Obstructive sleep apnea (OSA), characterized by partial or complete occlusion of the pharynx during sleep, results in persistent inspiratory effort and interruption of airflow. During each episode of apnea, OSA patients develop increased transmural pressure in the aortic wall. Accordingly, to test the hypothesis that the presence of OSA would be associated with greater thoracic aortic size, we prospectively assessed 150 consecutive patients, newly referred to the sleep clinic in our institution, in a crosssectional study to confirm OSA. The patients underwent sleep study and chest computed tomography (CT)-derived thoracic aortic diameter. In this particular period, a chest CT was performed within 3 months of the sleep study upon informed consent to our protocol. Exclusion criteria included: 1) prior history of aortic dissection, aortic valvular disease, and clinical characteristics of Marfan's syndrome; 2) central sleep apnea; 3) treatment for sleep apnea; and 4) dialysis. The outer diameter of the ascending aorta was measured by caliper within the CT image. Overnight sleep study was performed using cardiopulmonary monitoring (Morpheus, Teijin Inc., Tokyo, Japan). The apnea-hypopnea index (AHI) was quantified as the frequency of apneas and hypopneas per hour of bed time. OSA was defined as AHI Ն10/h. The data are presented as mean Ϯ SD or frequencies. To determine the independent factors, the multiple linear regression model with backward elimination technique was used, including older age, male gender, blood pressure, hypertension, dyslipidemia, diabetes mellitus, ischemic heart disease, smoking, and AHI. Comparisons between the 2 groups were performed by Student t test for the unadjusted aortic diameter and by analysis of covariance for the adjusted aortic diameter.The patients' mean age was 60 Ϯ 11 years; 125 (83%) were men, with mean body mass index of 24.7 Ϯ 3.1 kg/m 2 . Fifty-nine percent of patients had hypertension. At assessment, 91% of patients had already taken prescribed antihypertensive medications. One hundred ten patients (73%) had OSA. On univariate analysis, older age, male gender, body mass index, systolic blood pressure, pulse pressure, hypertension, dyslipidemia, ischemic heart disease, and AHI were positively correlated with thoracic aortic size. On multivariate analysis, older age (per 10-year increase, coefficient 1.82, 95% confidence interval [CI]: 1.13 to 2.34, p Ͻ 0.001), male gender (coefficient 3.25, 95% CI: 1.63 to 4.87, p Ͻ 0.001), and AHI (per 10-event/h increase, coefficient 0.62, 95% CI: 0.25 to 0.98, p Ͻ 0.001) remained as factors associated with greater thoracic aortic diameter. Contrarily, there was no significant independent relationship between blood pressure/hypertension and thoracic aortic size. Additionally, patients with OSA had a significantly greater thoracic aortic size than those without OSA (p Ͻ 0.001) (Fig. 1), even if adjusted for older age and male gender (p Ͻ 0.001).Increased thoracic aortic size is known to be related to aging, male, genetic mutation including M...
Objective-Statins reduce cardiovascular-related morbidity and mortality, but their effects on inflammation in atherosclerosis are not fully understood. We investigated whether statins can modulate cytotoxic functions of CD4 T cells in acute coronary syndrome (ACS).Methods and Results-Fresh CD4 T cells were isolated from 55 patients with ACS without statin treatment on admission and from 34 age-matched controls. CD4 T cells collected from ACS patients induced endothelial cell apoptosis significantly more than control T cells. The TNF-related apoptosisinducing ligand (TRAIL) receptor DR5 was strongly upregulated on endothelial cells, and TRAILspecific antibodies effectively blocked CD4 T cell-mediated apoptosis, indicating that T cellmediated endothelial death was dependent on the TRAIL pathway. Expression of both the activating antigen CD69 and TRAIL was enhanced on ACS T cells. In in-vitro assays rosuvastatin, fluvastatin, and pitavastatin directly blocked CD4 T cell-mediated endothelial cell apoptosis and reduced T cellexpression of CD69 and TRAIL through TCR-induced Extracellar signal-Regulated Kinases (ERK) activation.Conclusions-Activated CD4 T cells expressing TRAIL are enriched in the blood of ACS patients and induce endothelial injury, which may contribute to the destabilization of the plaque. Early statin therapy may suppress T cell-mediated endothelial cell damage in atherosclerotic plaques and thus prevent cardiovascular events.
Aim: Menopause and subsequent estrogen deficiency correlate with the development of atherosclerosis and cardiovascular diseases in women. However, the relationship between estrogen deficiency and development of atherosclerosis with inflammatory infiltrates is not fully understood. We sought to determine whether perimenopausal women (PMW) exhibited T cell dysfunction related to the expression of adhesion molecules and accelerated endothelial cell (EC) apoptosis. Methods: Fresh CD4 T cells were isolated from 48 PMW and 54 healthy control women with regular menstrual cycles (CW), and investigated cytotoxicity to ECs by apoptosis assay. The adhesion molecules on CD4 T cells were examined by flow cytometry. CD4 T cell rolling and adhesion on ECs were analyzed by adhesion assay under laminar flow. Results: CD4 T cells from PMW with low estradiol levels induced significant EC apoptosis (P 0.0152). Furthermore, cytotoxic CD4 T cells from PMW strongly expressed P-selectin glycoprotein ligand-1 (PSGL-1) and integrin 2 (P 0.0001 and P 0.0285, respectively) but not L-selectin or integrin M when compared to CD4 T cells from CW. Estradiol levels negatively correlated with only PSGL-1 expression (R 0.781, P 0.0002), and estradiol treatments inhibited both PSGL-1 expression (P 0.0133) and T cell-induced EC apoptosis (P 0.018). An estrogen receptor antagonist inhibited these effects of estradiol (P 0.0355 and P 0.0097, respectively). Moreover, PSGL-1 expression correlated with T cell adhesion to ECs under laminar flow conditions (R 0.636, P 0.0355) and with EC apoptosis (R 0.614, P 0.0196). PSGL-1 specific antibodies effectively suppressed T cell adhesion (P 0.0057) and EC apoptosis (P 0.001) indicating that CD4 T cell-mediated EC apoptosis depended on PSGL-1 adhesion in PMW. Conclusions: PSGL-1-expressing cytotoxic CD4 T cells are abundant in PMW with low estradiol levels may contribute to T cell-mediated atherosclerotic development.
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Background: Apoptosis of vascular smooth muscle cells and endothelial cells in the fibrous cap is prone to plaque vulnerability. Recently, we found that CD4 T cells trigger the TRAIL/TRAIL receptor 2 (DR5) pathway and cause VSMC apoptosis in acute coronary syndrome (ACS). We also showed that activated plasmacytoid dendritic cells (pDC) produce INFα through TRL9 and amplify cytotoxic CD4 T cell functions by enhancing TRAIL expression. In this study, we examined whether soluble TRAIL (sTRAIL) in peripheral blood shows changes in ACS that may serve as predictive marker of vulnerable patients. Methods and Results: The sTRAIL levels were measured by ELISA in 110 patients undergoing coronary angiography, including 90 ACS patients and 20 chest pain syndrome patients without apparent coronary atherosclerosis. Fresh CD4 T cells were isolated from the peripheral blood of patients. The sTRAIL levels were lower in ACS than in controls (P<0.001). CD4 T cells capable of inducing HUVEC apoptosis expressed high levels of TRAIL in ACS patients (P<0.03), and negatively correlated with the sTRAIL levels (R=0.372, P<0.02). To examine whether sTRAIL levels could be used as marker of vulnerable patients with ACS, we measured sTRAIL levels in the time course and compared them with CPK and TnT after onset of ACS. While CPK and TnT of acute myocardial infarction elevated in the acute phase and recovered after 3days, sTRAIL showed negative parallel changes. Meanwhile, sTRAIL showed the same changes in unstable angina without CPK and TnT elevation. The levels of sTRAIL more decreased in patients with multiple coronary artery stenosis than in that without coronary artery stenosis while the levels of hsCRP did not. Furthermore, given a cutoff value of 48.6pg/ml, sTRAIL was able to discriminate ACS from control groups with sensitivity of 62.4%, specificity of 85.0%, and area under the receiver-operating characteristic curve (AUC) of 0.736. In contrast, an hsCRP cutoff value of 1.25mg/l showed lower sensitivity (47.3%), specificity (77.8%), and AUC (0.597) for the diagnosis of ACS. Conclusions: Monitoring of TRAIL levels in ACS patients with both acute myocardial infarction and unstable angina was found useful in predicting vulnerability in patients with vulnerable plaques.
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