Vital exhaustion, defined as excessive fatigue, feelings of demoralization, and increased irritability, has been identified as a risk factor for incident and recurrent cardiac events, but there are no population-based prospective studies of this association in US samples. We examined the predictive value of vital exhaustion for incident myocardial infarction or fatal coronary heart disease in middle-aged men and women in 4 US communities. Participants were 12,895 black or white men and women enrolled in the Atherosclerosis Risk In Communities (ARIC) study cohort and followed for the occurrence of cardiac morbidity and mortality from 1990 through 2002 (maximum follow-up 13.0 years). Vital exhaustion was assessed using the 21-item Maastricht Questionnaire and scores were partitioned into approximate quartiles for statistical analyses. High vital exhaustion (fourth quartile) predicted adverse cardiac events in age-, gender-, and race-center–adjusted analyses (1.69, 95% confidence interval 1.40 to 2.05) and in analyses further adjusted for educational level, body mass index, plasma low-density lipoprotein and high-density lipoprotein cholesterol levels, systolic and diastolic blood pressure levels, diabetes mellitus, cigarette smoking status, and pack-years of cigarette smoking (1.46, 95% confidence interval 1.20 to 1.79). Risk for adverse cardiac events increased monotonically from the first through the fourth quartile of vital exhaustion. Probabilities of adverse cardiac events over time were significantly higher in people with high vital exhaustion compared to those with low exhaustion (p = 0.002). In conclusion, vital exhaustion predicts long-term risk for adverse cardiac events in men and women, independent of established biomedical risk factors.
Although support for a positive association between vital exhaustion—defined as a state of excessive fatigue, increased irritability, and demoralization—and coronary heart disease (CHD) has accumulated, most of the evidence has been derived from European populations. There are no population-based prospective studies of vital exhaustion and acute coronary syndromes in US samples. Using data from the Atherosclerosis Risk In Communities (ARIC) study cohort, the present analysis tested whether subjects with high vital exhaustion compared to their low exhaustion counterparts were at increased risk for incident myocardial infarction (MI) and fatal CHD. The ARIC study permitted a test of this hypothesis in a sample of middle-aged white or black men and women. We hypothesized that participants with high vital exhaustion compared to their low exhaustion peers would be at increased risk for adverse cardiac events and that a monotonic increase in risk from low to high exhaustion would be observed. The ARIC study includes sufficient numbers of cardiac events to systematically examine the effects of vital exhaustion, adjusting for known predictors of cardiovascular disease progression.
Methods
Participants in this analysis were black or white men and women 48 to 67 years of age who were enrolled in the ARIC study cohort at visit 2. ARIC is a large, population-based, prospective study of the cause and natural history of atherosclerosis. A detailed description of study participants and research methods has been provided elsewhere. In brief, participants were selected through probability sampling from 4 US communities of Washington County, Maryland; suburban Minneapolis, Minnesota; Forsyth County, North Carolina; and Jackson, Mississippi. In Jackson, only black participants were sampled. ARIC baseline examinations were obtained from 1987 to 1989 (visit 1), after which participants returned at approximately 3-year intervals for 3 follow-up clinical examinations. Hospitalizations and deaths during the follow-up period were identified through annual telephone interviews and ongoing hospital surveillance. Participants for this analysis were the 14,348 ARIC cohort members (92.2%) who returned for the second clinic visit from 1990 to 1992 (visit 2). Excluded from analyses were 311 participants with missing data on prevalent CHD, 761 with prevalent CHD, 38 with a racial/ethnic identity other than black or white, 46 black participants from the Washington County and suburban Minneapolis field centers (hence, all black participants included in these analyses were enrolled in Jackson or Forsyth County), and 297 with incomplete responses on the vital exhaustion questionnaire, resulting in a final sample of 12,895.
Vital exhaustion is defined as excessive fatigue, feelings of demoralization, and increased irritability and is often considered a form of adaptation to prolonged distress. Vital exhaustion was assessed using the 21-item Maastricht Questionnaire ( Appendix ). Responses to the questionnaire are coded as yes = 2, don’t know = 1, and no = 0. Two items, questions 9 and 14, are reversed coded (yes = 0, don’t know = 1, no = 2). Responses are summed to obtain an overall vital exhaustion score, which ranges from 0 to 42, with higher scores representing more exhaustion. Cronbach alpha for internal consistency has been reported as 0.89.
At each clinic visit, participants were evaluated on a series of physiologic and behavioral parameters. Trained technicians who used standardized protocols conducted the examinations. Participants reported information regarding cigarette smoking, race/ethnicity, and level of educational attainment. Blood pressure levels were assessed using a random-zero sphygmomanometer after resting for 5 minutes. The average of the second and third of 3 consecutive measurements was used to calculate systolic and diastolic blood pressure levels. Hypertension was defined as a diastolic blood pressure ≥90 mm Hg, a systolic blood pressure ≥140 mm Hg, or use of antihypertensive medication within the previous 2 weeks. High-density lipoprotein (HDL) cholesterol was measured enzymatically after precipitation of apolipoprotein B–containing lipoproteins. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula. Diabetes mellitus was defined as a fasting serum glucose level ≥126 mg/dl, a nonfasting serum glucose level ≥200 mg/dl, and/or a history of diabetes, insulin therapy, or oral hypoglycemic medication use. Body mass index was defined as weight (kilograms) divided by height (meters) squared.
Incident cardiac events (acute MI or fatal CHD) were ascertained in the follow-up period from the participant’s clinic visit in 1990 to 1992 through December 31, 2002 (average 10.9 years, maximum 13.0). Events were identified by annual telephone interviews and hospital surveillance and validated through abstraction of medical record and death certificates. For in-hospital events, trained abstractors obtained from the medical record presenting symptoms, electrocardiographic (ECG) readings, cardiac enzyme levels, and other supportive diagnostic indicators. A maximum of 3 12-lead ECG tracings were submitted to the University of Minnesota ECG Reading Center, where these data were interpreted using the Minnesota Code. Criteria for MI were based on a combination of chest pain, cardiac enzymes, ECG changes, and autopsy findings. Criteria for fatal CHD were based on a combination of chest pain, underlying diagnosis from the death certificate, and other supportive diagnostic indicators from the medical record. Additional information on out-of-hospital deaths was gathered from the decedent’s next of kin, the patient’s physician, and/or the coroner’s or medical examiner’s report. Two physicians on the ARIC morbidity and mortality classification committee reviewed the documents and assigned the diagnosis; a third panel member adjudicated any discrepancies. Detailed descriptions of the procedures used in the ascertainment of cardiac events have been reported previously.
Means and percentages were used to describe baseline CHD risk factors by approximate quartiles of vital exhaustion. One-way analyses of variance were used to examine differences in means for continuous variables across quartiles; chi-square tests were used to examine differences in proportions for categorical variables. Cox proportional hazards regression analyses were used to assess effects of overall vital exhaustion and component depressive affect and fatigue on risk for adverse cardiac events. Covariates in the regression analyses were age, race-center, cigarette smoking status, pack-years of cigarette smoking, level of educational attainment, gender, body mass index, systolic and diastolic blood pressure levels, plasma LDL and HDL cholesterol levels, and diabetes mellitus. Two models were fit, 1 adjusting for age, race-center, and gender and a second adjusting for all covariates. The Kaplan-Meier product limit method was used to estimate cumulative probabilities of adverse cardiac events over time. The log-likelihood ratio test was used to assess differences in these probabilities across levels of exhaustion. All analyses were conducted using SAS 8.2 (SAS Institute, Cary, North Carolina).
Results
In the follow-up period from 1990 to 2002 (138,015 person-years), 800 incident cardiac events occurred, equivalent to a crude rate of 5.8 per 1,000 person-years. Mean vital exhaustion scores ± SD were significantly higher in women (12.1 ± 8.9) than in men (7.9 ± 7.6, p <0.0001) and higher in black participants (12.2 ± 9.1) than in white participants (9.7 ± 8.4, p <0.0001). Vital exhaustion scores were positively skewed with an overall mean of 10.30 ± 8.6.
A baseline CHD risk factor profile indicated that participants in the highest quartile of vital exhaustion compared to their peers in the lowest were slightly older, heavier, and more likely to be women and black with a less than high school education. They also smoked more cigarettes, were more likely to be diabetic and hypertensive, and were more likely to have higher systolic blood pressure and HDL cholesterol levels. Most of these associations were markedly graded across quartiles of vital exhaustion ( Table 1 ). Seventy-one percent of women in the cohort were postmenopausal, most of whom were in the lower quartiles of depressive affect. Prevalences of overall antidepressant and corticosteroid use were 4% and 1%, respectively.
| Vital Exhaustion | p Value ⁎ | ||||
|---|---|---|---|---|---|
| Quartile 1: 0–4 (low) | Quartile 2: 5–8 | Quartile 3: 9–15 | Quartile 4: 16–42 (high) | ||
| Participants | 4,177 (32%) | 2,576 (20%) | 3,045 (24%) | 3,097 (24%) | |
| Age (years) | 56.5 ± 5.6 | 56.9 ± 5.7 | 57.0 ± 5.8 | 57.1 ± 5.8 | <0.0001 |
| Women | 1,717 (41%) | 1,422 (55%) | 1,936 (64%) | 2,243 (72%) | <0.0001 |
| White | 3,412 (82%) | 1,985 (77%) | 2,211 (73%) | 2,100 (68%) | <0.0001 |
| < High School | 547 (13%) | 434 (17%) | 681 (22%) | 1,016 (33%) | <0.0001 |
| Ever-smokers | 2,492 (60%) | 1,518 (59%) | 1,835 (60%) | 1,800 (58%) | 0.34 |
| Pack-years of cigarette smoking | 14.1 ± 19.8 | 14.9 ± 20.6 | 15.5 ± 20.8 | 16.6 ± 23.6 | <0.0001 |
| Body mass index | 27.3 ± 4.6 | 27.7 ± 5.2 | 28.0 ± 5.5 | 29.0 ± 6.2 | <0.0001 |
| Diabetes mellitus | 463 (11%) | 325 (13%) | 449 (15%) | 599 (19%) | <0.0001 |
| Hypertension | 1,225 (29%) | 859 (33%) | 1,103 (36%) | 1,268 (41%) | <0.0001 |
| Systolic blood pressure (mm Hg) | 120.2 ± 17.5 | 121.9 ± 18.2 | 121.9 ± 19.0 | 122.4 ± 20.2 | <0.0001 |
| Diastolic blood pressure (mm Hg) | 72.5 ± 9.8 | 72.6 ± 10.0 | 72.0 ± 10.5 | 71.9 ± 10.7 | 0.01 |
| Plasma high-density lipoprotein cholesterol (mg/dl) | 48.5 ± 16.1 | 50.3 ± 17.2 | 50.8 ± 17.2 | 51.0 ± 16.9 | <0.0001 |
| Plasma low-density lipoprotein cholesterol (mg/dl) | 133.0 ± 34.4 | 132.8 ± 36.6 | 132.5 ± 37.2 | 133.5 ± 39.0 | 0.74 |
⁎ Chi-square test of association or 1-way analyses of variance for comparison of means.
The highest quartile of vital exhaustion predicted adverse cardiac events in age-, gender-, and race-center–adjusted analyses ( Table 2 ). After additional adjustment for level of educational attainment, body mass index, plasma LDL and HDL cholesterol levels, systolic and diastolic blood pressure levels, cigarette smoking status, pack-years of cigarette smoking, and diabetes mellitus, the hazard ratio was attenuated but remained statistically significant (p for linear trend <0.0001, using the actual vital exhaustion scores; Table 2 ). The effect estimate was not appreciably altered when antidepressant use was added to the model (1.43, 95% confidence interval 1.16 to 1.77). Risk for adverse cardiac events increased monotonically from the lowest to highest quartile of vital exhaustion. The Kaplan-Meier product limit estimate of the cumulative probability of adverse cardiac events is depicted in Figure 1 . The multivariate-adjusted hazard ratios for the relationship of depressive symptoms and fatigue to adverse cardiac events were 1.56 (95% confidence interval 1.25 to 1.96) and 1.43 (95% confidence interval 1.18 to 1.74), respectively.
| Regression Models | Incident Events (n = 800) | |
|---|---|---|
| Hazard Ratios (95% confidence intervals) | p Value | |
| Model 1 ⁎ | ||
| Exhaustion quartile 1 (reference) | 1.00 | |
| Exhaustion quartile 2 | 1.08 (0.88–1.33) | 0.45 |
| Exhaustion quartile 3 | 1.28 (1.06–1.56) | 0.01 |
| Exhaustion quartile 4 | 1.69 (1.40–2.05) | <0.0001 |
| Model 2 † | ||
| Exhaustion quartile 1 (reference) | 1.00 | |
| Exhaustion quartile 2 | 1.02 (0.82–1.27) | 0.84 |
| Exhaustion quartile 3 | 1.18 (0.97–1.45) | 0.10 |
| Exhaustion quartile 4 | 1.46 (1.20–1.79) | 0.0002 |
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