Rob van Diest

Novel Conformation-Specific Antibodies Against Matrix γ-Carboxyglutamic Acid (Gla) Protein: Undercarboxylated Matrix Gla Protein as Marker for Vascular Calcification

Objective—Matrix γ-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.

Salivary cortisol patterns in vital exhaustion

OBJECTIVE The syndrome of vital exhaustion (VE), a risk indicator for myocardial infarction, is characterized by excessive fatigue, irritability, and demoralization. Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is a potential pathogenic mechanism in fatigue syndromes, but little is known about HPA function in syndromal VE. METHOD We assessed basal free cortisol levels and responses to a speech task and to morning awakening by collecting multiple saliva samples over 2 days from 29 VE men and 30 controls. RESULTS VE subjects reported higher perceived stress, poorer sleep, and greater fatigue than controls. Basal cortisol levels were lower in VE subjects, especially in the evening, and were negatively associated with fatigue. Overall cortisol responses to the speech task were similar in VE and control groups, although VE subjects were less likely to show large (> or =2.76 nmol/l) responses. The cortisol response to awakening was associated with concurrent fatigue and poor sleep quality. CONCLUSION These findings suggest a subtle HPA hypoactivity in VE, which may arise through chronic stress and associated sleep disturbances.

Acute l-5-hydroxytryptophan administration inhibits carbon dioxide-induced panic in panic disorder patients

Previous research showed that lowering the availability of serotonin to the brain by tryptophan depletion increases the vulnerability of panic disorder patients for an experimental 35% CO(2) panic challenge. The results also suggested that increased availability of serotonin inhibits the response to such a challenge. In the present study, this latter possibility is examined. The reaction of 24 panic disorder patients and 24 healthy volunteers to a 35% CO(2) panic challenge was assessed following administration of 200-mg L-5-hydroxytryptophan (the immediate precursor of serotonin) or placebo. L-5-Hydroxytryptophan significantly reduced the reaction to the panic challenge in panic disorder patients, regarding subjective anxiety, panic symptom score and number of panic attacks, as opposed to placebo. No such effect was observed in the healthy volunteers. L-5-Hydroxytryptophan acts to inhibit panic, which supports a modulatory role of serotonin in panic disorder.

Carbon dioxide-induced emotion and respiratory symptoms in healthy volunteers

A number of evidences have established that panic and respiration are closely related. Clinical studies indicated that respiratory sensations constitute a discrete cluster of panic symptoms and play a major role in the pathophysiology of panic. The aim of the present study was to explore the phenomenology of an experimental model of panic in healthy volunteers based on the hypothesis that: (1) we can isolate discrete clusters of panic symptoms, (2) respiratory symptoms represent a distinct cluster of panic symptoms, and (3) respiratory symptoms are the best predictor of the subjective feeling of panic, as defined in the DSM IV criteria.Sixty-four healthy volunteers received a double inhalation of four mixtures containing 0, 9, 17.5 and 35% CO2, respectively, in a double-blind, cross-over, random design. An electronic visual analog scale and the Panic Symptom List (PSL) were used to assess subjective ‘fear/discomfort’ and panic symptoms, respectively. Statistical analyses consisted of Spearmans correlations, a principal component factor analysis of the 13 PSL symptoms, and linear regressions analyses.The factor analysis extracted three clusters of panic symptoms: respiratory, cognitive, and neurovegetative (r2=0.65). Respiratory symptoms were highly related to subjective feeling of fear/discomfort specifically in the CO2-enriched condition. Moreover, the respiratory component was the most important predictor of the subjective feeling of ‘fear/discomfort’ (β=0.54).The discrete clusters of symptoms observed in this study were similar to those elicited in panic attacks naturally occurring in patients affected by panic disorder. Consistent with the idea that respiration plays a crucial role in the pathophysiology of panic, we found that respiratory symptoms were the best predictors the subjective state defined in the DSM IV criteria for panic.

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.

Sleep Complaints in Panic Disorder Patients

Patients with anxiety disorders often report difficulty sleeping. The present study assesses the prevalence of sleep complaints in panic disorder (PD) patients, compares them with sleep complaints in a normal population, and investigates the role of comorbid depression and nocturnal panic attacks in sleep complaints in the PD patients. Seventy PD patients and 70 healthy controls were asked about their subjective sleep characteristics by means of the Sleep-Wake Experience List, which assesses sleep/arousal complaints over a 24-hour period. Sixty-seven percent of the PD patients reported sleep complaints, compared with 20% of the controls. Eighty-six percent of the depressed PD patients and 59% of the nondepressed had sleep difficulties; 77% of the PD patients with nocturnal panic attacks reported sleep complaints, versus 53% of the PD patients without nocturnal panic. It is concluded that PD patients demonstrate a higher prevalence of sleep complaints than normal controls; this can only partly be explained by comorbid depression, and cannot be explained by the presence of nocturnal panic attacks.

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 (&khgr;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. MIF = macrophage migration inhibitory factor; CAD = coronary artery disease; IL = interleukin; TNF = tumor necrosis factor; ACTH = adenocorticotrope hormone; HPA = hypothalamic–pituitary–adrenocortical; PCI = percutaneous coronary intervention; EXIT = Exhaustion Intervention Trial; MQ = Maastricht Questionnaire; MIVE = Maastricht Interview for Vital Exhaustion; EDTA = ethylenediaminetetraacetic-treated; ELISA = enzyme-linked immunosorbent assay; Ab = antibody; CV = coefficient of variation; TMB = tetramethylbenzidine solution; CABG = coronary artery bypass graft surgery.

Vital exhaustion: behavioural and biological correlates

Purpose of review Cardiovascular disease remains the leading cause of mortality in the western world. The absence of smoking, hypertension, hyperlipidaemia, diabetes and a sedentary lifestyle in over 50% of patients with atherosclerosis indicates that additional risk factors remain to be identified. One putative risk factor is vital exhaustion, a state characterized by fatigue, irritability, and general malaise that precedes the onset of coronary artery disease in more than half of all cases. Although epidemiological studies have shown that vital exhaustion predicts cardiovascular disease in both healthy and cardiac populations, the origin of these symptoms is poorly understood. Recent findings Stress-related changes in haemostasis and infections/inflammation may constitute important pathways that link vital exhaustion with cardiovascular disease. In line with these findings, the hypothesis is put forward that the exhaustion before a cardiac event in fact reflects an adaptive response of the host that is triggered by pro-inflammatory cytokines during an infectious period. Summary A better understanding of stress-related immune dysregulation not only enhances the knowledge of specific psychobiological mechanisms in cardiovascular disease, but also gives insight into the origins of the mental state of coronary patients.