <.05). In addition, high baseline hostility predicted significantly smaller diastolic blood pressure improvements (r = -0.29, p < .05).
CONCLUSIONS: These results indicate that psychological risk factors may have globally negative effects on the course of treatment and suggest particular factors that may warrant attention in trials targeting cardiac symptom reduction.
Key Words: myocardialischemia • ambulatory electrocardiographic monitoring • exercisetreadmill testing • stress
Abbreviations: CASIS = Canadian Amlodipine/Atenolol in Silent Ischemia Study.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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In the study described here, we examined a less-well-known but equally relevant area of stress research, namely, the role(s) that psychological characteristics might play in the process of medical treatment (8). With an increasingly older society, and concurrently higher prevalence rates of age-related diseases, identifying factors that can improve the effectiveness of treatment and cut overall costs is of strong interest to all parties involved.
Evidence from high-profile cardiac studies suggests that psychological factors may be as detrimental to disease recovery as to disease development. Studies show, for example, that high stress levels in the aftermath of myocardial infarction predict 1-year mortality and rehospitalization (9, 10) and that interventions designed to reduce stress can produce improvements on a variety of biological risk factors and increase survival rates above those accorded by standard treatment alone (8, 11). Importantly, the short-term costs of added psychosocial interventions seem to reduce long-term costs considerably by cutting down on the number of expensive rehospitalizations (12).
Given these encouraging treatment results, it is surprising to learn that psychosocial interventions are a component of only a relatively small proportion of cardiac rehabilitation programs. It is estimated that <50% of rehabilitation programs include specific psychosocial interventions, although this number seems to be increasing (13, 14). Several factors may be contributing to this situation. For one, we remain unclear about the mechanisms through which psychological variables may moderate cardiac treatment outcomes (eg, do they decrease initial treatment effectiveness or instead precipitate relapse?), nor do we have convincing evidence to indicate which psychological characteristics (eg, depression, anger, daily events, etc.) most reliably predict treatment effects. An improved understanding of how psychological factors affect treatment and what variables should be targeted would therefore facilitate efforts to improve existing psychosocial and psychiatric treatment protocols.
This article provides evidence on these issues using data collected from CASIS, which included comprehensive measurements of physical and psychological risk factors during the course of treatment (15). Based on the published literature, our specific prediction was that higher status of known psychological risk factors would predict poorer treatment responses for a number of cardiac end points.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Patients were excluded if they required digitalis, had undergone cardiac surgery or had had a stroke within the previous 6 months, or if they had electrocardiographic abnormalities that would render the ST segment unreadable (eg, left bundle branch block, atrial fibrillation, or atrial flutter). Ten Canadian academic centers, each enrolling 8 to 10 patients, participated in the study. The study protocol was approved by the ethics committee at each participating center, and all patients provided written informed consent.
Study Design
The study consisted of a randomized, double-blind trial conducted uniformly at each of the 10 centers. After a baseline evaluation, made after withdrawal of antiischemic medication, all patients were evaluated while receiving a combination of amlodipine plus atenolol. Each treatment phase lasted 3 weeks, with end points (results of exercise treadmill testing, Holter monitoring, and psychological testing) being assessed at the end of the treatment periods.
Dose Titration
During combination therapy, initial daily dosage levels were 5 mg of amlodipine and 50 mg of atenolol. If this combination was well tolerated, the daily dosages were increased to 10 mg and 100 mg, respectively, after 1 week. Patients received the final dosage of combination therapy for at least 2 weeks before exercise and ambulatory testing.
Exercise Testing
Symptom-limited exercise treadmill testing was conducted using the protocol of Bruce et al. (16). Twelve-lead electrocardiograms were recorded at baseline, at the end of each 3-minute stage of the protocol, at the onset of 1.0-mm ST segment depression, at the occurrence of anginal symptoms, and at peak exercise. ST segment depression was evaluated 0.06 to 0.08 seconds after the J point was reached and determined as 1 mm or greater ST depression from the patient’s own resting baseline value. Exercise was limited by moderate to severe symptoms of angina, breathlessness, or exhaustion or by the occurrence of hypotension or more than three beats of ventricular tachycardia.
Ambulatory Electrocardiographic Monitoring
Patients underwent 48-hour ambulatory electrocardiographic monitoring on 2 successive days at the end of the baseline and combination treatment phases. Three channel recordings were obtained on magnetic tape using either a Marquette model 8005 or Delmar Avionics model 459 amplitude modulated recorder. Both meet American Heart Association criteria for adequate frequency response to record the ST segment. After careful skin preparation, pregelled electrodes were applied to monitor leads V5, II, and AVF. After calibration, baseline recordings were obtained with the patient in the left and right lateral decubitus, supine, prone, and standing positions and after 1 minute of hyperventilation in the standing position. Resting (supine) blood pressure levels were also measured at this time.
Tapes were analyzed by a skilled technologist using a Marquette laser Holter scanner. All episodes were overread by a cardiologist. The ST segment was measured 0.08 seconds after the J point was reached. An ischemic episode was defined as at least 1 mm of planar or downsloping ST depression from baseline lasting for at least 1 minute and separated from an adjacent episode by at least 1 minute. The onset, maximal ST deviation, and offset of each episode were printed on paper at a rate of 25-mm per second, and the ST segment trend data for the entire recording period were saved for future reference. For each patient, the number of episodes in 48 hours, total duration of ischemia, and integral of ST depression over time were recorded.
Psychological Testing
Participants completed a battery of psychological instruments on the day after exercise treadmill testing, including measures of depression (Beck Depression Inventory (BDI), Ref. 17), hostility (Cook-Medley Hostility Questionnaire (CMHQ), Ref. 18), daily stress (Daily Stress Inventory (DSI), Ref. 19), and Type A behavior (Framingham Type A Scale (FTAS), Ref. 20).
Statistical Analyses
We used simple descriptive statistics to assess patients’ baseline and posttreatment demographic, psychological, and cardiac characteristics. To evaluate the effectiveness of the drug treatment protocol, we performed separate repeated-measures analyses of variance comparing frequency and duration of ischemia, resting blood pressure and heart rate, total exercise time, peak ST segment depression values, and the incidence of angina at baseline with those observed after the combination treatment. 
levels for these tests were set at 0.01 to maintain an overall risk of Type I error of 0.05. Exploration of possible gender differences in these effects was prevented by the insufficient number of women (15) completing the trial.
We investigated questions concerning the relations between cardiac treatment variables and psychological risk factors using stepwise regression techniques. Baseline self-reported measures of daily stress, Type A behavior, depression, and hostility were used as psychological predictors of treatment effects. (Although other psychological measures were completed by participants, eg, response style measures and symptom reporting index (15), we focused our analyses on standard psychosocial risk factors.) Dependent measures consisted of change scores observed for six cardiac variables: 1) the number of ambulatory ischemic episodes, 2) treadmill exercise time, 3) maximum ST depression, 4) diastolic and 5) systolic blood pressure, each of which was calculated as the total improvement occurring from the baseline to posttreatment periods, and 6) posttreatment angina. We set two-tailed levels at 0.05 for these tests. In each of the six total analyses, baseline values of the dependent measures were given forced entry at step 1, followed by stepwise entry of the four psychological predictors. This permitted an assessment of treatment changes after controlling for initial disease severity. Power analyses, with N = 80, two-tailed = 0.05, and an estimated R2 increment of 5% for psychological effects after controlling for baseline values, indicated that power levels for these tests were approximately 0.65. We judged this value to be suboptimal but adequate for our analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Descriptive Statistics
Table 1 provides means, standard deviations, and statistical test results for relevant demographic, psychological, and cardiac variables. Results from separate repeated-measure analyses revealed highly significant treatment effects during the combination treatment phase on all measured cardiac variables (F(1,73) = 57.8, 64.0, 7.8, 54.8, 81.0, and 9.0 for reductions in ischemic frequency, improvements in treadmill exercise time, reductions in maximum ST depression, diastolic and systolic blood pressure indexes, and a reduced incidence of angina, respectively (for all, p < .01). The confidence intervals shown in Table 1 estimate the extent of change occurring from baseline to the posttreatment period (eg, the 95% CI for total reductions in the number of ischemic episodes was 4.1–7.0; note that this interpretation does not apply to the angina variable, for which the CI provides the 95% estimate of angina reported at posttreatment). Analyses provided in a previous report (21) also indicated that improvements in blood pressure, exercise time, ischemic activity, ST depression, and angina incidence were each significantly greater with combination treatment than with placebo treatment.
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Psychological Stress and Treatment Effects
This set of analyses consisted of two steps: an examination of the association(s) between known psychological risk factors and a set of statistically distinct cardiac variables and identification, when present, of meaningful differences among the psychological characteristics in their respective predictive capacities. Intercorrelations among the six cardiac treatment variables were uniformly modest, with the exception of the relationship between diastolic and systolic blood pressure improvements (r = 0.42, p < .001). No other association approached statistical significance (r = -0.16 to 0.16, p > .2), supporting the use of each outcome measure as a separate indicator of treatment effects.
Table 2 presents the regression models for each of the six treatment recovery variables. Baseline levels of each dependent measure were given forced entry at step 1 of each analysis. Significant psychological predictors follow, accompanied by F and F change values, ß weights, corresponding probability levels, and the percentage of variance explained.
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The ß values shown in Table 2 provide a means of assessing the clinical impact of these relationships. By multiplying the value of a significant ß coefficient by the standard deviation of the outcome or dependent variable, one obtains a type of effect size that indicates the amount of change in the outcome measure that is associated with a change of 1 SD in the predictor. For example, the ß coefficient for daily stress in the prediction of improvements in exercise performance was 0.26. Based on this number, an individual reporting level of daily stress 1 SD above normal (which in this sample was about 8 points) experienced approximately 23.5 seconds less improvement on treadmill exercise testing relative to the overall sample (0.26 x exercise changes SD (90.5) = 23.5). Because exercise testing was terminated by ST depression >1 mm, fatigue, or other cardiac symptoms, this result suggests that more highly stressed patients retained a lower threshold for cardiac events after treatment.
Using the same logic, although patients overall showed an average of 5.5 fewer ischemic episodes after treatment, individuals reporting daily stress levels 1 SD above normal averaged an improvement of only 4.4 episodes (-0.16 x 6.6 = 1.1 episode, on average, less improvement on this variable). Finally, although angina was reported by approximately 40% of the complete sample at final exercise testing, more highly stressed participants (>1 SD above average) reported angina in almost 90% of cases.
The relations between cynical hostility and blood pressure improvements were even more straightforward. Patients averaged reductions of 9.5 and 17.7 points on diastolic and systolic blood pressure criteria, respectively. The hostility ß weights (-0.2 and -0.21 for diastolic and systolic blood pressure, respectively) indicate that patients with hostility scores 1 SD above normal (about 12 points) averaged approximately 2.3 (0.2 x 11.5) and 3.7 (0.21 x 17.4) points less improvement in response to treatment.
Comparisons Among Psychological Predictors
Intercorrelations within our set of psychological measures are shown in Table 3. These values are significant in every case (r = 0.26–0.49; for all, p < .05) but do not indicate unacceptable levels of redundancy. It is well known, however, that even modest intercorrelations between predictor variables can produce multicollinearity effects in regression analyses (22). The most reliable solution to this problem is to use only orthogonal predictors, but this often cannot be done with psychological measures. Our more limited goal was to identify differences in the abilities of our psychological measures to predict cardiovascular changes. The objective of this exercise was to judge whether the daily stress and hostility measures functioned as significantly better predictors relative to the Type A behavior and depression instruments.
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levels to somewhat overcome the confound of low power in our conclusions. As shown in Table 4, hostility scores were significantly better predictors of systolic blood pressure changes (at the 0.10 level) than either depression or daily stress measures and outperformed all other psychological variables in the prediction of diastolic changes. In contrast, reliable differences were almost entirely lacking with respect to cardiac treatment variables. Although daily stress consistently predicted treatment effects across a number of outcome measures, the size of these relations was not significantly larger than those seen using the other psychological measures.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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The findings of this study are in accordance with those of previous investigations (8, 9) in showing reduced treatment effects among patients reporting psychological distress; however, they also extend previous research by identifying specific physiological mechanisms through which psychological factors may influence the course of treatment. Rather than indicating a single channel of influence, our results suggest that psychological factors can have deleterious effects on a number of cardiac health variables. Importantly, this finding also implies that interventions targeting these factors could have the potential to produce equally broad enhancements to standard treatment protocols (11).
Our efforts to identify possible differences among our psychological predictors led to two main findings. First, hostility scores were significantly better predictors of blood pressure changes than were other psychological measures. Because hostility has been linked to a variety of blood pressure end points in previous research, including hyperreactivity to laboratory stressors (24), resting laboratory levels (25), and ambulatory means (26), these associations should not be easily dismissed. On the other hand, the results presented here also concur with previous findings in showing that blood pressure–hostility relations are relatively modest at best (27), accounting for rather small (2–4 points) inhibitory effects in blood pressure changes among our sample.
The second finding, that daily stress levels evinced consistent, but not significantly larger, relationships with changes in cardiac treatment variables relative to depression, hostility, and Type A measures, is likely a result of both statistical power limitations and a lack of true differences among these variables. Only a handful of studies have documented self-reported stress and coronary prognosis; however, the evidence implicates high stress as a risk factor for early mortality and additional heart attacks (8, 9, 28). Our results are compatible with the findings of these studies and, by indicating that highly stressed patients may not respond as well to treatment as others, point to a mechanism that could at least partially account for these findings.
Clinical Issues and Study Limitations
The current results support the presence of statistically reliable relationships between psychological factors and patients’ responsiveness to treatment. An equally challenging question, however, concerns the clinical relevance of these findings. We used ß weights from our regression equations to establish one marker of clinical impact, showing, for instance, that more highly stressed patients had average improvements of about 57 seconds on exercise performance after the combined treatment compared with 80.6 seconds for the overall group. This means that members of the high-stress group showed about two-thirds of the improvement of the complete sample with respect to treadmill performance, a standard that would represent a meaningful effect to most clinicians. On the other hand, the regression weights ranged from -0.16 to -0.26 for psychological impact and fall into the category of small effects based on Cohen’s (29) tables. Thus, whereas the psychological effects shown here are statistically significant and clearly deserve attention in future research trials, we cannot confirm the degree to which they are clinically valuable.
A second issue concerns the lack of statistical or clinical relationships we observed with our measure of depression. A growing body of evidence suggests that depression and depression-related constructs (eg, vital exhaustion) are useful predictors of the appearance and course of cardiovascular disease (30, 31). Although reliable associations between treatment effects and depression scores were lacking in this study, this finding may well be a product of the measurement tool used and not the construct of depression itself. That is, because items on the Beck Depression Inventory place considerable emphasis on physical and behavioral symptoms that may be produced by the presence of disease as well as depression, this may not be an ideal instrument for examining depression effects among groups of patients with coronary artery disease. In addition, the patients in the CASIS cohort reported depression levels that were well within normal limits and showed limited variability (mean = 7.9, SD = 5.1), suggesting that a type of floor effect could be operating. For these reasons, we hesitate to rule out potential influences of depression on the course of treatment.
Finally, a clear weakness of the study is that because the effects we have described are purely correlational, they cannot, in themselves, implicate causal relations between the psychological factors assessed here and the treatment of coronary disease. Although we took steps to control for competing explanations when conducting our analyses (eg, by controlling for baseline levels of the treatment effect variables), this does not eliminate more subtle effects, such as differential adherence to treatment regimens or other behaviors (eg, poorer diets, exercise, or lifestyle habits) that could also underlie these relations. An additional possibility, that the subjective nature of several of the cardiac measures used here (eg, exercise performance and the reporting of angina) may have influenced the pattern of results, also exists. However, the robust pattern of relationships shown between psychological factors and cardiac treatment measures, whether of subjective or objective nature, indicates that this explanation can at best account only partially for the reported effects.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGMENTSREFERENCES |
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Received for publication November 16, 1998.
Revision received July 1, 1999.
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REFERENCES |
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This article has been cited by other articles:
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  C. D. Sofhauser Psychosocial Antecedents of Hostility in Persons with Coronary Heart Disease J Holist Nurs, September 1, 2003; 21(3): 280 - 300. [Abstract] [PDF]
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 L. A. Chaput, S. H. Adams, J. A. Simon, R. S. Blumenthal, E. Vittinghoff, F. Lin, E. Loh, and K. A. Matthews Hostility Predicts Recurrent Events among Postmenopausal Women with Coronary Heart Disease Am. J. Epidemiol., December 15, 2002; 156(12): 1092 - 1099. [Abstract] [Full Text] [PDF]
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 S. Springer, A. Fife, W. Lawson, J. C.K. Hui, L. Jandorf, P. F. Cohn, and G. Fricchione Psychosocial Effects of Enhanced External Counterpulsation in the Angina Patient: A Second Study Psychosomatics, April 1, 2001; 42(2): 124 - 132. [Abstract] [Full Text]
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