Summary prepared by Katri Raikkonen in collaboration with the Allostatic Load Working Group. Last revised September, 1997.

Chapter Contents:
a  Definition
b. Measurement of Vital Exhaustion
c. Convergent and Divergent Validity of Vital Exhaustion
d. Vital Exhaustion as a Predictor of Disease
e. Vital Exhaustion and Pathophysiological Mechanisms
f.  Vital Exhaustion and Behavioral Intervention
g. References

Definition

Vital Exhaustion (VE) has three defining characteristics: (1) feelings of excessive fatigue and lack of energy, (2) increasing irritability, and (3) feelings of demoralization (Appels, 1990; Appels & Mulder, 1988a). People often attribute these feelings to overwork, or to problems at work or in other important life areas that the person has not been able to solve, or to a real or symbolic loss (Appels & Mulder, 1988a; Appels, Falger & Schouten, 1993). Therefore, it has been suggested that VE is a mental state at which people arrive when their resources for adapting to stress are broken down.

The concept of VE grew out of an interest in understanding the mental state of 'undue fatigue' and 'lack of energy', a state that, according to the cardiological literature precedes myocardial infarction (MI) and sudden cardiac death (for a review, see Appels, 1990). The prevalence estimates of fatigue and anenergia before these events vary from study to study but range from 30 to 60% (for a review, see Appels & Mulder, 1988a; Appels, 1990). The exact nature of these feelings had, however, not been studied in depth prior to VE.

Measurement of Vital Exhaustion

Based on interviews with MI patients, a set of items was selected and tested in a case-control study (Appels, 1980). Of these items, 37 were found to discriminate between future cases of coronary heart disease and a healthy group of controls. This pool of 37 items formed a questionnaire labeled as Form A of the Maastricht Questionnaire (see Appels & Mulder, 1988a: Appendix 2).

Following the construction of the Form A, Form B of the Maastricht Questionnaire was constructed. Form B was constructed because further analyses with Form A showed that the power of Form A to predict future MI was based upon only 10 of it's 37 items (Appels & Mulder, 1988a). The researchers had, however, added 21 items to the scale, and of these items 8 were predictive of future disease. Based upon these analyses the Form B of the Maastricht questionnaire was constructed with 21 items (see Appels & Mulder, 1988b for details of constructing the scale).

Convergent and Divergent Validity of Vital Exhaustion

VE and depression appear to overlap both conceptually and empirically. A correlation coefficient as high as .73 has been reported between measures of VE and depression (Raikkonen, Lassila, Keltikangas-Jarvinen & Hautanen, 1996). However, although almost all depressed patients will have elevated exhaustion scores, only half of exhausted subjects will have symptoms that suggest depression or imply dysphoria (Van Diest & Appels, 1991). Furthermore, the key characteristics of depression, i.e., depressed mood, lowered self-esteem and guilt feelings as measured by the Profile of Mood States (POMS) across 21 consecutive days, are not present in VE (Van Diest & Appels, 1991). Exhaustion is rather characterized by decreased vigor and increased fatigue. For further discussion of convergent and divergent validity of VE and other tiredness-related constructs, see Kop (1994).

Vital Exhaustion as a Predictor of Disease

Appels and Mulder (1988a) followed 3,877 middle-aged men, who were free of coronary heart disease at the initial screening for 4.2 years. In these men VE predicted increased risk for MI when controlling simultaneously for blood pressure, smoking, cholesterol, and use of antihypertensive drugs. A further analysis showed an association with risk of angina pectoris (OR(age-adjusted) = 1.86, p <.03), and with non-fatal myocardial infarction (OR(age-adjusted) = 2.28, p < .001), while no association was found between VE and fatal coronary events (Appels & Mulder, 1989). So far, all the data on VE and coronary risk had been on men. Therefore, Appels, Falger and Schouten (1993) tested whether VE would precede the onset of MI in women as well. The relative risk associated with VE in women, after controlling for traditional risk factors, and menopausal status, was 2.75, p<.0l. More recently, it has been shown that VE is associated with the severity of coronary artery disease among women and men referred to precutaneous transluminal coronary angioplasty (Kop et al., 1993; Kop, 1997), and that VE predicts new cardiac events after successful coronary angioplasty (Kop et al., 1994; Kop, 1997; Mendes de Leon et al., 1996). Further analyses with the coronary angioplasty patients have demonstrated that the tiredness subcomponent of VE appears the foremost predictor of recurrent coronary events (Kop, 1995). Demoralization is marginally related to new events, while the component comprising of insomnia and irritability are not predictive of new cardiac events.

Vital Exhaustion and Pathophysiological Mechanisms

It has been suggested that VE may exert its pathophysiological influence on cardiovascular disease through lipid metabolism (Van Doornen & VanBlockland, 1989). VE is, however, also associated with increased levels of insulin and C-peptide in response to glucose challenge, and with enhanced insulin to glucose ratio in middle-aged healthy men (Raikkonen, Keltikangas-Jarvinen & Hautanen, 1994). Furthermore, VE, and specifically its' components measuring fatigue and demoralization, correlate with abdominal obesity in those men having a low body mass index (Raikkonen, Hautanen & Keltikangas-Jarvinen, 1994). Evidence also exists that VE is associated with measures that are indicative of impaired fibrinolysis (Kop et al., 1993; Raikkonen, Lassila, Keltikangas-Jarvinen & Hautanen, 1996). The impaired fibrinolysis appears, however, to be secondary to or mediated by the effects VE on insulin (Raikkonen et al., 1996).

Individuals under a great deal of stress may, however, not only show a single metabolic aberration but a full range of metabolic and disease indicators characteristic of a syndrome labeled as 'syndrome X' or the Insulin Resistance Syndrome. In a sample of middle-aged, healthy men VE was, indeed, associated with the clustering of abdominal obesity, augmented glycemic responses to glucose ingestion, dyslipidemia and deficient fibrinolysis at the level of PAI-1 antigen (Raikkonen, Keltikangas-Jarvinen, Hautanen & Adlercreutz, 1996).

The metabolic changes associated with VE may be attributable to sympathetic, adrenomedullary and hypothalamic-pituitary-adrenocortial system alterations. It has been demonstrated that a decrease of basal cortisol and a compensatory increase of basal andrenocortiotropic hormone (ACTH) secretion, as well as an increased ratio of 17-hydorxyprogesterone (17-OHP) to 11-deoxycortisol and an increase of cortisol to ACTH stimulation are among the pituitary-adrenocortical alterations associated with hyperinulinemia, dyslipidemia and abdominal obesity components of the IRS (Hautanen & Adlercreutz, 1996; Hautanen Raikkonen & Adlercreutz, 1997). Of these alterations VE was associated with an increase in the ratio of 17-OHP to I 1-deoxycortisol after ACTH stimulation (Raikkonen, Keltikangas-Jarvinen, Hautanen & Adlercreutz, 1997). The path analytic model applied to examine the neuroendocrine mechanisms that would relate VE to metabolic alterations demonstrated that the change of adrenal steroid biosynthesis, compatible with a mild decrease in the activity of 21 -hydroxylase, indeed, served as a pathway from VE to metabolic alterations.

Vital Exhaustion and Behavioral Intervention

Appels, Bar, Lasker, Flamm and Kop (1997) conducted a 'feasibility study' to test whether behavioral group intervention (e.g., group discussions, breathing-relaxation, hostility and anger control) would reduce VE and the risk of restenosis after successful precutaneous coronary angioplasty (see Kop et al., 1994 and Kop, 1997 for the association between VE and recurrent coronary events after successful angioplasty). The intervention resulted in a significant decrease of VE after the 18-months of follow-up (control group showed no decrease in VE scores). The intervention also resulted in reduction of the risk of a new cardiac events across the 18-months of follow-up: Ten percent (n = 3) of the patients in the intervention group experienced a new cardiac event compared to 23% (n = 15) in the control group (OR = 0.43, 95% CI 0.14 - 1.38). Even though there are notable limitations in this first intervention study on VE that preclude definite conclusions of the feasibility of the behavioral intervention, "the significant decrease in the exhaustion scores and the estimate of the effect size support our conviction that a large-scale clinical trial justifies the efforts it takes" (Appels et al., 1997, p. 216).

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