Usefulness of Type D personality and kidney dysfunction as predictors of interpatient variability in inflammatory activation in chronic heart failure.

Tumor necrosis factor-alpha (TNF-alpha), soluble TNF-alpha receptors 1 and 2 (sTNFR1/2), and interleukin (IL)-6 are powerful predictors of mortality in chronic heart failure (CHF). Little is known, however, about the origins of proinflammatory cytokine production or the determinants of substantial interpatient variability in inflammatory activation. We prospectively examined kidney dysfunction and Type D personality (tendency to experience and inhibit emotional distress) as predictors of interpatient variability in these markers of inflammatory activation. At baseline, 125 patients with CHF were assessed for kidney dysfunction and Type D. Serum levels of proinflammatory cytokines (TNF-alpha, sTNFR1, sTNFR2, IL-6), the anti-inflammatory cytokines IL-10, and IL-1 receptor antagonist were measured at 1-year follow-up. Type D patients had higher levels of sTNFR1 (p = 0.009) and sTNFR2 (p = 0.001) and lower levels of IL-10 (p = 0.006) than patients without Type D and kidney dysfunction. Patients with kidney dysfunction also had elevated levels of sTNFR1 and sTNFR2 (p <0.0001), but their IL-10 level was not decreased. Type D personality and kidney dysfunction predicted increased sTNFR1/IL-10 and sTNFR2/IL-10 ratios (p < or =0.007); Type D also predicted an increased IL-6/IL-10 ratio (p = 0.013). Other predictors were spironolactone and older age. After adjusting for these variables, the odds for elevated ratios (highest 20%) were still increased in Type D patients (all odd ratios >3.00). In conclusion, Type D personality and kidney dysfunction independently predicted unfavorable cytokine profiles in patients with CHF and may enhance our understanding of interpatient variability in inflammatory activation in these patients.

The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification.

OBJECTIVE: Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a vitamin K-dependent protein and a strong inhibitor of vascular calcification. Vitamin K deficiency leads to inactive uncarboxylated MGP (ucMGP), which accumulates at sites of arterial calcification. We hypothesized that as a result of ucMGP deposition around arterial calcification, the circulating fraction of ucMGP is decreased. Here we report on the development of an ucMGP assay and the potential diagnostic utility of monitoring serum ucMGP levels. METHODS AND RESULTS: An ELISA-based assay was developed with which circulating ucMGP can be determined. Serum ucMGP levels were measured in healthy subjects (n = 165) and in four patient populations; patients who underwent angioplasty (n = 30), patients with aortic stenosis (n = 25), hemodialysis patients (n = 52), and calciphylaxis patients (n = 10). All four patient populations had significantly lower ucMGP levels. In angioplasty patients and in those with aortic stenosis, some overlap was observed with the control population. However, in the hemodialysis and calciphylaxis populations, virtually all subjects had ucMGP levels below the normal adult range. CONCLUSION: Serum ucMGP may be used as a biomarker to identify those at risk for developing vascular calcification. This assay may become an important tool in the diagnosis of cardiovascular calcification.

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.

Vagus-brain communication in atherosclerosis-related inflammation: a neuroimmunomodulation perspective of CAD.

The current understanding of the pathophysiology of atherosclerosis leading to coronary artery disease (CAD) emphasizes the role of inflammatory mediators. Given the bidirectional communication between the immune and central nervous systems, an important question is whether the brain can be "informed" about and modulate CAD-related inflammation. A candidate communicator and modulator is the vagus nerve. Until now, the vagus nerve has received attention in cardiology mainly due to its role in the parasympathetic cardiovascular response. However, the vagus nerve can also "inform" the brain about peripheral inflammation since its paraganglia have receptors for interleukin-1. Furthermore, its efferent branch has a local anti-inflammatory effect. These effects have not been considered in research on the vagus nerve in CAD or in vagus nerve stimulation trials in CAD. In addition, various behavioural interventions, including relaxation, may influence CAD prognosis by affecting vagal activity. Based on this converging evidence, we propose a neuroimmunomodulation approach to atherogenesis. In this model, the vagus nerve "informs" the brain about CAD-related cytokines; in turn, activation of the vagus (via vagus nerve stimulation, vagomimetic drugs or relaxation) induces an anti-inflammatory response that can slow down the chronic process of atherogenesis.

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.

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.

Characteristics and performance of an immunosorbent assay for human matrix Gla-protein.

BACKGROUND: Matrix gammacarboxyglutamate (Gla)-protein (MGP) is a strong inhibitor of soft tissue calcification and is mainly produced by chondrocytes and vascular smooth muscle cells (VSMCs). MGP-deficient mice have extensive calcifications of cartilage and arteries leading to osteopenia, fractures and blood vessel ruptures. Promotor polymorphisms resulting in decreased expression levels were found to be associated with an increased risk for cardiovascular disease in humans. METHODS: Recently, an ELISA-based assay has become available with which MGP may be detected in the circulation. The principle of the test kit is that of a competitive immunoassay using a monoclonal antibody against MGP bound to the microtiter plate. RESULTS: Here, we report on a critical evaluation of this assay and its potential diagnostic utility in diseases associated with the degeneration of the arterial vessel wall and cartilage. The biochemical performance of the kit is satisfactory, and significant differences were found between a number of patient cohorts and the reference population. Serum MGP concentrations were significantly decreased in patients with angina pectoris and in various cartilage diseases. CONCLUSIONS: The assay allows comparison of groups and may become a suitable marker for risk assessment or diagnosis in cardiovascular disease and osteoarthritis.