Long-Term Outcomes of Patients with Self-Expandable Transcatheter Heart Valve Embolized in the Aorta.

This study assesses the long-term outcomes of patients who suffered from self-expandable transcatheter heart valve (THV) embolized in the aorta in transcatheter aortic valve implantation (TAVI).We retrospectively reviewed the patients with self-expandable THV embolized in the aorta. Follow-up computed tomography was performed to assess the THV migration, struct fractures, and device-related aortic complications.Of the 539 TAVI patients, 11 suffered from self-expandable THV embolized in the aorta. Two patients underwent open-heart surgery to remove the embolized THVs in the ascending aorta. Embolized THVs were repositioned in the aortic arch distal to the left subclavian artery (n = 3) and the thoracic descending aorta (n = 6). Three patients died during a median follow-up time of 40 months. The remaining eight survivors presented with New York Heart Association functional class I or II at the last follow-up. Degeneration of embolized prostheses with thick leaflets and rolled cusp edges was observed in three patients. There was no evidence of valve migration, strut fracture, prosthesis-associated aortic complication, and thrombosis attached on embolized valve for all patients with THVs repositioned in the aorta.Self-expandable THV embolization can be effectively managed in TAVI. Although some embolized valves exhibited leaflet degeneration, the long-term safety of repositioning embolized self-expandable THV in the aorta is assured.

Focal adhesion kinase mediated signaling on atrial fibrosis in patients with valvular atrial fibrillation / 中国胸心血管外科临床杂志

@#Objective To explore the changes of focal adhesion kinase (FAK) in the fibrotic atrium of patients with valvular atrial fibrillation and explore its downstream signaling pathways. Methods A total of 45 patients with mitral valve disease were included in this study and were divided into a valvular atrial fibrillation group (VAF, ≥6 months, 25 patients) and a sinus rhythm group (SR, 20 patients) based on having atrial fibrillation or not. The atrial appendage tissue was obtained during the operation , histopathological examination and Western blotting were performed. The degree of atrial fibrosis and changes in FAK and its downstream pathways in fibrotic myocardium were observed. Results This study revealed a higher degree of atrial fibrosis in valvular atrial fibrillation and disordered cell arrangement. Expression of fibroblast differentiation marker alpha smooth muscle actin (α-SMA) was significantly increased in atrial fibrillation, and the expression of FAK and downstream AKT/S6K pathway proteins was up-regulated, while the other signal was observed, there was no significant change in ERK1/2 signaling pathway. Conclusion Atrial fibrosis in valvular atrial fibrillation is an important feature of atrial structural remodeling. We found overproduction of collagen fibers disrupted the continuity of atrial myocytes, leading to abnormal conduction and providing a matrix environment for the development of atrial fibrillation. The expression of focal adhesion kinase and downstream AKT/S6K signaling pathway in fibrotic myocardium may be involved in the process of atrial fibrosis, providing a basis for the study of its mechanism.

Influence of fog on the signal to interference plus noise ratio of the imaging laser radar using a 16-element APD array.

This paper investigates the signal to interference plus noise ratio (SINR) performance of the imaging laser radar (ILR) system operating at a wavelength of 905 nm using an avalanche photodiode array under the fog condition. We analysis the glow image of the light source, which is formed by the laser spot irradiated on a standard Lambertian target. Based on the proposed theoretical model, we determine the interference due to the glow inter-channel crosstalk under different fog conditions for a targeted channel. We show that, for transmission spans less than several tens of meters the interference due to glow crosstalk is higher than the fog (light to medium) induced losses. However, for a link range longer than 21 m the glow crosstalk induced interference is lower than the heavy fog induced attenuation. The proposed system performance is evaluated by developing an experimental test bed and using a dedicated indoor atmospheric chamber under homogeneously controlled fog conditions. We show that, under different fog conditions experimental results for changing SINR levels match well with the predicted data. The results shown can be used for design optimization of the ILR system when operated under fog conditions.

Imaging transparent intact cardiac tissue with single-cell resolution.

We developed a new method, SUT (Scheme Update on tissue Transparency), to view cardiac microstructures and unveil the molecular changes underlying cardiac diseases. SUT is an effective method to clear whole-hearts from different species. Over the course of 4 - 6 days we obtained transparent whole-layer left ventricular tissues from mice with only an approximate 1% protein loss. In addition, EAL (Electrophoretic Antibody Labeling) was used to achieve fast antibody labeling by electric force, which significantly reduced antibody incubation time from days to hours. SUT, together with EAL and modern imaging techniques, were successfully used to visualize three-dimensional spatial distribution of various molecules in cardiac tissue. We also observed changes in the number and phenotypes of fibroblasts during post-myocardial infarction in a stereoscopic pattern. We believe that our technique opens a new avenue to explore the mechanisms underlying cardiac diseases.

Targeted inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis and Preserves Heart Function in Adverse Cardiac Remodeling.

Cardiac fibrosis in post-myocardial infarction (MI), seen in both infarcted and non-infarcted myocardium, is beneficial to the recovery of heart function. But progressively pathological fibrosis impairs ventricular function and leads to poor prognosis. FAK has recently received attention as a potential mediator of fibrosis, our previous study reported that pharmacological inhibition of FAK can attenuate cardiac fibrosis in post MI models. However, the long-term effects on cardiac function and adverse cardiac remodelling were not clearly investigated. In this study, we tried to determine the preliminary mechanisms in regulating CF transformation to myofibroblasts and ECM synthesis relevant to the development of adverse cardiac remolding in vivo and in vitro. Our study provides even more evidence that FAK is directly related to the activation of CF in hypoxia condition in a dose-dependent and time-dependent manner. Pharmacological inhibition of FAK significantly reduces myofibroblast differentiation; our in vivo data demonstrated that a FAK inhibitor significantly decreases fibrotic score, and preserves partial left ventricular function. Both PI3K/AKT signalling and ERK1/2 are necessary for hypoxia-induced CF differentiation and ECM synthesis; this process also involves lysyl oxidase (LOX). These findings suggest that pharmacological inhibition of FAK may become an effective therapeutic strategy against adverse fibrosis.

Inhibition of osteopontin reduce the cardiac myofibrosis in dilated cardiomyopathy via focal adhesion kinase mediated signaling pathway.

BACKGROUND: Osteopontin (OPN) is a pleiotropic cytokine, which has been shown to a close relationship with cardiac fibrosis. Overexpression of OPN in cardiomyocytes induces dilated cardiomyopathy (DCM). This research is to study whether inhibition of OPN could reduce myocardial remodelling in DCM, and if this process is focal adhesion kinase (FAK) dependent, which is recently found an important signal molecule in fibrosis. METHOD: Eight-week-old cTnTR141W transgenic mouse of DCM were injected with OPN-shRNA in left ventricular free wall, which could inhibit the OPN expression. Six weeks later, echocardiographic examinations were performed to test left ventricle function and heart tissues were harvested to test the quality of FAK by western blot and severity of fibrosis by masson staining. Human cardiac fibroblast was administrated with OPN, and FAK inhibition by PP2 was treated 2 h before OPN was given. Expression of α-SMA and collagen-I were tested by western blot and real-time PCR assay. RESULTS: OPN-shRNA group has a relatively high ejection fraction (EF), fractional shortening (FS), LV free wall thickness and a less sever cardiac fibrosis. In vitro, OPN could increase collagen-I and α-SMA expression, and this process can be inhibited by FAK inhibitor. CONCLUSION: Inhibition of OPN could reduce the LV remodeling and dysfunction in DCM mice, which may attribute to the suppression of collagen-I secretion in fibroblast through a FAK/Akt dependent pathway.

Dilatation of the initially non-aneurysmal ascending aorta after replacement of a bicuspid versus tricuspid aortic valve.

Objective To compare the aortic diameter after isolated aortic valve replacement (AVR) in patients with a bicuspid (BAV) or tricuspid aortic valve (TAV) and an initially normal ascending aorta. Methods Patients with an ascending aortic diameter of < 45 mm who had undergone isolated AVR were studied. Ultrasonic cardiographic measurements of the ascending aortic diameter made pre- and postoperatively and follow-up data concerning adverse aortic events and death were analyzed. Results A total of 613 patients were included in this retrospective study; of these, 211 had a BAV and 402 had a TAV. In both groups, the ascending aorta significantly expanded but was non-aneurysmal during follow-up; however, the difference between the two groups was not significant. Cox regression analysis showed no significant effect associated with the presence of a BAV on adverse aortic events or death. Conclusion Dilatation of the ascending aorta was observed after AVR in both groups, but was not more pronounced in patients with a BAV. Long-term follow-up for ascending aortic aneurysm is necessary after AVR in both patients with a BAV and those with a TAV.

Pharmacological Inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis in Mice Cardiac Fibroblast and Post-Myocardial-Infarction Models.

BACKGROUND: To investigate the role of focal adhesion kinase (FAK)-mediated signaling in hypoxia-induced cardiac fibroblasts (CFs) differentiation and cardiac fibrosis post-myocardial infarction (MI) on a mice model. METHODS: CFs of neonatal C57BL/6 mice were treated under normoxic, hypoxic, or hypoxic+PP2 (known as a Src kinase family inhibitor) conditions. Gene expressions of FAK, alpha-smooth muscle actin (α-SMA) and collagen type I alpha 1 (Col1α1), or α-SMA and vimentin levels were performed by RT-PCR and immunofluorescence staining, respectively. Thirty mice were surgically treated into Sham (n=7) and MI (n=23) groups; and FAK inhibitor PF-562271 was given to six survivor MI mice (as PF group, from 15 survivors). Heart function and collagenous tissues were examined by echocardiography, as well as by Masson's trichrome and Sirius red staining, respectively. Type I collagen, FAK protein, mTOR, ERK1/2, AKT, P70S6K and phospho-FAK levels were also analyzed. RESULTS: FAK inhibition with PP2 significantly decreased CFs differentiation and collagen synthesis under hypoxia treatment. In vivo, PF-562271 treatment resulted in fibrosis attenuation; however, deteriorated heart function of MI mice could not be significantly improved. PF-562271 may affect phospho-mTOR (p<0.05), phospho-ERK1/2 (p<0.01), phospho-AKT (p<0.001) and phospho-P70S6K (p<0.05) to exert its benefits. FAK can be activated either under hypoxia in CFs or MI in a mouse model to promote fibrosis. However, pharmacological inhibition of FAK can attenuate fibrosis response. CONCLUSION: This study provides novel evidence that FAK inhibition may become a promising pharmaceutical strategy to attenuate fibrosis post-MI.

Focal adhesion kinase mediates atrial fibrosis via the AKT/S6K signaling pathway in chronic atrial fibrillation patients with rheumatic mitral valve disease.

BACKGROUND: Atrial fibrosis, as a hallmark of atrial structural remodeling, plays a critical role in the maintenance of chronic atrial fibrillation (AF), but the mechanisms responsible for atrial fibrosis are still uncertain. Fibrogenesis represents a complex process in which focal adhesion kinase (FAK) plays an important role. Therefore, we investigated the role of FAK-mediated signaling in atrial fibrosis in patients with chronic AF related to rheumatic mitral valve disease (RMVD). METHODS: Atrial appendages were excised from 45 patients with RMVD and either chronic AF (n=25, AF >6 months) or sinus rhythm (n=20). Fibrosis was assessed by histology, and FAK and its two downstream pathways (AKT/S6K and ERK1/2) were evaluated by western blotting. We further evaluated the role of FAK in fibrogenesis by culturing neonatal rat cardiac fibroblasts to determine the importance of FAK-regulated signaling in cardiac myofibroblast differentiation induced by transforming growth factor-ß1 (TGFß1). RESULTS: Our study revealed that FAK can regulate its downstream signaling to cause fibrosis in atrial tissue and activate isolated fibroblasts. Histology revealed a significant increase in atrial fibrosis in AF patients. The phosphorylation of FAK and its downstream AKT/S6K signaling was increased secondary to TGFß1-induced high expression of α-SMA, a marker of myofibroblast activity. FAK and AKT inhibitors suppressed α-SMA expression in TGFß1-induced fibroblasts. However, ERK1/2 signaling seemed to be unrelated to the fibrotic process in AF patients. CONCLUSION: The FAK-mediated AKT/S6K signaling pathway participated in atrial fibrogenesis and this finding may contribute to the prevention of atrial fibrosis associated with chronic AF in patients with underlying cardiac disease.

Protein analysis of atrial fibrosis via label-free proteomics in chronic atrial fibrillation patients with mitral valve disease.

BACKGROUND: Atrial fibrosis, as a hallmark of atrial structure remodeling, plays an important role in maintenance of chronic atrial fibrillation, but interrelationship of atrial fibrosis and atrial fibrillation is uncertain. Label-free proteomics can implement high throughput screening for finding and analyzing pivotal proteins related to the disease.. Therefore, we used label-free proteomics to explore and analyze differentially proteins in chronic atrial fibrillation patients with mitral valve disease. METHODS: Left and right atrial appendages obtained from patients with mitral valve disease were both in chronic atrial fibrillation (CAF, AF≥6 months, n = 6) and in sinus rhythm (SR, n = 6). One part of the sample was used for histological analysis and fibrosis quantification; other part were analyzed by label-free proteomic combining liquid chromatography with mass spectrometry (LC-MS), we utilized bioinformatics analysis to identify differential proteins. RESULTS: Degree of atrial fibrosis was higher in CAF patients than that of SR patients. 223 differential proteins were detected between two groups. These proteins mainly had vital functions such as cell proliferation, stress response, focal adhesion apoptosis. We evaluated that serine/threonine protein kinase N2 (PKN2), dermatopontin (DP), S100 calcium binding protein B (S100B), protein tyrosine kinase 2 (PTK2) and discoidin domain receptor tyrosine kinase 2 (DDR2) played important roles in fibrotic process related to atrial fibrillation. CONCLUSION: The study presented differential proteins responsible for atrial fibrosis in chronic atrial fibrillation patients through label-free proteomic analysis. We assessed some vital proteins including their characters and roles. These findings may open up new realm for mechanism research of atrial fibrillation.

Co-application of ricin A chain and a recombinant adenovirus expressing ricin B chain as a novel approach for cancer therapy.

AIM: To develop a novel ricin-based approach for the safe and effective therapy of cancer. METHODS: The ricin A chain (RTA) was expressed in Escherichia coli in the form of a 6XHis-tagged fusion protein and purified with Ni(2+)-NTA affinity resin. A replication-deficient ricin B chain (RTB)-expression adenovirus green fluorescence protein (AdGFP-RTB) was constructed. RTA and AdGFP-RTB were tested for cytotoxicity either individually or in combination in human cell lines HEK293, HeLa, SMMC7721, and HL7702. Cell viability was determined with trypan blue staining or MTT assay. RESULTS: The expression and release of RTB, as well as the entry of RTA into AdGFP-RTB-infected cells were confirmed. When RTA and AdGFP-RTB was used individually, neither was toxic to the cells. When they were applied together, significant cell death was observed in all of the cell lines tested. The cell-killing effect correlated with the amount of RTA protein used, with cell mortality at about 60% at 4.8 mu g RTA in combination with AdGFP-RTB at 100 pfu/cell. No major cell killing was seen when RTA was used in combination with a control adenovirus AdGFP. The treatment of healthy HeLa cells with the virusfree supernatant from AdGFP-RTB/RTA-treated HeLa cells resulted in cell death, suggesting the formation of RTA/RTB complex, and a potential by-stander effect. CONCLUSION: The new approach was successful in vitro. Further modifications of the adenovirus vector, as well as an in vivo study are needed to confirm its potential in cancer therapy.

[Antitumor effect of recombinant T7 phage vaccine expressing xenogenic vascular endothelial growth factor on Lewis lung cancer in mice].

BACKGROUND & OBJECTIVE: Angiogenesis plays an important role in growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) is considered as a fundamental regulator for angiogenesis. This study was to construct a recombinant T7 phage vaccine expressing xenogenic VEGF on the capsid, and test its inhibitory effect on Lewis lung cancer cells in mice. METHODS: VEGF gene was cloned by reverse transcription-polymerase chain reaction (RT-PCR) from human lung cancer tissues, and inserted into phage using T7 Select10-3b kit to construct T7 Select10-3b_VEGF vaccine. The titer of prepared phage reached 1x10(13) pfu/ml. C57BL/6J mice were randomly divided into 3 groups: T7 Select10-3b_VEGF vaccine group (T7-VEGF), T7 phage (T7) group, normal saline (NS) group (10 mice/group). Each mouse was injected with Freundos adjuvant mixed with 1x10(12) pfu/200 microl T7 Select10-3b_VEGF, or T7, or normal saline once a week for 4 weeks. Lewis lung carcinoma model (LL/2) was established in C57BL/6J mice after 4-week immunization. Tumor growth and mouse's physical status were observed during immunization. Tumor weight and serum level of specific anti-VEGF antibody were measured by enzyme-linked immunosorbent assay (ELISA). Microvessel density (MVD) of tumors was detected by immunohistochemistry 14 days after the inoculation of tumor cells. RESULTS: Tumor weight of T7-VEGF vaccine group,T7 group, and NS group were (0.543+/-0.259)g, (0.982+/-0.359)g, (1.169+/-0.460)g, respectively. Tumor weight of T7-VEGF vaccine group was significantly lower than that of NS group (P<0.01). Serum anti-VEGF antibody level in T7-VEGF vaccine group was 1:1,000. MVD was significantly lower in T7-VEGF vaccine group than in NS group (8.5+/-0.8 vs 18.5+/-1.6, P<0.05). MVD in T7 group was 16.4+/-1.3. CONCLUSION: Recombinant T7 phage vaccine expressing xenogenic VEGF can break immunologic tolerance against self-VEGF and inhibit the growth of Lewis lung cancer cells.