Mindfulness-based intervention in patients with persistent pain in chest (MIPIC) of non-cardiac cause: a feasibility randomised control study.

OBJECTIVE: The study evaluated the feasibility of mindfulness-based cognitive therapy (MBCT) in patients with non-cardiac chest pain by assessing their willingness to participate and adhere to the programme, and for these data to help further refine the content of MBCT for chest pain. PATIENTS AND METHODS: This prospective 2:1 randomised controlled trial compared the intervention of adapted MBCT as an addition to usual care with just usual care in controls. Among 573 patients who attended the rapid access chest pain clinic over the previous 12 months and were not diagnosed with a cardiac cause but had persistent chest pain were invited. The intervention was a 2-hour, weekly, online guided 8-week MBCT course. Compliance with attendance and the home practice was recorded. Enrolled patients completed the Seattle angina questionnaire (SAQ), Hospital Anxiety and Depression Scale, Cardiac Anxiety Questionnaire, Five-Facet Mindfulness Questionnaire, and Euro Quality of Life-5 Dimensions-5 Level at baseline assessment and after 8-week period. RESULTS: Persistent chest pain was reported by 114 patients. Of these, 33 (29%) patients with a mean age of 54.2 (±12.2) years and 68% women, consented to the study. Baseline questionnaires revealed mild physical limitation (mean SAQ, 76.8±25), high levels of anxiety (76%) and depression (53%), modest cardiac anxiety (CAQ,1.78±0.61) and mindfulness score (FFMQ, 45.5±7.3). Six patients subsequently withdrew due to bereavement, caring responsibilities and ill health. Of the remaining 27 participants, 18 in the intervention arm attended an average of 5 sessions with 61% attending ≥6 sessions. Although not statistically powered, the study revealed a significant reduction in general anxiety, improved mindfulness and a trend towards improvement in SAQ scores in the intervention arm. CONCLUSION: One-third of patients with persistent non-cardiac chest pain were willing to participate in mindfulness-based therapy. An improvement in anxiety and mindfulness was detected in this feasibility study. A larger trial is required to demonstrate improvement in chest pain symptoms.

Inconsistency in aortic stenosis severity between CT and echocardiography: prevalence and insights into mechanistic differences using computational fluid dynamics.

Objectives: The aims of this study were to evaluate the inconsistency of aortic stenosis (AS) severity between CT aortic valve area (CT-AVA) and echocardiographic Doppler parameters, and to investigate potential underlying mechanisms using computational fluid dynamics (CFD). Methods: A total of 450 consecutive eligible patients undergoing transcatheter AV implantation assessment underwent CT cardiac angiography (CTCA) following echocardiography. CT-AVA derived by direct planimetry and echocardiographic parameters were used to assess severity. CFD simulation was performed in 46 CTCA cases to evaluate velocity profiles. Results: A CT-AVA>1 cm2 was present in 23% of patients with echocardiographic peak velocity≥4 m/s (r=-0.33) and in 15% patients with mean Doppler gradient≥40 mm Hg (r=-0.39). Patients with inconsistent severity grading between CT and echocardiography had higher stroke volume index (43 vs 38 mL/m2, p<0.003) and left ventricular outflow tract (LVOT) flow rate (235 vs 192 cm3/s, p<0.001). CFD simulation revealed high flow, either in isolation (p=0.01), or when associated with a skewed velocity profile (p=0.007), as the main cause for inconsistency between CT and echocardiography. Conclusion: Severe AS by Doppler criteria may be associated with a CT-AVA>1 cm2 in up to a quarter of patients. CFD demonstrates that haemodynamic severity may be exaggerated on Doppler analysis due to high LVOT flow rates, with or without skewed velocity profiles, across the valve orifice. These factors should be considered before making a firm diagnosis of severe AS and evaluation with CT can be helpful.

Myometrial contractility influences oxytocin receptor (OXTR) expression in term trophoblast cells obtained from the maternal surface of the human placenta.

BACKGROUND: Oxytocin (OXT) acts through its specific receptor (OXTR) and increased density of OXTR and/or augmented sensitivity to OXT were postulated as prerequisites of normal onset of labor. Expression of OXTR in the placental term trophoblast cells has not yet been analyzed in the context of contractile activity of the uterus. Here we examine comparatively OXT contents in the placental tissue adjacent to the uterine wall and expressions of OXTR in this tissue and corresponding isolated placental trophoblast cells. METHODS: Twenty eight placentae after normal labors at term (group I, N = 14) and after cesarean sections performed without uterine contractile activity (group II, N = 14) have been collected. Tissue excised from the maternal surface of examined placenta was used for OXT concentration measurement, cytotrophoblast cell cultures preparation and immunohistochemistry of OXTR. Concentration of OXT was estimated in the tissue homogenates by an enzyme immunoassay with colorimetric detection. Cytotrophoblast cells were isolated using Kliman's method based on trypsin, DNase, and a 5-70% Percoll gradient centrifugation. The cultures were incubated for 5 days in normoxia. Both placental specimens and terminated cytotrophoblast cultures were fixed and embedded in paraffin before being immunostained for OXTR. Using light microscopy with computed morphometry for quantitative analysis, OXTR expressions were estimated in calibrated areas of the paraffin sections. RESULTS: There were not significant differences between the groups in respect to the mean OXT concentration. However, in both groups the median value of OXT concentration was significantly (p < 0.05) higher in the tissue obtained from the peripheral regions of the maternal surface of the placenta, compared to the samples from the central region of this surface. In placental tissue the mean expression of OXTR in group I was significantly (p < 0.05) increased by approximately 3.2-fold and 3.45-fold (the samples collected from central and peripheral regions, respectively) compared to the values obtained in group II. In the isolated primary trophoblast cultures the differences were even more evident (p < 0.02) and the mean change in OXTR expression in group I comprised approximately 6.9-fold increase and 6.5-fold increase (the samples collected from central and peripheral regions, respectively) compared to the values obtained in group II. CONCLUSIONS: Upregulation of OXTR within placental trophoblast cells localized close or adherent to uterine wall may play a crucial role in labor with efficient contractile activity (vaginal delivery). Further studies may disclose if this local OXT/OXTR signaling is utilized in the third stage of labor to elicit placental detachment or contribute in a more versatile way throughout the labor period.

Computational fluid dynamic study of hemodynamic effects on aortic root blood flow of systematically varied left ventricular assist device graft anastomosis design.

OBJECTIVES: To quantify the range of blood flow parameters in ascending aorta that can result from various angulations of outflow graft anastomosis of a left ventricular assist device (LVAD) to the aortic wall, as a means to understand the mechanism of aortic valve insufficiency. METHODS: A realistic aorta model with LVAD anastomosis was generated from computed tomographic images of a patient. Based on this model, the LVAD anastomosis geometry parameters, such as anastomosis locations, inclination angle, and azimuthal angle (cross-sectional plane) of the graft, were varied, to create 21 models. With the assumption of no flow passing the aortic valve, and a constant flow rate from the LVAD cannula, computational fluid dynamics simulations were used to study the blood flow patterns in the ascending aorta. In addition, pulsatile flows were assumed in the LVAD cannula, with the aortic valve opened during peak systole, for 2 specific anastomosis configurations, to evaluate the influence of the pulsatile flow profile and the transvalvular flow on the aortic flow patterns. RESULTS: Changes in the inclination angle, from 60° to 120°, or the azimuthal angle, from 90° to 120°, or moving from a lower to a higher anastomosis position, causes significant changes for all flow parameters. A lower anastomosis location, an inclination angle ≥90°, and an azimuthal angle of 60° or 120° are all capable of reducing blood flow stagnation in the aortic root and producing normal wall shear stress and moderate pressure values in the region. CONCLUSIONS: Carefully chosen anastomosis geometry is likely to be able to generate a close-to-normal hemodynamic environment in the aortic root. Greater knowledge of aortic valve remodeling may make possible the creation of favorable flow patterns in the aortic root, through optimization of surgical design to reduce or delay the occurrence of aortic valve insufficiency.

Aspirin Action in Endothelial Cells: Different Patterns of Response Between Chemokine CX3CL1/CX3CR1 and TNF-α/TNFR1 Signaling Pathways.

PURPOSE: TNF-α induces fractalkine (CX3CL1) and its receptor CX3CR1 in endothelial cells through NF-қB activation. NF-қB inhibitors may reduce the expression of CX3CL1, and modulation of the CX3CL1/CX3CR1 signaling was proposed as a new target for aspirin. We examined the effects of aspirin on CX3CL1 and TNF-α production, as well as CX3CR1 and TNFR1 expression. METHODS: HUVECs isolated after term pregnancies (N = 28) were cultured in vitro. Lipopolysaccharide (1 µg/ml) was used as CX3CL1 inducer. HUVECs were exposed to six different concentrations of aspirin (between 1.0 and 6.0 mM) during 7 days. The levels of CX3CL1 and TNF-α in the culture media were measured using ELISA. After termination of the cultures, mean expressions of CX3CR1 and TNFR1 were examined in the immunostained paraffin sections using quantitative immunohistochemistry. RESULTS: Aspirin significantly (p < .05) decreased CX3CL1 production, and the mean decrease in CX3CL1 production was inversely proportional to increased (p < 0.05) expression of CX3CR1. The combined mean CX3CL1 concentrations, including all time points, equaled 782.18 ± 74.4 pg/ml in aspirin treated HUVECs compared to a total concentration of 2467.53 ± 127.5 pg/ml combined from the respective time points in the controls. An inhibition of TNF-α production in HUVECs after pretreatment with aspirin was observed. Unlike in the case of CX3CR1 expression, there were no signs of TNFR1 upregulation. CONCLUSIONS: Autoregulation between CX3CL1 and CX3CR1 may explain overexpression of CX3CR1 as the compensatory effect in aspirin-treated HUVECs. Inhibition of CX3CR1 could prevent thrombotic complications in the early period after discontinuation of aspirin.

Chorioamnionitis (ChA) modifies CX3CL1 (fractalkine) production by human amniotic epithelial cells (HAEC) under normoxic and hypoxic conditions.

BACKGROUND: Chemokine CX3CL1 possesses unique properties, including combined adhesive and chemotactic functions. Human amniotic epithelial cells (HAEC) show expression of CX3CL1 receptor (CX3CR1) and produce CX3CL1 in response to both physiologic and pathologic stimuli. Chorioamnionitis (ChA) is a common complication of pregnancy and labour. ChA is often accompanied by local hypoxia because of the high oxygen consumption at the site of inflammation. We examined comparatively (ChA-complicated vs. normal pregnancy) CX3CR1 expression and the effects of hypoxia, lipopolysaccharide (LPS), and CX3CR1 blockade on CX3CL1 production in HAEC cultured in vitro. METHODS: HAEC have been isolated using trypsinization, and cultured under normoxia (20% O2) vs. hypoxia (5% O2). According to the experimental design, LPS (1 µg/ml) and neutralizing anti-CX3CR1 antibodies were added at respective time points. Mean CX3CL1 concentration in the supernatant samples were determined by ELISA. Expression of immunostained CX3CR1 was analyzed using quantitative morphometry. RESULTS: We have found that the mean levels of CX3CL1 and CX3CR1 expression were remarkably (p < 0.05) higher in ChA, compared to normal pregnancy. Significantly increased expression of CX3CR1 was observed in ChA during both normoxia and hypoxia. Hypoxia exposure produced decrease in the mean concentration of CX3CL1 in both groups, however this reduction was stronger in normal pregnancy. In normoxia, LPS-evoked rise in the mean concentration of CX3CL1 was higher (p < 0.05) in normal pregnancy. This response was positively correlated with CX3CR1 expression. Blockade of CX3CR1 canceled the secretory response to LPS in all groups. CONCLUSIONS: ChA-complicated pregnancy up-regulates CX3CR1 in HAEC cultured in vitro with simultaneous increase in CX3CL1 production. Hypoxia-resistant production of CX3CL1 may be responsible for ChA-related complications of pregnancy and labor.

CX3CL1 (fractalkine) and TNFα production by perfused human placental lobules under normoxic and hypoxic conditions in vitro: the importance of CX3CR1 signaling.

OBJECTIVE: Inflammation and hypoxia activate the fractalkine (CX3CL1) receptor (CX3CR1)-related signaling pathway. Tumor necrosis factor alpha (TNFα) induces CX3CL1, influencing a mechanism of CX3CL1 autoregulation by CX3CR1 expression. We compared spontaneous and lipopolysaccharide (LPS)-induced CX3CL1 and TNFα production by human placenta under normoxic vs. hypoxic conditions, with respect to CX3CR1 expression and its functional status. METHODS: Placental lobules of term placentae (N = 24) were perfused extracorporeally. CX3CL1 and TNFα concentrations were measured in the perfusion fluid by ELISA. LPS, anti-CX3CR1 antibodies and pirfenidone were used in respective subgroups. After perfusion, CX3CR1 expression was estimated in placental tissue using quantitative immunohistochemistry, and the final results were adjusted for the mean microvascular density. RESULTS: The highest increase in CX3CL1 concentration in response to LPS was observed in hypoxia (p < 0.05). Unlike in normoxia, anti-CX3CR1 administration in hypoxia significantly reduced the LPS-evoked response. CX3CR1 expression was augmented by hypoxia and reached 260.9 ± 41 (% ±SEM) of the reference value in normoxia. Positive immunostaining for CX3CR1 corresponded to the vascular endothelium. Pirfenidone inhibited hypoxia + LPS-related increase in TNFα production and prevented the up-regulation of CX3CR1. CONCLUSION: The modulatory influence of TNFα on CX3CR1 expression in hypoxia and CX3CL1/CX3CR1 interaction may serve as a compensatory mechanism to preserve or augment the pro-inflammatory course of intercellular interactions in placental endothelium.

Fractalkine (CX3CL1) and its receptor CX3CR1 may contribute to increased angiogenesis in diabetic placenta.

Chemokine CX3CL1 is unique, possessing the ability to act as a dual agent: chemoattractant and adhesive compound. Acting via its sole receptor CX3CR1, CX3CL1 participates in many processes in human placental tissue, including inflammation and angiogenesis. Strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokines secretion, CX3CL1 may act locally as a key angiogenic factor. Both clinical observations and histopathological studies of the diabetic placenta have confirmed an increased incidence of hypoxia and inflammatory reactions with defective angiogenesis. In this study we examined comparatively (diabetes class C complicated versus normal pregnancy) the correlation between CX3CL1 content in placental tissue, the mean CX3CR1 expression, and density of the network of placental microvessels. A sandwich enzyme immunoassay was applied for CX3CL1 measurement in placental tissue homogenates, whereas quantitative immunohistochemical techniques were used for the assessment of CX3CR1 expression and the microvascular density. Significant differences have been observed for all analyzed parameters between the groups. The mean concentration of CX3CL1 in diabetes was increased and accompanied by augmented placental microvessel density as well as a higher expression of CX3CR1. In conclusion, we suggest involvement of CX3CL1/CX3CR1 signaling pathway in the pathomechanism of placental microvasculature remodeling in diabetes class C.