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OBJECTIVE: In coronary artery disease (CAD), concomitant peripheral arterial disease (PAD) entails increased systemic inflammatory profile and more severe coronary atherosclerosis. We investigated the relationship between the inflammatory status in the affected limb and CAD severity. METHODS: In 46 CAD+PAD and 31 CAD-alone patients, the inflammatory status of the leg circulation was measured by the transfemoral gradients of neutrophil myeloperoxidase (MPOx) content and interleukin-6 (IL-6). CAD severity was defined by evaluating coronary artery endothelial function, number of significant coronary stenoses, and prevalence of three-vessel CAD and myocardial infarction (MI). RESULTS: In the affected limb of CAD+PAD patients, the transfemoral gradients of neutrophil MPOx content and IL-6 were higher (P < .01, for both) than in the healthy leg of CAD-only patients. At multivariate analysis, CAD+PAD patients with transfemoral gradients of MPOx and IL-6 > median had a more compromised coronary artery endothelial function (P < .05, for both). Furthermore, CAD+PAD patients with transfemoral gradients of neutrophil MPOx content > median showed an independent association with a greater number of significant coronary stenoses, and a greater prevalence of three-vessel CAD and previous MI (P < .01, for all). A more severe coronary atherosclerosis was observed also in CAD+PAD patients with transfemoral gradients of IL-6 > median vs those with IL-6 < median, although differences were not statistically significant. CONCLUSION: In CAD patients, the coexistence of PAD does not necessarily entail a more severe coronary atherosclerosis. Only those with an inflammatory status of the affected limb presents more severe CAD. Future studies will clarify whether the presence of peripheral inflammation plays a mechanistic role in CAD evolution

Non-alcoholic fatty liver disease, characterized by hepatocyte apoptosis, is distinct in fatty liver and non-alcoholic steatohepatitis, the more severe form. Apoptotic cell death is caspase-dependent and associated with mitochondrial membrane depolarization and cytochrome c release. Adhering to the hypothesis that the exposure of hepatocytes to free fatty acids, resulting in increased ROS production and mitochondrial damage, is balanced by the presence of antioxidant substances, circulating levels of gamma-glutamyl transferase, cytochrome c, triglycerides and unconjugated bilirubin were explored in patients suffering from non-alcoholic fatty liver disease with different severity. One hundred and eighty-six consecutive patients who presented recent ultrasound feature of bright liver without any liver disease of known origin were enrolled, eighty-nine of whom underwent liver biopsy. Forty-five subjects were allocated on the basis of histology in fatty liver group while 44 patients formed the group with non-alcoholic steatohepatitis. A cohort of 27 young, lean, apparently healthy individuals was selected as control group. The levels of gamma-glutamyl transferase were normal or slightly increased, while unconjugated bilirubin concentrations were elevated in all the spectra of non-alcoholic fatty liver disease. Comparing the present results with relevant findings from other studies dealing with diseases characterized by apoptosis, we did not find high circulating levels of cytochrome c in non-alcoholic fatty liver disease. What is more, our patients, categorized as suffering from simple fatty liver or from the more severe non-alcoholic steatohepatitis, had similar levels of cytochrome c and gamma-glutamyl transferase, p=0.19 and 0.11. Serum triglycerides were higher in patients with non-alcoholic fatty liver disease than in the healthy group, p=0.001. These findings likely reflect a balance between oxidative stress and anti-oxidant response rather than a lack of reliability of cytochrome c as a reliable biomarker of mitochondrial damage.

Background—Tissue factor (TF) is the main initiator of coagulation in vivo. Recently, however, a role for TF as a cell receptor involved in signal transduction has been suggested. The aim of the present study was to assess whether activated factor VII (FVIIa) binding to TF could induce smooth muscle cell (SMC) proliferation and to clarify the possible intracellular mechanism(s) responsible for this proliferation. Methods and Results—Cell proliferation was induced by FVIIa in a dose-dependent manner, as assessed by [3H]thymidine incorporation and direct cell counting, whereas no response was observed with active site–inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid of enzymatic activity. Similarly, no proliferation was observed when binding of FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal–regulated kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by transient ERK phosphorylation in Western blots and by suppression of proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK phosphorylation was not observed with FVIIai or when cells were pretreated with AP-1. Conclusions—These data indicate a specific effect by which binding of FVIIa to TF on the surface of SMCs induces proliferation via a coagulation-independent mechanism and possibly indicate a new link between coagulation, inflammation, and atherosclerosis.