A Path Model of Chronic Stress, the Metabolic Syndrome, and Coronary Heart Disease

PETER P. VITALIANO, PHD, JAMES M. SCANLAN, PHD, JIANPING ZHANG, MS, MARGARET V. SAVAGE, PHD, IRL B. HIRSCH, MD, AND ILENE C. SIEGLER, PHD, MPH
Objective: We tested a theoretical stress model cross-sectionally and prospectively that examined whether relationships of chronic stress, psychophysiology, and coronary heart disease (CHD) varied in older adult men (N 47), older adult women not using hormone replacement therapy (HRT) (N 64), and older adult women using HRT (N 41). Method: Structural equations examined relationships of CHD with 1) chronic stress (caring for a spouse with Alzheimers disease and patient functioning), 2) vulnerability (anger and hostility), 3) social resources (supports), 4) psychological distress (burden, sleep problems, and low uplifts), 5) poor health habits (high-caloric, high-fat diet and limited exercise), and 6) the metabolic syndrome (MS) (blood pressure, obesity, insulin, glucose, and lipids). Results: Caregiver men had a greater prevalence of CHD (13/24) than did noncaregiver men (6/23) (p .05) 27 to 30 months after study entry. This was influenced by pathways from caregiving to distress, distress to the MS, and the MS to CHD. In men, poor health habits predicted the MS 15 to 18 months later, and the MS predicted new CHD cases over 27 to 30 months. In women, no caregiving-CHD relationship occurred; however, 15 to 18 months after study entry women not using HRT showed distress-MS and MS-CHD relationships. In women using HRT, associations did not occur among distress, the MS, and CHD, but poor health habits and the MS were related. Conclusions: In older men, pathways occurred from chronic stress to distress to the metabolic syndrome, which in turn predicted CHD. Older women not using HRT showed fewer pathways than men; however, over time, distress, the MS, and CHD were related. No psychophysiological pathways occurred in older women using HRT. Key words: stress, coronary disease, gender, metabolic syndrome, hormone replacement, path analysis.

AD Alzheimers disease; BP blood pressure; BMI body mass index; CHD coronary heart disease; CVD cardiovascular disease; DBP diastolic blood pressure; HDLC high-density lipoprotein cholesterol; HRT hormone replacement therapy; LV latent variable; LVPLS latent variable partial least square; MLE maximum likelihood estimation; MS metabolic syndrome; MV manifest variable; PLS partial least squares; RMS root mean square; SBP systolic blood pressure; SES socioeconomic status; TG triglycerides.

INTRODUCTION There is extensive em1pirical support for the hypothesis that chronic stress is associated with cardiovascular disease. Greenwood et al. (1) reviewed 14 prospective studies of humans, and almost all of the studies found relationships of stress with CVD or coronary heart disease. Pickering et al. (2) found that in persons with high job strain, blood pressure increased over time, both at home and at work. Unfortunately, few of these studies focused on men over 65 years of
Departments of Psychiatry and Behavioral Sciences and Medicine, University of Washington (P.P.V., J.M.S., J.Z., M.V.S.), Seattle, Washington, and Department of Psychiatry and Behavioral Sciences, Duke University (I.C.S.), Durham, North Carolina. Address reprint requests to: Peter P. Vitaliano, PhD, University of Washington, Department of Psychiatry and Behavioral Sciences, Box 356560, Seattle, WA 98195-6560. Email: pvital@u.washington.edu Received for publication July 27, 2000; revision received June 22, 2001.

age and still fewer included older women. Because older adults are less resilient to stress and illness than are younger adults and chronic stress may be more related to CHD in older than in younger adults, this is an important area of study. Indeed, in the absence of good health habits, even healthy older adults exhibit greater risks for CVD. These include greater BP (3), body fat (3), and insulin and glucose (4). Hence, 72% of persons over age 65 have CVD, and 25% have CHD (5). Importantly, CHD prevalence in women increases dramatically after age 50, suggesting that without hormone replacement therapy, postmenopausal women may lose much of their CHD protection (6). Our literature review of research on chronic stress and CHD noted the absence of studies that used theoretical models to guide their research and hypotheses. Moreover, few studies used prospective designs with naturally occurring (and ecologically valid) chronic stressors in older men and women. Still fewer studies examined psychosocial, behavioral, and physiological measures to represent predisposing, mediating, and outcome variables within the same investigation. Here, we attempted to narrow this gap. However, to meet the above requirements as well as have a large sample would have been prohibitively expensive. Instead, we used a moderately sized sample and a theoretical model of distress to crosssectionally and prospectively examine interrelationships of a natural chronic stressor and psychosocial, physiological, and biomedical variables. We did this in older adult men, women not using HRT, and women using HRT. Our model posits that chronic stress, personal vulnerabilities, and personal and social resources lead to psychological distress and poor health habits. Distress

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and poor health habits, in turn, lead to physiological disregulation (Figure 1, top) (7). Later, we will discuss how the model constructs and pathways from chronic stress, personal vulnerabilities, and personal and social resources may be used to predict psychobehavioral responses (psychological distress and poor health habits).

Fig. 1.

Top, theoretical path model for chronic stress and CHD. Bottom, path model for chronic stress and CHD with manifest variables.

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We will also review how these responses can lead to physiological disregulation, which may be followed by CHD. Pathways From Chronic Stress, Vulnerabilities, and Resources to Psychological Distress and Poor Health Habits The model proposed here is an attempt at a parsimonious and analytic depiction of most aspects of the cognitive-phenomenologic model of stress (CPMS) (8). Here, distress is a function of potentially stressful events, personal vulnerabilities, social resources, coping, and their reciprocal relationships. Both the CPMS and the proposed model emphasize relationships between chronic

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insulin levels exist in persons at risk for CHD (50, 47) and in persons with atherosclerosis with and without ischemia (51, 52). Hyperinsulinemia also predicts CHD 5 to 10 years later, independent of diabetes and other risk factors (47, 50); however, the prediction results from insulin resistance and not directly from hyperinsulinemia. The synergistic effects of insulin resistance, obesity, hypertension, and hyperlipidemia form a construct called the metabolic syndrome (53), which is a predictor of CHD (47). Psychosocial Correlates and Predictors of the MS and CHD Distress combined with overeating and inactivity can lead to greater levels of obesity, insulin, glucose, BP, and plasma lipids (53). Psychosocial correlates and predictors of CHD include greater chronic stress, anger, and hostility (54, 55), higher levels of psychological distress (55, 56), lower social supports (57), lower SES (58), and poorer health habits (59). Finally, the lack of positive experiences is associated with a greater waist-hip ratio (60) and worse glycemic control (61). Research Questions Given the proposed model and its supporting literature, we examined whether older persons under chronic stress would manifest greater CHD prevalence than older persons not under such stress and whether the model pathways would relate to CHD prevalence. We also examined several associated questions about the pathways in Figure 1, top, and their potential roles as mediators of relationships of chronic stress with CHD: 1. Is variability in distress influenced by chronic stress, vulnerabilities, and resources? 2. Is variability in poor health habits influenced by chronic stress and distress? 3. Is variability in the MS influenced and/or predicted by distress and poor health habits? 4. Is CHD prevalence influenced and/or predicted by elevated MS values? 5. Do intermediate pathways mediate relationships between chronic stress and CHD? 6. Given the potential compounding of chronic stress across time, do the above relationships become stronger over time? 7. Are the above relationships modified by gender and HRT use? To examine these questions, we defined persons under chronic stress as persons caring for a spouse with Alzheimers disease. Spouse caregivers experience numerous stressors (physical, emotional, and financial) (62), hassles (62), anger (63), and depressed mood (63) relative to matched control subjects, and such variables are associated with hostility (64). The demands of caregiving coupled with the biological vulnerabilities of aging put spouse caregivers at increased risk for CVD and CHD (65) and make them an appropriate group for examining the above questions. We excluded persons with diabetes. Diabetes is associated with insulin-glucose disregulation, increased risk for depression, and cardiovascular complications. Its premorbid presence would have complicated our analyses and subsequent inferences. METHODS Participants
Caregiver couples were recruited from 1) mailings to physicians, 2) the University of Washington Alzheimers disease (AD) registry, 3) the AD Association, and 4) printed and electronic media. Criteria for care recipient inclusion were 1) living with a spouse who is the primary caregiver, 2) 60 years old, and 3) diagnosis of possible or probable primary degenerative dementia based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) III (66), the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Associations (NINCDS-ADRDA) (67), and exclusion criteria, which are provided in much greater detail elsewhere (68). Noncaregivers were recruited from senior centers, retirement organizations, and the media. They and their spouses (noncare recipients) had to be 60 years old and functioning independently (as did the caregivers). No exclusion criteria for major illnesses were used a priori for caregivers and noncaregivers. This provided a more representative sample of older adults. Because Alzheimers disease is a progressive degenerative disorder, we used the course of this disease as a chronic stressor for spouse caregivers. We assessed their temporal psychophysiological reactions to such stress relative to noncaregivers at two points in time (time 1 was study entry, and time 2 was 1518 months later). One year after time 2 (or 2730 months after study entry), we also obtained these subjects medical records. Finally, at times 1 and 2 we examined cognitive and behavioral measures in care recipients and noncare recipients. At time 1, the samples consisted of 90 spouse caregivers and their spouses (care recipients with AD) and 88 noncaregiver spouses (and their spouses). From time 1 to time 2, we had attrition of 13 caregivers because of the following reasons: 3 care recipients did not decline and were thought not to have AD, 5 caregivers died (3 from heart attacks and 2 from strokes), 1 got divorced, 1 noncaregiver moved, and 3 refused to continue. Five noncaregivers were lost to follow-up because of the following reasons: one noncaregiver died of a stroke, two spouses of noncaregivers died (one from cancer and one from CHD), and two noncaregivers moved. Five caregivers and three noncaregivers with verified diabetes (see medical records below) were excluded in the current analyses. Finally, although an attempt was made to group-match the caregivers and noncaregivers on age and gender, the percentage of women using HRT in each group was left to chance. Complete data were available on 72 caregivers (24 men, 28 women not using HRT, and 20 women using HRT) and 80 noncaregivers (23 men, 36 women not using HRT, and 21 women using HRT).

Measures Used to Assess Constructs

Measures of chronic stress. Caregiver status (caregiver vs. noncaregiver) was assessed according to the above inclusion and exclusion criteria. Care recipient mental status was measured by the Mini-Mental

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Status Exam (69). It assesses orientation, memory, etc. Care recipient functioning was measured by the Record of Independent Living (70). It assesses competence in maintenance (eg, feeding and washing) and higher functioning (eg, reading and recreation) (Figure 1, top). Measures of personal resources. The Revised Ways of Coping Checklist (71) assessed problem-focused coping (eg, came up with a couple of different solutions to the problem). SES was operational-

between MVs.1 To address whether LVs were separate constructs, we examined the r values of the residuals. Interpretation of the LVs was based on 1) the r and values between LVs, 2) the amounts of variability in the endogenous LVs explained by their predictors, 3) the magnitude of the r values between LVs for which no r was theorized, and 4) an overall nonprobability fit index (ie, unexplainedPLS0.76(ofc))-.76(ofhd,)leofmu-502.76(ofsm57002.3.76(ofsample)-.76(ofsTDs)-.76(ofth))-.76(ofLISREL)-.76(ofbecause)-323.1.5j-29.3552 -estim02

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Record of Independent Living at time 2. Tables 1 and 2 contain health-related, psychosocial, and demographic data for the MVs used to assess the LVs in Figure 1, bottom, and for other variables of interest. MVs are compared primarily for caregivers and noncaregivers (or for their spouses) stratified by gender and HRT (men, women not using HRT, and women using HRT). At each time, male caregivers were more obese and reported more depressed mood, more burden, fewer uplifts, fewer social supports, less problem-focused coping, and less education than did male noncaregivers. Caregiver women not using HRT reported less exercise than their noncaregiver counterparts as well as more depressed mood, sleep
TABLE 2.

problems, and burden at both times. Caregiver women using HRT reported more depressed mood, sleep problems, and burden and fewer uplifts than their noncaregiver counterparts at both times. Male caregivers reported less burden at time 1 and fewer sleep problems at times 1 and 2 than did each group of female caregivers. Finally, cognitive and functional impairments were greater for AD victims than for spouses of noncaregivers (Table 2). Relationships of Caregiving With CHD Point prevalence. Dates of diagnoses were used to estimate CHD at or before study entry and in the 27- to

Psychosocial and Demographic Variables Used to Measure Latent Variables at Times 1 and 2, Stratified by Caregivers/Noncaregivers, Gender, and HRTa Men Women Not Using HRT Caregivers (N 28) 20.9 (5.4) 14.1 (7.5) 1.2 (1.0) 2.1 (1.4) 2.0 (1.4) 3.1 (1.1) 8.3 (4.2) 7.5 (4.1) 11.0 (4.7) 10.7 (4.1) 39.3 (10.3) 38.0 (7.1) 58.1 (23.9) 58.1 (19.0) 28.3 (7.0) 28.6 (6.7) 13.2 (4.8) 12.1 (3.5) 24.8 (6.2) 25.3 (4.9) 28.2 (6.2) 28.4 (7.0) 26.2 (4.7) 27.4 (6.1) 27.9 (5.5) 28.8 (6.2) 26.3 (6.0) 25.2 (7.3) 5.4 (1.2) 5.3 (1.1) 14.7 (3.5) 15.4 (4.1) 13.5 (2.1) $25,000 Noncaregivers (N 36) 28.8 (1.3)** 29.0 (1.2)** 0.0 (0.0)** 0.0 (0.1)** 0.1 (0.1)** 0.0 (0.1)** 5.7 (4.1)* 4.7 (2.9)** 7.6 (3.2)** 7.5 (4.1)** 27.1 (2.7)** 27.1 (2.5)** 61.7 (19.3) 57.8 (19.0) 27.3 (6.9) 26.0 (6.8) 11.9 (3.3) 11.3 (2.6) 26.5 (4.1) 26.7 (3.9) 30.2 (5.3) 31.8 (4.7)* 27.6 (5.1) 28.3 (3.5) 29.5 (4.0) 30.1 (4.5) 27.1 (4.6) 26.8 (4.7) 5.6 (0.7) 5.5 (0.8) 13.1 (5.4) 13.8 (4.7) 13.8 (2.4) $35,000 Women Using HRT Caregivers (N 20) 18.4 (5.8) 10.4 (7.6) 1.7 (1.2) 2.8 (1.6) 3.0 (1.1) 3.6 (1.4) 8.7 (3.4) 7.9 (3.2) 10.9 (5.2) 11.5 (6.1) 40.2 (10.0) 40.2 (10.7) 62.4 (18.5) 64.4 (24.5) 27.2 (5.4) 25.4 (5.0) 11.9 (2.0) 11.2 (1.7) 24.0 (4.6) 26.1 (4.3) 29.4 (4.3) 29.4 (7.0) 28.1 (5.2) 27.4 (3.9) 29.6 (4.4) 30.7 (4.9) 24.9 (8.4) 27.2 (6.7) 5.4 (1.0) 5.5 (1.2) 16.8 (3.8) 17.0 (5.0) 14.5 (2.2) $30,000 Noncaregivers (N 21) 28.9 (1.2)** 28.8 (1.3)** 0.0 (0.0)** 0.0 (0.0)** 0.0 (0.0)** 0.0 (0.1)** 3.4 (2.5)** 4.7 (3.4)** 7.5 (4.1)* 7.9 (3.5)* 26.0 (1.2)** 25.9 (1.5)** 81.0 (22.8)** 78.9 (20.1)* 26.9 (6.3) 25.7 (6.2) 11.9 (3.1) 12.0 (2.9) 27.5 (4.2)* 26.6 (4.3) 35.5 (4.2)** 35.2 (4.1)** 29.9 (3.6) 31.5 (4.2)** 33.0 (3.3)** 33.3 (3.7) 30.4 (5.4)* 30.3 (4.7) 5.7 (0.6) 5.6 (0.6) 16.0 (5.6) 16.8 (7.4) 15.0 (2.8) $35,000

Variables

Time

Caregivers (N 24) 19.0 (5.0)c 13.8 (6.7) 1.0 (0.8) 1.9 (1.5) 1.9 (1.4) 2.9 (1.4) 6.8 (4.1) 6.2 (2.9) 7.2 (4.1) 7.6 (3.6) 32.3 (6.6) 34.3 (8.8) 61.4 (27.9) 53.2 (23.1) 28.0 (6.5) 27.3 (7.3) 12.3 (4.4) 12.0 (2.4) 26.4 (3.5) 25.9 (4.8) 31.8 (4.9) 30.6 (3.8) 29.4 (3.9) 27.9 (3.4) 30.3 (4.3) 28.6 (4.3) 27.8 (5.5) 28.1 (6.6) 5.6 (0.7) 5.4 (0.9) 14.4 (4.4) 15.4 (4.1) 14.0 (2.3) $35,000

Noncaregivers (N 23) 28.8 (1.5)** 29.0 (1.2)** 0.0 (0.0)** 0.0 (0.0)** 0.0 (0.1)** 0.1 (0.1)** 3.6 (2.3)** 4.5 (2.6)* 6.2 (4.0) 6.5 (4.5) 26.3 (1.8)** 25.7 (0.96)** 70.8 (26.2) 68.8 (23.2)* 27.6 (5.6) 26.8 (5.2) 12.3 (2.6) 11.5 (2.3) 26.4 (4.0) 27.5 (4.0) 32.0 (4.8) 32.6 (3.9) 28.8 (3.6) 30.1 (2.9)* 30.2 (5.8) 30.7 (2.7)* 29.1 (5.7) 30.1 (4.5) 5.9 (0.2)* 6.0 (0.0)** 18.1 (4.9)* 16.1 (5.9) 17.4 (3.7)** $45,000

Mini-Mental Status Maintenance functioningb Higher functioningb Depression Sleep problems Burden Uplifts Trait anger Anger-out Anger control ISEL Tangible Support ISEL Self-Esteem ISEL Belonging ISEL Appraisal Social support satisfaction Problem-focused coping Education (yr) Income (median)
a b

T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1 T2 T1/T2 T1/T2

All comparisons are between caregivers and noncaregivers (or their spouses) within each stratum. Values are for spouses of caregivers or noncaregivers. c Mean (SD). * p .05; ** p .01.

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30-month interval thereafter. At study entry (time 1), no differences existed in the point prevalence of CHD for caregivers and noncaregivers (Figure 2); however, 27 to 30 months later, the point prevalence of CHD in caregiver men (54%; 13/24) was higher than in noncaregiver men (26%; 6/23) ( 2(1) 3.85; p .05) (Figure 2, top). Incidence. In the 27- to 30-month interval after

block (in which the LV is viewed as an effect rather than a cause of the MVs) to estimate the poor health habits LV. Here, LVPLS estimates the LV as a linear combination of the MVs to maximize the relationship with other LVs (85).4 Despite this procedure, poor health habits was still quite variable. Based on the regression weights, poor health habits were defined by diet in men at time 1. However, over time, exercise became increasingly im-

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18-path coefficients and 18-R2 values from chronic stress, vulnerability, and resources to distress. In 14 of 18 cases (in bold) these predictors explained significant total variance (R2) in distress6; namely 46.1% to 70.0%. In all strata, positive relationships between chronic stress and distress were very strong (R2 30% 45%, Table 3). Predictors were also related vulnerability and social resources were related (negatively) in women, and negative relationships between social resources and distress were larger in women not using HRT (R2 20.4% and 28.4%) than in women using HRT (R2 13.4% and 15.0%) and two to five times larger than in men. Also, the positive relationship of vulnerability with distress was significant in men at time 1, significant in women not using HRT at both times, and never significant in women using HRT. Is variability in poor heath habits influenced by chronic stress and distress? Depending on the stratum and time of study, six of the 12 paths from chronic stress and distress to health habits were significant (total R2 5.8% to 32.8%) (Table 3). Is variability in the MS explained by distress and poor health habits? Depending on the stratum and time of study, six of the 12 paths from distress and poor health habits to the MS were significant (total R2 6.8% to 23.0%). Figure 3 contains the final models for the strata. Emboldened paths were significant at times 1 and 2, dotted paths were only significant at time 1, dashed paths were only significant at time 2, and deleted paths were nonsignificant at both times. The pathway from distress to the MS was significant at both times in men, significant at time 2 in women not using HRT, and never significant in women using HRT. The relationship of poor health habits with the MS, although insignificant in men, is significant in women not using HRT at time 1 and significant in women using HRT at both times (explaining 15.2% and 20.7% of the variance, respectively). Is CHD prevalence explained by elevated MS values? The pathway from the MS to CHD is significant in men (R2 14.8%) and women not using HRT at time 2 (R2 7.3%) and never significant in women using HRT. Do intermediate pathways mediate relationships of chronic stress with CHD? In men, the relationship of chronic stress with CHD at time 2 (Figure 2, top) may have been mediated because it became insignificant in the presence of significant pathways (Figure 3, top) from chronic stress to distress, distress to the MS, and the MS to CHD. Do the relationships determined in the previous five research questions become stronger over time? In women not using HRT, several pathways are significant at time 2 that were not significant at time 1. These include chronic stress to health habits, distress to the MS, and the MS to CHD. In men, pathways from social resources to distress and from the MS to CHD were significant at time 2 but not at time 1. Are the above relationships modified by gender and HRT use? Extensive modification occurred for poor health habits with the MS. In men, this relationship was driven primarily by associations of sedentary behaviors with all variables in the MS. In women not using HRT, this relationship was driven primarily by associations of sedentary behaviors with insulin, glucose, and obesity. However, in women using HRT, this relationship was driven primarily by the association of fat intake with glucose. Evaluation of Overall Cross-Sectional Models To evaluate models, six criteria are recommended (83, 85): 1) LVs should have more than three MVsin our models, all LVs had three to five MVs except CHD; 2) measurement loadings should be 0.55 here, 98 of 120 reflective paths met this criterion; 3) the total R2 for endogenous LVs (ie, resources, poor health habits, distress, MS, and CHD) should be 0.10 here, 21 of 30 LVs had total R2 0.10 (this is calculated by adding over the R2 values for the paths leading to each LV); and 4) each path should explain 1.5% of the variance in a predicted LV here, 52 of 66 paths met this criterion. Criteria 5 and 6 involve comparing the observed model to the null (no paths among LVs) and saturated (paths between all exogenous and endogenous LVs) models. An observed model should be parsimonious and closer to the saturated than the null model. Criterion 5 uses the average R2 values for endogenous LVs. Criterion 6 uses the root mean square Cov(E, U). The RMS of the covariance between the MV residuals compares the relative goodness of fit of the observed to the saturated and null models. Table 4 shows the average R2 values and RMS Cov(E, U) for all strata as well as comparisons of null and saturated models. At time 1, the models for each stratum were similar in overall predictiveness (average R2 19% to 22%). However, by time 2 the R2 for men increased from 19.4% to 32.2%, and the model for men explained 9% more variance than did the time 2 model for women not using HRT. The average R2 values and the RMSs of all models were close to the saturated models, except for the time 1 RMS in women using HRT. Prospective PLS Results: Predicting CHD in Men In men, we were able to do prospective analyses with time 1 LVs predicting new cases of CHD after

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time 1. Figure 4 illustrates the models for men free of CHD at time 1 (N 39) for whom 11 new cases had been diagnosed in the following 27 to 30 months. Although vulnerability and resources were also used in these analyses, for parsimony they are not depicted in the Figures. In Figure 4, top, significant paths (R2 9.9%) occurred from chronic stress to distress to the MS (all at time 1) and then to new CHD cases in the following 27 to 30 months. Although a path occurred from distress to poor health habits, the latter was not related to the MS at time 1. In Figure 4, bottom, chronic stress, distress, and poor health habits at time 1 and the MS at time 2 were used to explain and predict CHD 27 to 30 months after time 1. Here, a path occurred from chronic stress to distress to health habits at study entry, then to the MS assessed 15 to 18 months later, and from the MS to CHD. Although all psychosocial measures were assessed before CHD, three of the 11 new cases of CHD in men occurred before the MS at

Fig. 3.

Path model that results from each stratum. Top, men; middle, women not using HRT; bottom, women using HRT. Bold line significant path at both time 1 and time 2; dotted line significant path at time 1; dashed line significant path at time 2; no line no significant path at either times.

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time 2. Hence, part of this analysis is not prospective, but as noted below, it is unlikely that the MS followed the development of CHD. DISCUSSION Three groups of older adults were used to test a theoretical stress model and to examine cross-sectional and prospective interrelationships of chronic stress, psychobehavioral constructs, the MS, and CHD. Although some paths were consistent across men, women not using HRT, and women using HRT, other paths varied considerably. In all strata, positive relationships between chronic stress and distress were

suggesting that women not using HRT had pathways intermediate between men and women using HRT. In contrast to men and women not using HRT, at both times, women using HRT showed a complete absence of pathways from distress to the MS and from the MS to CHD (Figure 3, bottom). However, because this study lacked random assignment to HRT, it is unclear whether weak psychophysiological pathways in women using HRT (vs. women not using HRT) resulted from HRT, untapped differences between these women, or both. We do not know why women

habits to the MS was large and significant at both times (Table 3). It is very important to note that the prospective analyses of CHD incidence in men yielded results that were quite different from the cross-sectional analyses. These results suggest different interpretations than those afforded by cross-sectional work. Cross-sectionally, distress directly influenced variability in the MS, but poor health habits did not. In contrast, distress at time 1 did not directly predict the MS at time 2, but it did predict the MS via poor health habits at time 1. As such, distress may have immediate associations with the MS, -293.2 at

P. P. VITALIANO et al.
Advances, Conclusions, and Implications Despite these limitations, we believe this analysis has advantages. The theoretical stress model chain of pathways from psychosocial constructs to the MS and on to CHD has rarely been examined in one sample. It allowed us to assess the relative importance of variables relating chronic stress to psychophysiological variables in older adults. In contrast to checklists of life events, we studied a prototypic chronic stressor (caregiving) that reflects real life experiences and has important relevance to society. Moreover, caregivers and noncaregivers were nondiabetic, thus yielding results unconfounded by this disease. By examining men, women not using HRT, and women using HRT, we were able to compare the potential importance of gender and HRT in psychophysiological processes. Men (N 47) had the strongest relationship between distress and the MS, and women using HRT (N 41) had the weakest relationship, with women not using HRT (N 64) between these extremes. By measuring anger, hostility, and distress, we were able to show that anger and hostility contributed to distress, but that distress had a more direct relationship with metabolism. This suggests that the interface of such effects may be important to cardiovascular and metabolic disregulation. In men, the pathway from distress to the MS was one of the largest pathways from caregiving to CHD. Hence, although caregiving may activate distress, the distress reaction may precipitate metabolic reactions. This was seen when we reanalyzed the model without chronic stress. The use of two time points showed that relationships grew stronger over time and that some variables may have lagged effects. In pathways connecting chronic stress, distress, MS, and CHD, 8 of 9 associations across the three strata showed increases from time 1 to time 2, suggesting that reactions to chronic stress may accumulate in older adults. The cross-sectional and prospective results for men suggest that distress may have immediate associations with both the MS and poor health habits, but health habits may not have an immediate association with the MS. Conversely, prior distress does not directly predict future MS, but it does predict metabolic changes through alterations in health habits measured 15 to 18 months before the MS. The longitudinal design also allowed us to observe that the model predicted CHD in the 27- to 30-month interval after time 1 in men who had no record of CHD at time 1. Therefore, it was less likely that relationships of distress and the MS were due exclusively to preexisting CHD problems. In the absence of protective behaviors (eg, good diet and exercise), even healthy older adults experience changes that increase their vulnerability to CHD (3, 100), namely, greater insulin resistance from sedentary behavior and greater adipose tissue (47, 101). Aging, poor health habits, and chronic stress may jointly exacerbate pathophysiology and lead to even greater health risks, particularly if chronic stress and CHD have been present for many years. Caregiving is a situation of high demand, low control, and psychological challenges. Such situations may trigger CHD events and/or result in CHD progression (11). In this study, by time 2, spouse caregivers had already provided full-time care for an average of 53 months, and by the time medical records were obtained, they had been caregiving for an average of 5.4 years (53 12 65 months). In some of these caregivers, a physiological load threshold may have been reached because in only 27 to 30 months, the point prevalence of CHD increased by 19% in caregivers and 8% in noncaregivers (33% in male caregivers and 13% in male noncaregivers). This is provocative because caregivers may be unable to provide home care if they become ill, and in response to this, society will incur tremendous costs. In 1996, approximately 15 billion dollars was spent on AD patients in nursing homes (102). Moreover, in 1996, for every extra month that persons with AD were cared for in the community, $1.35 billion in institutional costs of care nationwide were saved (102). Thus, identifying individuals who are most vulnerable to the ill effects of caregiving may be a first step to targeting interventions with the greatest benefits, both from a humanitarian and fiscal perspective. We hope that the current work will begin to accomplish this goal. Drs. Vitaliano, Scanlan, Savage, and Zhang were supported by National Institute of Mental Health Grant RO1 MH57663, National Institute on Aging Grant RO1 AG10760, and National Institutes of Health, Clinical Research Center Grant M01-RR00037; Dr. Siegler was supported by National Heart, Lung, and Blood Institute Grant RO1 HL55356, National Institute on Aging Grants 1RO1 AG12458 and RO1 AG19605, and National Cancer Institute Grant PO1CA72099. We thank Drs. Karen Moe and Nancy Woods for comments on the manuscript and Roslyn Siegel for clerical support. REFERENCES
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