Course of anxiety symptoms over an 18-month period in exhausted patients post percutaneous coronary intervention.

OBJECTIVE: Anxiety is a neglected risk factor in coronary artery disease. We examined the different courses of anxiety over an 18-month period in patients post percutaneous coronary prevention (PCI) and the predictors of group membership of these courses. METHODS: Consecutive exhausted PCI patients (n = 638), participating in the EXhaustion Intervention Trial (EXIT), were assessed for depression at baseline using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition and for symptoms of anxiety at baseline, 6, and 18 months using the State Trait Anxiety Inventory (state only). SAS procedure TRAJ was used to examine courses of anxiety symptoms over an 18-month period. RESULTS: Five trajectories were identified: nonanxious (13.2%), mildly anxious (39.7%), decreasingly anxious (11.6%), moderately anxious (29.3%), and severely anxious (6.3%), with four of them being stable over 18 months. Multinomial logistic regression analyses showed that angina pectoris, major depression, the use of anxiolytics, and low educational level distinguished moderate-to-severe anxious patients from nonanxious. The absence of angina and major depression and not using diuretics explained the decreasing trend in anxiety in one of the trajectories. CONCLUSIONS: Anxiety trajectories varied across patients, with four of five being stable over 18 months. In clinical practice, knowledge of these trajectories and their determinants may help identify distinct groups of patients with potentially differential risks of adverse health outcomes.

Poor health-related quality of life is a predictor of early, but not late, cardiac events after percutaneous coronary intervention.

Poor health-related quality of life (HRQL) is associated with mortality in cardiac patients. Patients (N=667) with poor HRQL after percutaneous coronary intervention had a higher incidence of early (< or =6 months) major adverse cardiac events (MACE) than did patients with good HRQL, whereas there was no difference for late (>6 months) MACE over a 2-year follow-up period. Poor HRQL remained an independent predictor of early, but not late MACE, adjusting for other risk factors. The same pattern was found for early and late death/non-fatal myocardial infarction. However, further research is warranted before recommending the use of HRQL measures as screening tools in clinical practice.

Exhaustion is associated with low macrophage migration inhibitory factor expression in patients with coronary artery disease.

OBJECTIVE: Macrophage migration inhibitory factor (MIF), a protein secreted by immune cells and the pituitary gland, may be associated with coronary artery disease (CAD) and the mental state of coronary patients. The first origin of MIF suggests positive, the second negative associations. The aim of this study was to explore the direction of the association of MIF with CAD and of MIF with exhaustion, if any. METHODS: Participants were 194 patients who had been recently treated by percutaneous coronary intervention (PCI) and who were exhausted at the start of the study. Half entered a behavioral intervention program. MIF, C-reactive protein, interleukin (IL)-6, IL-1 receptor antagonist, and neopterin were measured in blood collected 6 weeks after PCI (baseline) and 6 and 18 months after baseline. A single measurement of MIF was also available for 129 age- and sex-matched healthy individuals (reference group). RESULTS: At baseline, MIF in patients undergoing PCI was significantly lower than in the reference group (p < .01). New cardiac events occurred twice as often in the lowest quartile than in the highest quartile of MIF concentrations. However, the association was not significant (chi(2) = 2.27; df = 3; p = .52). During follow up, MIF concentrations increased significantly in patients undergoing PCI (p < .001). At 18 months, MIF concentrations were significantly lower in the exhausted patients than in the nonexhausted patients (p = .02). hsCRP, IL-1ra, IL-6, and neopter in concentrations did not change over this time period. CONCLUSIONS: The data are suggestive of a negative association of MIF with CAD and of MIF with exhaustion. The observation that those patients who remained exhausted had lower concentrations of MIF fits into earlier observations that suggested that exhausted coronary patients may be characterized by a hypoactivity of the hypothalamic-pituitary-adrenocortical axis.

Effects of a behavioural intervention on quality of life and related variables in angioplasty patients: results of the EXhaustion Intervention Trial.

OBJECTIVES: The EXhaustion Intervention Trial investigated the effect of a behavioural intervention programme on exhaustion, health-related quality of life (HRQL), depression, anxiety, hostility, and anginal complaints in angioplasty patients who felt exhausted after percutaneous coronary intervention (PCI). METHODS: Seven hundred ten patients were randomized into an intervention group and a usual care control group. The group intervention focused on stressors leading to exhaustion and on support of recovery. HRQL (measured by the MacNew questionnaire), exhaustion [measured by the Maastricht Questionnaire and the Maastricht Interview Vital Exhaustion (MIVE)], anxiety (measured by the State-Trait Inventory), and depression (measured by the structured clinical interview for DSM-IV) were assessed at intake and at 6 and 18 months. Presence of anginal complaints was assessed at 18 months. RESULTS: The intervention had a significant beneficial effect on all psychological factors except hostility and on the presence of anginal complaints. The effect of the intervention on exhaustion, as assessed by the MIVE, was modified by a previous history of coronary artery disease (CAD). Gender modified the effect of the intervention on exhaustion and on anxiety, the strongest effect being observed in women. CONCLUSIONS: The behavioural intervention improved HRQL and related psychological factors. Somatic comorbidity and a history of CAD limited the effect of the intervention.

Relative lack of depressive cognitions in post-myocardial infarction depression.

BACKGROUND: Depression has been associated with adverse clinical events in myocardial infarction (MI) patients, but many questions about the nature of post-MI depression remain unanswered. We examined whether depressive cognitions characteristic of depression in psychiatric patients are also present in post-MI patients with major depression (MD). METHODS: Non-depressed (n=40) and depressed (n=40) post-MI patients, and psychiatric outpatients (n=40) treated for clinical depression, matched on age and sex, were interviewed using a structured clinical interview to diagnose DSM-IV MD. All patients also completed the Beck Depression Inventory (BDI) and the Beck Cognition Checklist-Depression subscale (CCL-D). RESULTS: Mean levels of depressive cognitions were considerably higher in depressed psychiatric patients compared with depressed post-MI patients (34.9 versus 28.0; p=.013), and higher in depressed post-MI patients compared with non-depressed post-MI patients (28.0 versus 17.8; p<.0001), adjusted for age, sex, educational level, and marital status. Younger age (p=.024), absence of a partner (p=.016) and depressed psychiatric status (p=.016) were independently associated with depressive cognitions. Psychiatric patients also had higher mean levels of depressive symptoms as compared to depressed post-MI patients (25.1 versus 17.8; p=.001). LIMITATIONS: This study is based on a cross-sectional design. CONCLUSIONS: The symptom presentation of MD in post-MI patients is both quantitatively and qualitatively different from that seen in psychiatric patients, suggesting that depressive symptoms in post-MI patients differ in content from those in psychiatric patients. These findings could have important consequences for the design and contents of therapeutic programs for treating depression in post-MI patients.

Inflammatory markers predict late cardiac events in patients who are exhausted after percutaneous coronary intervention.

Chronic inflammation is one of the main underlying mechanisms in the development of coronary artery disease (CAD). We investigated the prognostic value of inflammatory markers for cardiac events occurring more than 6 months after percutaneous coronary intervention (PCI), i.e. late cardiac events, furthermore we investigated the temporal stability of these markers. Exhausted patients (234) recently treated by successful PCI were studied. Serum samples collected about 6 weeks after PCI (baseline), 6 and 18 months after baseline were analyzed for CRP, IL-6, tumour necrosis factor (TNF-alpha), IL-10, IL-1ra, IL-8 and neopterin. In the mean cardiac follow-up of 24 months, 25 late cardiac events occurred. Cox proportional hazards analysis was used to determine the prognostic value. Elevated concentrations of IL-6 at baseline and 6 months later increased the risk of late cardiac events (RR 3.9, CI 1.7-9.0, p 0.00 and RR 3.6, CI 1.6-8.5, p 0.00). Elevated concentrations of CRP and IL-10 at baseline also increased the risk of late cardiac events (RR 2.5, CI 1.1-5.7, p 0.04 and RR 2.5, CI 1.1-5.6, p 0.03) as did IL-1 receptor antagonist at 6 months (RR 2.6, CI 1.1-6.1, p 0.04). Temporal stability was high for most markers, but highest for IL-6. These results support the assumption that chronic inflammation is a pathophysiological mechanism in the development of CAD.

Psychological effects of a short behavior modification program in patients with acute myocardial infarction or coronary artery bypass grafting. A randomized controlled trial.

OBJECTIVE: The effects of a short intervention on behavioral risk factor modification in patients with coronary artery disease (CAD) on Type A behavior, vital exhaustion, and depression were studied in a randomized controlled trial. METHODS: Acute myocardial infarction patients or patients who underwent coronary artery bypass grafting (CABG) were randomly assigned to an 8-week multiple risk modification group program (n = 94) or to a control group (n = 90) that received usual care with standard physical exercise training. Patients were assessed before intervention, directly after intervention, and at 9-month follow-up. RESULTS: The intervention was effective in reducing hostility and total Type A behavior at postintervention (P = .01) and at 9-month follow-up (P = .03). The intervention had no overall impact on vital exhaustion and depression, measured by the Beck Depression Inventory (BDI), whereas we unexpectedly found that the percentage of patients with major depression was reduced in the control group but not in the intervention group. CONCLUSION: The results indicate that a short behavioral intervention for coronary patients can result in relatively large and persistent reductions in cognitive aspects of Type A behavior and hostility, in particular. In view of the unwanted findings on the diagnosis of depression, however, we do not unequivocally advise the intervention to the general population of AMI and CABG patients.

Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification.

OBJECTIVE: Matrix gamma-carboxyglutamic acid (Gla) protein (MGP), a vitamin K-dependent protein, is a potent in vivo inhibitor of arterial calcification. We hypothesized that low endogenous production of MGP and impaired carboxylation of MGP may contribute to the development or the progression of vascular disease. METHODS AND RESULTS: Novel conformation-specific antibodies against MGP were used for immunohistochemistry of healthy and sclerotic arteries. In healthy arteries, MGP was mainly displayed around the elastin fibers in the tunica media. The staining colocalized with that for carboxylated MGP, whereas undercarboxylated MGP (ucMGP) was not detected. In atherosclerotic arteries, ucMGP was found in the intima, where it was associated with vesicular structures. In Mönckeberg's sclerosis of the media, ucMGP was localized around all areas of calcification. The results indicate that ucMGP is strongly associated with vascular calcification of different etiologies. In a separate study, serum MGP concentrations in a cohort of 172 subjects who had undergone percutaneous coronary intervention were significantly reduced compared with an apparently healthy population. CONCLUSIONS: These data show that impaired carboxylation of MGP is associated with intimal and medial vascular calcification and suggest the essentiality of the vitamin K modification to the function of MGP as an inhibitor of ectopic calcification.

Effects of treating exhaustion in angioplasty patients on new coronary events: results of the randomized Exhaustion Intervention Trial (EXIT).

BACKGROUND: Extreme fatigue is a common complaint in percutaneous coronary intervention (PCI) patients, and is associated with an increased risk for new cardiac events. The objective of the Exhaustion Intervention Trial (EXIT) was to determine whether a behavioral intervention on exhaustion reduces the risk of a new coronary event after PCI. METHODS AND RESULTS: Seven hundred ten consecutive patients, ages 35 to 68 years, who felt exhausted after PCI were randomized into an intervention group and a usual-care group. The intervention was based on group therapy focusing on stressors leading to exhaustion, and on support for recovery by promoting rest and making rest more efficient. One month after PCI, 50% of the patients felt exhausted. The intervention reduced the odds of remaining exhausted at 18 months by 56% in those without a previous history of coronary artery disease (CAD) (OR = 0.44; 95% CI 0.29-0.66), but had no effect on exhaustion in those with a history of CAD (OR = 0.93; 95% CI 0.56-1.55; p = .78). The intervention did not reduce the risk of a new coronary event within 2 years (RR = 1.14; 95%CI 0.82-1.57). Post-hoc analyses suggest that the effect of the intervention was limited by a positive history of CAD, the presence of a chronic, painful condition (especially rheumatism), and by opposite effects on early and late cardiac events. CONCLUSION: A behavioral intervention in PCI patients has a beneficial effect on feelings of exhaustion. It could not be demonstrated that the intervention reduces the risk of a new coronary event within 2 years.

Exhaustion and coronary heart disease: the history of a scientific quest.

This paper describes the development of the concept "vital exhaustion", the epidemiological evidence that this state belongs to the precursors of different manifestations of coronary artery disease, and the biological plausibility of the association between exhaustion and coronary artery disease. It further describes the main results of a randomized, controlled trial designed to determine whether a behavioural intervention reduces the risk of a new coronary event.

Group cohesion and working alliance: prediction of treatment outcome in cardiac patients receiving cognitive behavioral group psychotherapy.

BACKGROUND: Various definitions of both group cohesion and working alliance are used in theories on group psychotherapy, making the study of their relative contribution to the treatment outcome difficult. In this study, two different, nonoverlapping questionnaires were used to explore the relationship between group cohesion, working alliance and treatment outcome in a time-limited, structured cognitive behavioral group psychotherapy aiming at the reduction of coronary risk factors. METHODS: After having undergone percutaneous transluminal coronary angioplasty, 42 patients were treated with the aim to reduce exhaustion, anxiety, hostility and depression. The newly developed Group Cohesion Questionnaire (GCQ) and the Helping Alliance Questionnaire (HAQ-II, measuring the bond between individual patients and the group psychotherapist) were administered after the fifth and tenth treatment session. Exhaustion, quality of life, anxiety, blood pressure and heart rate were measured before and after treatment. To test the relationship between the GCQ, the HAQ-II and outcome variables, Pearson Product-Moment correlations and hierarchical regression was applied. RESULTS: Principal Component Analysis of the GCQ yielded two dimensions, the bond with the group as a whole and the bond with other group members. Hierarchical regression showed that both the bond with other group members and working alliance contributed significantly and independently to the prediction of posttreatment systolic and diastolic blood pressure as well as posttreatment quality of life (confidence). CONCLUSIONS: Conceptually and empirically, group cohesion and the working alliance may be considered to represent different relationships in a psychotherapy group, contributing in different ways to the treatment outcome in cardiac patients receiving cognitive behavioral group psychotherapy.

Herpes viruses, cytokines, and altered hemostasis in vital exhaustion.

OBJECTIVE: Infections with herpes viruses have been implicated in the pathogenesis of atherosclerosis. We tested the hypothesis that vital exhaustion (VE) is associated with multiple herpesvirus infections, such as herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus, and with an increase in pathogen burden (ie, the aggregated seropositivity to immunoglobulin G antibodies for herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus). In addition, we examined the association of VE and pathogen burden with measures of hemostasis and inflammation. METHODS: Blood samples were drawn from 29 men with VE and 30 male control subjects, all healthy and nonsmokers, to assess serological evidence of infection and measures of hemostasis and inflammation. RESULTS: VE is associated with a relatively high pathogen burden, altered hemostasis, and higher levels of cytokines, such as interleukin-6. Across all subjects, a relatively high pathogen burden was also associated with altered hemostasis but not with increased cytokine levels. The interaction of VE with pathogen burden revealed significant linear increases in measures of hemostasis and inflammation. Finally, immunoglobulin G antibody titer levels of individual herpesvirus infections were not associated with hemostatic measures or with cytokines. CONCLUSIONS: We conclude that stress-related alterations in hemostasis and inflammation are not necessarily linked to one particular herpesvirus infection but rather to an increase in aggregated seropositivity to herpesvirus infections.

Cholesterol changes in coronary patients after a short behavior modification program.

Serum cholesterol changes after an 8-week behavior modification program for patients with coronary artery disease (CAD) were studied in a randomized controlled clinical trial. Acute myocardial infarction (AMI) or coronary artery bypass grafting (CABG) patients were randomly assigned to the intervention (N = 94) or to usual care (N = 90). After 9 months' follow-up the intervention was effective in reducing total cholesterol and LDL cholesterol levels, particularly in patients with high baseline lipid levels. After correcting for changes in dose of statins during follow-up, effects were weakened, but for patients with high baseline cholesterol levels favorable effects remained. In these patients, the intervention group showed a decline of total cholesterol and LDL cholesterol levels of 20% and 29%, respectively, compared to a 12% and 19% reduction in the control group (p <.01). These effects could not be explained by changes in dietary fat consumption. An unexpected finding was a lower increase in HDL cholesterol in the intervention group than in the control group.

Diurnal variations in coagulation and fibrinolysis in vital exhaustion.

OBJECTIVE: Vital exhaustion (VE) predicts a first myocardial infarction (MI) and new cardiac events after a coronary angioplasty. To explore potential underlying pathophysiological mechanisms, we tested whether VE is associated with more pronounced diurnal variations in hemostasis. METHODS: Blood was drawn from 29 VE and 30 control males, all healthy and nonsmokers, to assess hemostatic measures at 7:00 AM and 6:00 PM. RESULTS: All measures of fibrinolysis were in their normal range and showed significant diurnal variations. These variations were more pronounced in VE as all fibrinolytic measures were significantly higher in VE at 7:00 AM and similar to those of controls at 6:00 PM, thus supporting our hypothesis with respect to fibrinolysis. Diurnal decreases in tPA and tPA-PAI ranged from 1.5 (VE) to 1.3 (controls), whereas the diurnal decrease in PAI-1 was more than fourfold in VE and 2.7-fold in controls. This suggests a decreased fibrinolytic capacity in VE during the early morning. All coagulation measures were in their normal range, and prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complexes, and activated factor VII showed significant diurnal variations. These variations were similar in VE and control individuals, thus not supporting our hypothesis with respect to coagulation. Finally, F1+2 and fibrinogen were both significantly higher throughout the day in VE. CONCLUSIONS: VE is associated with decreased early morning fibrinolysis and increased fibrinogen levels throughout the day. These hemostatic changes may promote thrombus formation and provide a potential pathophysiological mechanism by which VE is related to MI and its circadian variation.

Inflammation and the mental state before an acute coronary event.

Feelings of exhaustion have been found to belong to the precursors of acute coronary events. Guided by the current views of the pathogenesis of acute coronary syndromes, a two-stage model describing a feedback relationship between mental state and the disease process is presented. According to the presented model prolonged exposure to stress results in a state of exhaustion leading to increased susceptibility to inflammatory diseases. Inflammation, in turn, amplifies feelings of exhaustion and malaise through cytokine release. Results of a study of 15 exhausted and 15 nonexhausted angioplasty patients, showing elevated levels of interleukin-1ß and tumour necrosis factor-α in the exhausted patients, give empirical support to this model.