1 Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA.
2 Department of Pediatrics, School of Medicine, University of California San Francisco, San Francisco, CA.
3 Department of Medicine, School of Medicine, University of California San Francisco, San Francisco, CA.
4 General Internal Medicine Section, Medical Service, Veterans Affairs Medical Center, San Francisco, CA.
5 Department of Medicine, School of Medicine, Johns Hopkins Hospital, Baltimore, MD.
6 Wyeth-Ayerst Research, Radnor, PA.
7 Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
Received for publication January 22, 2002; accepted for publication May 29, 2002.
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ABSTRACT |
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coronary disease; hostility; postmenopause; risk factors; women
Abbreviations: Abbreviations: CHD, coronary heart disease; CI, confidence interval; HERS, Heart and Estrogen/progestin Replacement Study; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; RH, relative hazard.
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INTRODUCTION |
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To examine the relation between hostility and CHD risk in a clinical population, we analyzed data collected from a cohort of postmenopausal women with CHD enrolled in the Heart and Estrogen/progestin Replacement Study (HERS). Although prior research suggests that the risk associated with psychosocial factors occurs early in the disease process (4, 1113), several of the proposed mechanisms linking hostility and CHD could also contribute to recurrent events. Therefore, our objective was to determine whether hostility affects cardiovascular health once advanced atherosclerosis is present. We evaluated the effect of hostility on CHD outcomes in older women, the effect of postmenopausal hormone therapy on hostility score, and the interaction between hormone therapy and level of hostility.
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MATERIALS AND METHODS |
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Participants and setting
Entry into HERS required that participants be younger than age 80 years and have had documented coronary disease, defined by prior myocardial infarction, coronary artery bypass graft surgery, mechanical coronary revascularization, or angiographic evidence of at least a 50 percent occlusion of one or more major coronary arteries. Exclusion criteria included a clinical cardiac event (myocardial infarction or coronary revascularization procedure) within 6 months of randomization, a contraindication to hormone therapy or having received hormone therapy within the 3 months prior to the screening visit, uncontrolled hypertension (systolic blood pressure 200 mmHg or diastolic blood pressure
105 mmHg), uncontrolled diabetes mellitus (fasting blood sugar
300 mg/dl), elevated triglycerides (
300 mg/dl), New York Heart Association class IV or severe class III congestive heart failure, or a disease judged to be fatal within 4 years.
We enrolled 792 of the 2,763 HERS participants from eight of the HERS clinical centers: Hartford, Connecticut; Baltimore, Maryland; Pittsburgh, Pennsylvania (Oakland and West Penn); Chicago, Illinois; Iowa City, Iowa; La Jolla, California; and Stanford, California. Geographic selections were based on the interest of the principal investigator at each clinical site. All study sites were in the United States. The HERS Hostility Ancillary Study was conducted between 1993 and 1998.
Measurements
The Cook-Medley hostility scale (16), a 50-item component of the Minnesota Multiphasic Personality Inventory (MMPI), was used to measure hostility at the baseline, year 1, and closeout visits. To increase variance in the scores, the original yes/no format was revised to a four-item response scale: always true (three points), usually true (two points), usually false (one point), always false (zero points). Hence, the Cook-Medley hostility scale ranged from zero (nonhostile) to 150 (very hostile). Several studies have used the Cook-Medley cynicism subscale to evaluate the association between hostility and CHD events (9, 17, 18); thus, we also included the 13-item cynicism subscale in our analysis. When converted to the four-item response format, the cynicism scale ranges from zero (noncynical) to 39 (highly cynical).
Follow-up visits were conducted by each of the clinic sites and included an assessment of compliance with study medications and the recording of outcome and adverse events. Primary outcomes were nonfatal myocardial infarction (symptomatic or silent), CHD death (fatal myocardial infarction, sudden death within 1 hour of symptom onset, unobserved death in the absence of other known cause, and death during sleep), and CHD event (nonfatal myocardial infarction and CHD death). This definition of CHD death was narrower than the one used in the main HERS report (15). In the Hostility Ancillary Study, deaths due to coronary revascularization procedure or congestive heart failure were analyzed separately. Secondary cardiovascular outcomes included hospitalization for unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, stroke, transient ischemic attack, and peripheral arterial disease. Data pertaining to outcome measures were collected by the Coordinating Center at the University of California San Francisco. Two physicians at the HERS Coordinating Center, who were blinded to treatment assignment, independently reviewed all outcome events. An independent committee of cardiologists, also blinded to treatment assignment, adjudicated all primary outcomes. Participants were followed for an average of 4.1 years (range, 3.65.3 years).
Data analysis
Enrollment into HERS (February 1993September 1994) was initiated before the Hostility Ancillary Study began; therefore, not all participants were available for a baseline evaluation. A total of 425 women (54 percent of ancillary study participants) completed the Cook-Medley hostility questionnaire at baseline, and an additional 367 women (46 percent) were evaluated for the first time at the year 1 visit. Among the 792 participants, 630 (80 percent) completed a closeout questionnaire.
To evaluate the effect of postmenopausal hormone therapy, hostility scores at baseline, year 1, and closeout were compared by using linear mixed models. To analyze hostility as a risk factor for cardiovascular events, participants were classified by quartile of hostility score. Among women who had baseline and year 1 evaluations, this classification was made by using the baseline score. We used univariate and multivariate proportional odds models to identify the independent predictors of hostility quartile among baseline biologic, behavioral, and social risk factors for cardiovascular disease.
The incidence of CHD events was initially compared by quartile of hostility score using Kaplan-Meier survival curves. Independent associations between hostility quartile and CHD outcomes were assessed by using multivariable Cox proportional hazards regression models. Covariate selection was based on published data and known CHD risk factors in HERS.
Biologic covariates included body mass index (kg/m2); serum low density lipoprotein cholesterol, high density lipoprotein cholesterol, and triglyceride levels (mg/dl); lipoprotein(a) >25.3 mg/dl; creatinine clearance <40 ml/minute (Cockcroft-Gault equation (19)); diabetes (use of diabetic medications or self-reported history of diabetes); hypertension (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg, use of antihypertensive medication, or self-reported history of hypertension); prior history of myocardial infarction (2); and fair-to-poor self-rated general health. Demographic variables included age (years), race (White, non-White), education (years), and marital status (married, not married). Behavioral measures included current tobacco use, any current alcohol consumption, exercise (
3 times per week), and medication use (beta-blocker, aspirin, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor). The significant risk factors for nonfatal myocardial infarction or CHD death in HERS include non-White race, hypertension, low density lipoprotein cholesterol >130 mg/dl, high density lipoprotein cholesterol <35 mg/dl, diabetes, renal insufficiency (creatinine clearance <40 ml/minute), two or more prior myocardial infarctions, heart failure symptoms, and nonuse of HMG-CoA reductase inhibitors.
In a supplementary analysis, adjusted Cox model relative hazards were compared with unadjusted estimates to assess potential mediation of the relation between hostility and study outcomes. We also tested for interactions between medication (i.e., 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone, beta-blocker, aspirin, and HMG-CoA reductase inhibitor) and hostility score to determine whether treatment modified the effect of hostility or whether hostility modified the association between use of beta-blockers or HMG-CoA reductase inhibitors and cardiovascular outcomes. Finally, we examined interactions between hostility score and time of entry into the Hostility Ancillary Study.
In all survival analyses, follow-up was initiated, and covariates assessed, at the time of entry into the Hostility Ancillary Study. The proportional hazards assumption was verified by using log-log survival plots and by testing for interactions between hostility and time since randomization. Two-tailed tests in which p < 0.05 were considered statistically significant.
All analyses were performed by using SAS software, version 6.12 (SAS Institute Inc., Cary, North Carolina).
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RESULTS |
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The median cynical hostility subscale score was seven (interquartile range, sixnine). Results from analyses including cynicism subscores were similar to the hostility score findings. Compared with women whose cynicism scores were in the first quartile, women whose scores were in the fourth quartile were at greater risk of CHD events (RH = 2.12, 95 percent CI: 1.09, 4.12) and nonfatal myocardial infarction (RH = 2.31, 95 percent CI: 1.08, 4.96), independent of other CHD risk factors. Cynicism scores in the fourth quartile were not significantly associated with CHD death (RH = 1.42, 95 percent CI: 0.39, 5.13) or with the secondary CHD outcomes of unstable angina (RH = 0.60, 95 percent CI: 0.26, 1.37) and coronary artery bypass graft surgery/ percutaneous transluminal coronary angioplasty (RH = 1.11, 95 percent CI: 0.71, 1.74). The correlation between hostility scores and cynicism subscores was high (r = 0.84).
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DISCUSSION |
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Several mechanisms have been proposed to explain the association between hostility and CHD. The health behaviors model suggests that hostility serves as a marker for behaviors that increase risk for disease (20). In one study of middle-aged men (21), associations between cynicism and cardiovascular mortality were mediated by adverse health practices related to CHD outcomes (e.g., tobacco use, alcohol consumption, and low activity levels). However, in the HERS Hostility Ancillary Study, we found no evidence that the relation between hostility and CHD events was mediated or confounded by the behavioral and social risk factors that were measured.
An alternative mechanism linking hostility and CHD involves the sympathetic nervous system. Exaggerated adrenergic responses to stressful psychological stimuli can increase heart rate and blood pressure (2224), induce coronary vasoconstriction in atherosclerotic arteries (25, 26), and activate platelets (27). A triggering event, such as an outburst of anger, may precipitate a response that promotes the acute rupture of vulnerable plaque and thrombosis, increasing the risk of nonfatal myocardial infarction or CHD death (2830). Additionally, persons who have high levels of hostility tend to have more negative world views and feelings of chronic cynicism and mistrust, which may result in continual sympathetic nervous system arousal (31). Although the proximity to a stressful event was not examined in HERS, our finding that hostility is associated with nonfatal myocardial infarction and CHD death, but not with angina or revascularization procedure, is consistent with the cardiovascular reactivity hypothesis. Revascularization procedures are often elective and not representative of an acute pathophysiologic process. This finding also suggests that the results are not due to differential patient or physician behavior.
In the Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS), high levels of hostility diminished the benefits of anti-ischemic medications (i.e., amlodipine, atenolol) (32). We did not find evidence of an interaction between hostility and medication use (i.e., beta-blockers and HMG-CoA reductase inhibitors). In addition, beta-blockers may also modify the sympathetic response to a triggering event, such as an episode of anger, thereby reducing the risk of plaque rupture (28, 30). In the HERS Hostility Ancillary Study, beta-blockers did not appear to influence the association between hostility and CHD events. However, use of medications other than estrogen and progestin (0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone) was not randomized in HERS, so our ability to detect interactions may have been limited and subject to confounding by indication.
Specific traits in the hostility construct may act independently on CHD risk. We found an equally strong association with CHD events by using the cynicism subscore of the Cook-Medley hostility scale. This finding is in contrast to several prior studies that failed to find a significant relation between cynicism scores and CHD outcomes (9, 17, 18). Discrepancies between our research findings and those of other investigators may be due to differences in the populations studied (e.g., age, gender, CHD risk). However, when compared with the global Cook-Medley hostility score, cynicism subscores were only marginally less predictive of acute CHD events in older women (9). The HERS Hostility Ancillary Study findings indicate that, among postmenopausal women with CHD, the cynicism subscale and the full Cook-Medley hostility scale may be measuring similar psychosocial characteristics.
The Hostility Ancillary Study included a subgroup of women from selected HERS sites. Thus, although the women in HERS were comparable to women with CHD in the Third National Health and Nutrition Examination Survey (NHANES III) (33), a national probability sample of persons in the United States, our subsample may be less representative. Furthermore, our study findings may not apply to women without established CHD or to men.
Since the mid-1960s, mortality rates from cardiovascular disease have been declining, with the greatest decreases attributed to changes in risk factors (e.g., lifestyle modifications, tobacco use) (34). However, the variance in CHD is only partially explained by traditional risk factors, and, despite favorable trends, cardiovascular disease remains a leading cause of morbidity and mortality in women. As the population ages and the prevalence of women with CHD rises, efforts to identify modifiable CHD risk factors will become increasingly important. Prior research suggests that interventions during cardiac rehabilitation, such as counseling sessions, breathing-relaxation therapy, health education, and exercise, may favorably affect coronary-prone psychosocial characteristics and health outcomes (3537).
In summary, we have shown that hostility is a significant independent predictor of CHD events in postmenopausal women with known CHD. Further research is needed to confirm these findings and to assess the possible role of interventions directed at behavioral risk factors.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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