Incidence of Atrial Fibrillation in Postmenopausal Women with Endometrial Cancer.

Endometrial cancer (EC) has been associated with an increased risk of cardiovascular disease, including atrial fibrillation (AF). We performed a prospective, case-controlled analysis among 310 Bulgarian women with new-onset, histologically confirmed EC, free of AF at the baseline survey, and women with normal (senile) endometrium/endometrial hyperplasia as a control group (n = 205). The risk of AF as well as relationship of adiponectin (APN) and high sensitivity C-reactive protein (hs-CRP) levels with AF in women with EC were calculated by Cox proportional hazards models. During the mean follow-up of 2.5 ± 0.5 years, new-onset AF had occurred in 11.7% of women with EC vs. 5.8% in the control group (p < 0.01). The risk of AF was highest in the first 6 months after new-onset EC, with an incidence rate ratio (IRR) of 1.19 (95% CI 1.10-1.29; p = 0.01). Women with EC, who were obese (body mass index (BMI) > 30 kg/m2) and younger (age < 60) were found to be more likely to develop AF (HR 1.95; 95% CI 1.18-3.32; p = 0.05). APN levels were not significantly associated with new-onset AF (95% CI 0.87-1.21; p = 0.063). However, the secondary analysis showed evidence of APN-AF association when adjusted for BMI (2.05; 95% CI 1.04-4.04; p = 0.037). We conclude that EC was significantly associated with the incidence of AF.

Factor VII Activating Protease Expression in Human Platelets and Accumulation in Symptomatic Carotid Plaque.

Background Factor VII activating protease (FSAP) is of interest as a marker for vascular inflammation and plaque destabilization. The aim of this study was to analyze the expression profile of FSAP in endarterectomy specimens that were taken from patients with asymptomatic and symptomatic carotid atherosclerotic plaques and to compare them with circulating FSAP levels. Methods and Results Plasma FSAP concentration, activity, and mRNA expression were measured in endarterectomy specimens and in monocytes and platelets. Plaque and plasma FSAP levels were higher in symptomatic patients (n=10) than in asymptomatic patients (n=14). Stronger FSAP immunostaining was observed in advanced symptomatic lesions, in intraplaque hemorrhage-related structures, and in lipid-rich areas within the necrotic core. FSAP was also colocalized with monocytes and macrophages (CD11b/CD68-positive cells) and platelets (CD41-positive cells) of the plaques. Moreover, human platelets expressed FSAP in vitro, at both the mRNA and protein levels. Expression is stimulated by thrombin receptor-activating peptide and ADP and reduced by acetylsalicylic acid. Conclusions Plasma FSAP levels were significantly increased in patients with symptomatic carotid stenosis and thus may be involved in plaque development This plaque-associated FSAP may be produced by platelets or macrophages or may be taken up from the circulation. To establish FSAP's utility as a circulating or plaque biomarker in patients with symptomatic carotid atherosclerotic plaques, further studies are needed.

Expression of the Marburg I Single Nucleotide Polymorphism (MI-SNP) and the Marburg II Single Nucleotide Polymorphism (MII-SNP) of the Factor VII-Activating Protease (FSAP) Gene and Risk of Coronary Artery Disease (CAD): A Pilot Study in a Single Population.

BACKGROUND Factor VII-activating protease (FSAP) has a role in vascular inflammation and may have a role coronary artery disease (CAD). The aim of this study was to investigate the association between two naturally occurring single nucleotide polymorphisms (SNPs) in the FSAP gene and the risk of coronary artery disease (CAD). MATERIAL AND METHODS Of 733 patients, 173 patients had symptoms of angina, and 560 patients had CAD confirmed by coronary angiography. All patients were genotyped for SNPs of the FSAP gene, Marburg I (MI-SNP) and Marburg II (MII-SNP), using 5' exonuclease TaqMan assays. Logistic regression analysis was used to evaluate the association between two gene polymorphisms, metabolic and other cardiovascular risk factors in patients with CAD. RESULTS The presence of MI-SNP and MII-SNP FSAP gene polymorphisms were not associated with the presence of CAD. However, the MII-SNP polymorphism was significantly associated with a reduced risk of developing CAD (OR=0.422; 95% CI, 0.194-0.920; P=0.035); the MI-SNP polymorphism was associated with absence of hyperlipoproteinemia (OR=0.601; 95% CI, 0.344-1.051; P=0.074). There was no significant association between expression of the MI-SNP and MII-SNP FSAP gene polymorphisms and the incidence of myocardial infarction, or of a history of diabetes mellitus, arterial hypertension, obesity, or smoking. CONCLUSIONS The MI-SNP and MII-SNP FSAP gene polymorphisms were not predictive or prognostic biomarkers for CAD or its main risk factors. However, the presence of the MII-SNP polymorphism was associated with a reduced risk of developing CAD.

Home monitoring after ambulatory implanted primary cardiac implantable electronic devices: The home ambulance pilot study.

BACKGROUND: The Home Monitoring (HM) system of cardiac implantable electronic devices (CIEDs) permits early detection of arrhythmias or device system failures. The aim of this pilot study was to examine how the safety and efficacy of the HM system in patients after ambulatory implanted primary CIEDs compare to patients with a standard procedure and hospitalization. HYPOTHESIS: We hypothesized that HM and their modifications would be a useful extension of the present concepts for ambulatory implanted CIEDs. METHODS: This retrospective analysis evaluates telemetric data obtained from 364 patients in an ambulatory single center over 6 years. Patients were assigned to an active group (n = 217), consisting of those who were discharged early on the day of implantation of the primary CIED, or to a control group (n = 147), consisting of those discharged and followed up with the HM system according to usual medical practices. RESULTS: The mean duration of hospitalization was 73.2% shorter in the active group than in the control group, corresponding to 20.5 ± 13 fewer hours (95% confidence interval [CI]: 6.3-29.5; P < 0.01) spent in the hospital (7.5 ± 1.5 vs 28 ± 4.5 h). This shorter mean hospital stay was attributable to a 78.8% shorter postoperative period in the active group. The proportion of patients with treatment-related adverse events was 11% (n = 23) in the active group and 17% (n = 25) in the control group (95% CI: 5.5-8.3; P = 0.061). This 6% absolute risk reduction (95% CI: 3.3-9.1; P = 0.789) confirmed the noninferiority of the ambulatory implanted CIED when compared with standard management of these patients. CONCLUSIONS: Early discharge with the HM system after ambulatory CIED implantation was safe and not inferior to the classic medical procedure. Thus, together with lower costs, HM and its modifications would be a useful extension of the present concepts for ambulatory implanted CIEDs.

New Task Force Criteria Provide Evolution in Diagnosis of Arrhythmogenic Cardiomyopathy in Patients without Typical Progression of the Disease.

BACKGROUND The original Task Force Criteria from 1994 for the clinical diagnosis of ARVC were highly specific and based on structural, histological, EKG, and familial features of disease. However, recommendations for clinical diagnosis and management of ARVC are sparse and lacked sensitivity for early disease. CASE REPORT Ventricular electrical instability and sudden cardiac death are the hallmarks of ARVC, and are often present before structural abnormalities. In this case report, we describe a patient who had detectable electrical abnormalities and structural changes that remained unchanged for over 10 years. CONCLUSIONS The disease progression in this case was defined as the development of a new 2010 TFC, which was absent at enrolment in 1994 and in 2008.

Monocyte CD40 expression in young healthy female smokers and/or oral contraceptives users without additional risk factors for atherosclerosis.

OBJECTIVE: Atherosclerosis, as an inflammatory disease, is characterized by pathologically altered levels of cytokines. We investigated whether smoking and/or oral contraceptives (OCs) affect the CD40/CD40L plasma levels and expression in young females without other risk factors for atherosclerosis. PATIENTS AND METHODS: A case-control single-center design was used. Expression levels of CD40/CD40L were analyzed in healthy non-pregnant, pre-menopausal, non-smoking women who did not take OCs (n=49), women who currently smoke and take OCs (n=40), and women who are only smokers (n=40) or currently take OCs (n=42). RESULTS: In OC users, there was a significant increase in CD40 mRNA expression in circulating monocytes as compared with smokers and control group. However, there were no significant differences in CD40 mRNA expression in monocytes between smokers and non-smokers. Interestingly, CD40 mRNA expression in women taking OCs and currently smoking was significantly decreased compared to only OC users (p<0.001). With regard to plasma CD40 levels there were significant differences between OC-users and control group. However, contrary to our expectations, there were no significant differences in expression levels of CD40L between four groups. In vitro experiments demonstrated enhanced CD40 mRNA and surface expression in human monocyte-derived macrophages stimulated with estrogens. Furthermore, nicotine pretreatment led to a suppression of estrogens stimulated CD40 induction. CONCLUSIONS: In young healthy females without additional risk factors for atherosclerosis, OCs, but not smoking, are associated with dramatic changes in CD40 gene and plasma levels. These findings may be providing an important link between OCs and enhancement of pro-inflammatory and atherothrombotic conditions in healthy women.

Regulation of monocyte/macrophage function by factor VII activating protease (FSAP).

OBJECTIVE: Factor VII activating protease (FSAP) is a novel regulator of vascular inflammation and hemostasis. However, the molecular mechanism by which circulating FSAP influences inflammatory events and progression of atherosclerosis is not yet entirely understood. Here we have investigated the influence of FSAP on monocyte/macrophage functions. METHODS: We stimulated human monocyte-derived macrophages with FSAP and analyzed their cellular responses. RESULTS: FSAP induced IκB-dependent NF-κB activation in a time- and concentration-dependent fashion. FSAP also activated the phosphorylation and proteolytic degradation of the inhibitor protein IκBα. The phosphorylation of the p65 subunit of NF-κB was induced by FSAP, which is known to contribute to the enhancement of DNA-binding activity of NF-κB. Concomitantly, FSAP up-regulated the expression of pro-inflammatory cytokines, matrix metalloproteinases, cell adhesion molecules and tissue factor. In the presence of FSAP there was increased monocytes adhesion and transendothelial migration in a beta2 integrin dependent manner. CONCLUSIONS: Our findings suggest that FSAP activates the NF-κB pathway and the associated downstream pro-inflammatory factors in monocytic cells. This adds to a spectrum of FSAP effects on the vascular system that may explain its association with cardiovascular diseases.

Nicotine modulation of factor VII activating protease (FSAP) expression in human monocytes.

AIM: Factor VII activating protease (FSAP) is a plasma serine protease involved in hemostasis and remodeling processes. Increased levels of circulating FSAP during pregnancy and in women using oral contraceptives (OCs) indicate that the hormonal status critically influences FSAP expression. In this respect, the aim of this study was to quantify nicotine modulation of FSAP expression in human monocytes/macrophages isolated from healthy female smokers and non-smokers, and from women who use OCs and smoke. METHODS: FSAP concentration and activity were measured in plasma samples obtained from healthy non-pregnant, pre-menopausal, non-smoking women who did not use OCs (n=69), non-pregnant, pre-menopausal women who currently smoke and use OCs (n=43), and women who are only smokers (n=40) or currently use OCs (n=48). Expressions of FSAP mRNA and protein in monocytes isolated from healthy non-pregnant female or healthy male donors were analyzed. RESULTS: Strongest circulating FSAP concentration and activity occurred in women with combined smoking and use of OCs compared to the control group. Enhanced FSAP levels were also observed in smoking women when compared to non-smokers. Ex vivo experiments demonstrated enhanced FSAP expression in monocytes isolated from women using OCs and currently smoking. Nicotine enhanced FSAP mRNA and protein levels in monocytes. CONCLUSIONS: Monocytes from healthy female smokers show a constitutively enhanced FSAP expression and this effect could be replicated in vitro by stimulating monocytes with nicotine. The upregulation of FSAP due to nicotine and OC usage may be linked to a higher incidence of arteriothromboembolic diseases related to their usage.

Tako-tsubo cardiomyopathy in a 92-year old woman.

Tako-Tsubo cardiomyopathy (TTC) is an acute reversible cause of segmental myocardial dysfunction that is poorly understood and cannot be explained by the occlusion of a single coronary vessel. Its clinical presentation is similar to that of acute coronary syndrome and is often precipitated by a severe psychological or physical stress.

Factor seven ativating potease (FSAP) levels during normal pregnancy and in women using oral contraceptives.

INTRODUCTION: Factor seven activating protease (FSAP) is a plasma serine protease involved in haemostasis and remodeling processes. We have investigated whether pregnancy or the use of oral contraceptives (OCs) influences circulating FSAP levels. The effect of female sex hormones on FSAP expression in cultured cells was also determined. MATERIALS AND METHODS: FSAP levels and activity was measured in plasma samples obtained at different gestation stages from healthy pregnant women (n=101), from non-pregnant women, pre-menopausal women who currently use OCs (n=48), and non-pregnant women who did not use OCs (n=69). RESULTS: In late pregnancy the plasma FSAP antigen (median 2.28 PEU/ml [range 1.11 to 2.62 PEU/ml]; p<0.001 vs control group) and activity (median 2.98 PEU/ml [range 1.05 to 4.24 PEU/ml]; p<0.001 vs control group) was significantly higher compared with levels in non-pregnant women and remained elevated after delivery. Plasma FSAP levels in women using OCs was also significantly elevated compared to the control group. Ex vivo experiments demonstrated enhanced FSAP expression in monocytes isolated from women using OCs. In vitro experiments showed that FSAP mRNA levels were strongly induced by estradiol in monocytes but not in hepatocytes. CONCLUSIONS: Increased levels of circulating FSAP in pregnancy and in women using OCs indicate that hormonal status critically influences FSAP expression. Hormonal influences could be observed in monocytes in vivo and ex-vivo but not in hepatocytes indicating cell-specific regulation. Future studies designed to investigate the role of FSAP in haemostasis and remodeling processes should consider the role of female sex hormones on FSAP expression.

Factor Seven Activating Protease (FSAP) expression in human monocytes and accumulation in unstable coronary atherosclerotic plaques.

OBJECTIVE: The Factor Seven Activating Protease (FSAP) is known to influence fibrinolysis and to play a critical role in the inhibition of vascular smooth muscle cell (VSMC) proliferation and migration as well as neointima formation. In order to define the role of FSAP in vascular pathophysiology we have investigated the expression of FSAP protein and mRNA in human vascular cells and coronary atherosclerotic plaques with defined clinical features. METHODS AND RESULTS: Directional coronary atherectomy (DCA) specimens from 40 lesions were analyzed for FSAP antigen and mRNA expression. Higher level of FSAP mRNA (p<0.001) as well as FSAP immunostaining (p<0.005) was observed in patients with acute coronary syndromes compared to patients with stable angina pectoris. FSAP antigen was found to be focally accumulated in hypocellular and lipid-rich areas within the necrotic core of atherosclerotic plaques. FSAP was also co-localized with CD11b/CD68 expressing cells in macrophage-rich shoulder regions of the plaques. Monocyte-derived macrophages expressed FSAP in vitro and this was further induced by pro-inflammatory mediators. CONCLUSIONS: FSAP accumulation in coronary atherosclerotic lesions is due to either local synthesis by monocytes/macrophages, or uptake from the plasma due to plaque hemorrhage. The higher expression of FSAP in unstable plaques suggests that it may destabilize plaque through reducing VSMC proliferation/migration and altering the hemostatic balance.