Vital exhaustion and cardiovascular disease: Are circulating fibrinogen and D-dimer levels a plausible link?

Abstract

Vital exhaustion has been implicated in the development and progression of cardiovascular disease. In addition, elevated levels of fibrinogen and D-dimer have been associated with an increased risk of cardiovascular disease. Some studies have suggested that fibrinogen and D-dimer are associated with acute, chronic, and perceived stress. In this issue, Kudielka et al examine the relationship between circulating fibrinogen and D-dimer levels and vital exhaustion in a cross-sectional study of middle-aged teachers in Germany, to examine the plausible link between chronic stress and the development of cardiovascular disease. This commentary discusses the limited available evidence of the mechanisms responsible for the association between vital exhaustion and the development of cardiovascular disease and highlights the limitations of previous research and discusses future directions.

• D-dimer
• fibrinogen
• vital exhaustion
• cardiovascular disease

Cardiovascular disease (CVD) is an important cause of morbidity and mortality in the Western world. It is estimated that by 2010, CVD will be the leading cause of death in developing countries (WHO 2007). There are many recognisable risk factors for the development of CVD—such as hypertension, smoking, obesity, diabetes mellitus, and hyperlipidaemia—but more recently, biomarkers (such as fibrinogen, D-dimer, plasminogen activator inhibitor-1, C-reactive protein and homocysteine) (Arnesen et al. 1995), and psychological risk factors (such as depression and vital exhaustion (VE); Prescott et al. 2003) have also been implicated in the development and progression of CVD.

Elevated levels of the soluble glycoprotein, fibrinogen, have been associated with an increased risk of CVD in both healthy and high risk individuals (Maresca et al. 1999). Factors which increase fibrinogen include advancing age, female sex, black race, smoking, obesity, physical inactivity, elevated blood cholesterol level, menopause, oral contraception and low socio-economic class (Kamath and Lip 2003). Fibrin D-dimer, the measurable fibrin breakdown product of the fibrin mesh that has been stabilised by factor XIII, is a marker for thrombosis. It has been shown to be an early diagnostic marker and predictor of CVD (Lip and Lowe 1995). In a prospective study and meta-analysis of the association of D-dimer and coronary artery disease (CAD), Danesh et al. (2001) demonstrated a significant association between baseline concentrations of circulating D-dimer and CAD, which seemed largely independent of classic risk factors. Other studies have suggested that fibrinogen and D-dimer are associated with acute (von Kanel et al. 2004a,b), chronic (von Kanel et al. 2006) and perceived stress (Jain et al. 2007). However, Kopp et al. (1998) recently showed no significant association between circulating fibrinogen and VE, a measure characterised by fatigue and depressive symptoms that may be an end state of prolonged psychological stress.

In another study, Toker et al. (2005) investigated the association between “burnout” and fibrinogen. They found that burnout in women was positively associated with fibrinogen level but not in men. Of note, VE is a closely related concept to burnout, a chronic effective state comprising emotional exhaustion, physical fatigue and cognitive weariness (Shirom 1989). However, VE combines elements of both depression and burnout. Previous studies investigating VE have failed to control for depression, which is a major limitation (Shirom 1989) as this condition is known to be independently associated with CAD (Barth et al. 2004; Van Melle et al. 2004)

In this issue of Stress, the study by Kudielka et al. (2007), examines the relationship between two biomarkers, circulating fibrinogen and D-dimer levels, and VE in a cross-sectional study of 150 healthy middle-aged teachers in Germany to examine the plausible link between chronic stress and the development of CAD. Kudielka et al. (2007) chose to study apparently healthy teachers as teaching is thought to be a stressful occupation with an increased risk of emotional exhaustion. Eligible participants were sent questionnaires for the psychometric assessment of VE and depressive symptoms. Blood samples were taken after an overnight fast and an assessment of the health behaviour of participants was made at the same visit.

This study revealed an increase in fibrinogen level in relation to VE score overall after controlling for potential confounders such as age, gender, body mass index, smoking, alcohol consumption, and physical activity. There was also a significant interaction between VE and gender after adjustment for covariates, but for men only. This supports previous findings that males exhibit an exaggerated stress induced haemorrheological stress response compared to age matched females (Thrall et al. 2007). The study did not show any association between VE score and D-dimer levels in either gender. This supports the findings in a study by von Kanel et al. (2004c) investigating the relationship of VE and inflammation to fibrinolysis in apparently healthy male and female subjects, which found no correlation between VE and D-dimer level but contradicts the findings of their 2006 study of chronically stressed Alzheimer caregivers, which showed D-dimer level to be significantly higher in this group compared to controls (von Kanel et al. 2006).

Thus, the literature is inconclusive regarding the association between elevated fibrinogen and D-dimer in response to VE. This is probably due to the small numbers of subjects involved and the heterogenous nature of previous studies. The mechanism for the possible association of VE with these biomarkers is still not completely understood and the present study by Kudielka et al in chronically stressed but otherwise healthy individuals, would (arguably) not bring us any closer to understanding this mechanism.

A strength of this study is that the population has a homogenous level of education and socio-economic status, which are known to influence plasma fibrinogen levels (Kamath and Lip 2003). Participants were also screened for depression and this was taken into account in the analysis of their results. However, the study is limited by the relatively small sample size, particularly the number of men included. Although this study included a high percentage of women, which the researchers state as “a strength” of the study, it fails to control for the menstrual cycle, menopause and oral contraception, all of which may affect fibrinogen levels. Therefore, any association between VE and fibrinogen which may have become apparent from this cohort may have been lost due to the failure to control for these important potential confounders.

Further, the study by Kudielka et al did not include any clinical cases of exhaustion, with the majority of participants having no exhaustion to being moderately exhausted. The authors state that the impact of exhaustion on fibrinogen level might have been greater if participants had been more exhausted, a conclusion expressed by previous researchers in this field (Kopp 1999).

In order to gain a better understanding of the mechanisms responsible for the association between psychological factors and the development of CVD, further prospective research involving much larger cohorts is required. In order to investigate further a causal relationship between exhaustion and fibrinogen and D-dimer and their association with the development of CVD, plasma levels of fibrinogen and D-dimer from clinically exhausted cases could be compared with healthy controls matched for covariates. These cohorts could be prospectively followed up with repeated biomarker level assessment to examine their association with the development of CVD.