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Calcification of the bicuspid aortic valve (BAV) involves differential expression of various RNA genes, which is achieved through complex regulatory networks that are controlled in part by transcription factors and microRNAs. We previously found that miR-195-5p regulates the osteogenic differentiation of valvular interstitial cells (VICs) by targeting the TGF-β pathway. However, the transcriptional regulation of miR-195-5p in calcified BAV patients is not yet clear. In this study, stenotic aortic valve tissues from patients with BAVs and tricuspid aortic valves (TAVs) were collected. Candidate transcription factors of miR-195-5p were predicted by bioinformatics analysis and tested in diseased valves and in male porcine VICs. SP2 gene expression and the corresponding protein levels in BAV were significantly lower than those in TAV, and a low SP2 expression level environment in VICs resulted in remarkable increases in RNA expression levels of RUNX2, BMP2, collagen 1, MMP2, and MMP9 and the corresponding proteins. ChIP assays revealed that SP2 directly bound to the transcription promoter region of miR-195-5p. Cotransfection of SP2 shRNA and a miR-195-5p mimic in porcine VICs demonstrated that SP2 repressed SMAD7 expression via miR-195-5p, while knockdown of SP2 increased the mRNA expression of SMAD7 and the corresponding protein and attenuated Smad 2/3 expression. Immunofluorescence staining of diseased valves confirmed that the functional proteins of osteogenesis differentiation, including RUNX2, BMP2, collagen 1, and osteocalcin, were overexpressed in BAVs. In Conclusion, the transcription factor Sp2 is expressed at low levels in VICs from BAV patients, which has a negative impact on miR-195-5p expression by binding its promoter region and partially promotes calcification through a SMAD-dependent pathway.

Calcified aortic valve disease (CAVD) is a cardiovascular disease closely related to cardiovascular morbidity and mortality. Osteogenesis differentiation of valvular interstitial cells (VICs) is the key process of CAVD. In this study, we investigated whether the circulating exosomes participated in the pathogenesis and progression of CAVD and explored the underlying mechanism. We constructed the CAVD model in rats to perform in-vivo experiments, and isolated the VICs to perfume in-vitro studies. A series of methods were used including exosomes extraction and identification, RNA sequencing, ALP activity assay, alizarin red staining, qRT-PCR, western blot, and luciferase reporter assay. RNA sequencing showed that the circulating exosomes from CAVD patients and the normal people exhibited aberrant long non-coding RNA level, among which RMST was significantly upregulated in the CAVD-derived circulating exosomes and in the calcified aortic valve tissues. ALP activity assay and alizarin red staining showed that RMST promoted the VICs calcification. Luciferase reporter assay indicated that RMST acted as the miR-195-5p sponge, and miR-195-5p could target the 3’UTR of Smad7. Further functional experiments revealed that RMST was enriched in the circulating exosomes, leading to the upregulation of Smad7 in through sponging miR-195-5p to promote osteogenic differentiation in VICs. Moreover, adipose-derived exosomes showed the same effect as the CAVD-derived circulating exosomes. In conclusion, we found that circulating exosomes from CAVD patients promoted the VICs calcification through delivering the lncRNA RMST which acted as the miR-195-5p sponge to regulate the Smad7 expression. These results provided a new understanding of the molecular mechanism of the progression of CAVD. Funding: This work was supported by National Natural Science Foundation of China (grant no. 81974033). Declaration of Interest: None to declare. Ethical Approval: The present research program had been reviewed and approved by the Ethics Committee of The First Affiliated Hospital of Nanjing Medical University.

Background Porcine aortic valve (PAV) and bovine aortic valve (BAV) are commonly used in aortic valve replacement (AVR) surgeries. A detailed comparison for their hemodynamic and structural stress/strain performances would help to better understand valve cardiac function and select valve type and size for AVR outcome optimizations. Methods Eight fluid-structure interaction models were constructed to compare hemodynamic and stress/strain behaviors of PAV and BAV with 4 sizes (19, 21, 23, and 25 mm). Blood flow velocity, systolic cross-valve pressure gradient (SCVPG), geometric orifice area (GOA), flow shear stresses (FSS), and stress/strain were obtained for comparison. Results Compared with PAV, BAV has better hemodynamic performance, with lower maximum flow velocity (7.17%) and pressure (9.82%), smaller pressure gradient (mean and peak SCVPG: 8.92% and 9.28%), larger GOA (9.56%) and lower FSS (6.61%). The averages of the mean and peak net pressure gradient values from 4 BAV models were 8.10% and 8.35% lower than that from PAV models. Larger valve sizes for both PAV and BAV had improved hemodynamic performance. Maximum flow velocity, pressure, mean SCVPG and maximum FSS from 25 mm BAV were 36.80%, 15.81%, 39.05% and 38.83% lower than those from 19 mm BAV. The GOA of PAV and BAV 25 mm Valve were 43.75% and 33.07% larger than 19 mm valves, respectively. BAV has lower stress on the leaflets than PAV. Conclusions BAV had better hemodynamic performance and lower leaflets stress than PAV. More patient studies are needed to validate our findings.

OBJECTIVES Our goal was to investigate the safety and feasibility of triport periareolar thoracoscopic surgery (TPTS) and its advantages in repairing adult atrial septal defect. METHODS Between January 2017 and January 2020, a total of 121 consecutive adult patients underwent atrial septal defect closure in our institution. Of these, 30 patients had TPTS and 31 patients had a right minithoracotomy (RMT). Operational data and clinical outcomes were compared between the 2 groups. RESULTS The total operation time, cardiopulmonary bypass time and aortic cross-clamp time in the TPTS group were slightly longer than those in the RMT group, but there were no differences between the 2 groups. Compared with the RMT group, the TPTS group showed a decrease in the volume of chest drainage in 24 h (98.6 ± 191.2 vs 222.6 ± 217.2 ml; P = 0.032) and a shorter postoperative hospital stay (6.5 ± 1.5 vs 8.0 ± 3.7 days; P = 0.042). The numeric rating scale on postoperative day 7 was significantly less in the TPTS group than in the RMT group (2.82 ± 1.14 vs 3.56 ± 1.42; P = 0.034). The patient satisfaction scale for the cosmetic results in the TPTS group was significantly higher than in the RMT group (4.68 ± 0.55 vs 4.22 ± 0.76; P = 0.012). No differences were found in postoperative complications. No in-hospital death or major adverse events occurred in the 2 groups. CONCLUSIONS TPTS is safe and feasible for the closure of adult atrial septal defect. Compared with RMT, it has been associated with less pain and better cosmetic outcomes.

BACKGROUND: Stand-alone minimally invasive radiofrequency (RF) ablation with left atrial (LA) appendectomy has been an effective surgical intervention for non-paroxysmal atrial fibrillation (AF) (NPAF) in patients with a medical history of thromboembolism for secondary stroke prevention. This study sought to assess the impact of this surgery on LA function. METHODS: A total of 37 NPAF patients with a medical history of stroke or thromboembolism were enrolled in this prospective observational study, all of whom underwent stand-alone minimally RF ablation with LA appendectomy. Echocardiography was used to evaluate LA function preoperatively and 1 week and 3 months postoperatively. All patients were divided into two groups (Group AF and Group SR) according to whether sinus rhythm (SR) was restored after the surgery. RESULTS: The surgery had no impact on LA function in Group AF. Once NPAF patients were restored to SR, LA minimal volume (LAV(min)) decreased immediately compared with pre-operation (22.98±13.76 vs. 17.68±9.52 mL; P

Aims Aortic valve calcification is more prevalent in chronic kidney disease accompanied by hypercalcemia. Secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) is a regulator of BMP2 signalling, but the role of SMOC1 in aortic valve calcification under different conditions has not been studied. This study aimed to investigate the roles of SMOC1 in aortic valve calcification under normal and high calcium conditions, focusing on the effects on aortic valve interstitial cells (AVICs). Methods and results SMOC1 was expressed by aortic valve endothelial cells and secreted into the extracellular matrix in non-calcific valves and downregulated in calcific aortic valves. In vitro studies demonstrated that HUVEC secreted SMOC1 could enter the cytoplasm of AVICs. Overexpression of SMOC1 attenuated warfarin-induced AVIC calcification but promoted high calcium/phosphate or vitamin D-induced AVIC and aortic valve calcification by regulating BMP2 signalling both in vitro and in vivo. Co-immunoprecipitation revealed that SMOC1 binds to BMP receptor II (BMPR-II) and inhibits BMP2-induced phosphorylation of p38 (p-p38) via amino acids 372–383 of its EF-hand calcium-binding domain. Inhibition of p-p38 by the p38 inhibitor SB203580 blocked the effects of SMOC1 on BMP2 signalling and AVIC calcification induced by high calcium/phosphate medium. In high-calcium-treated AVICs, SMOC1 lost its ability to bind to BMPR-II, but not to caveolin-1, promoting p-p38 and cell apoptosis due to increased expression of BMPR-II and enhanced endocytosis. Conclusions These observations support that SMOC1 works as a dual-directional modulator of AVIC calcification by regulating p38-dependent BMP2 signalling transduction according to different extracellular calcium concentrations.

To explore surgical management of complex coarctation of aorta (COA) concomitant with intracardiac abnormality, in order to provide recommendations for safe and reliable treatment.Totally, six adult cases demonstrating complex COA concomitant with intracardiac abnormality were reviewed from our department between May 2012 and June 2017. Four patients were male and two patients were female, the age range being 43.8±10.6 years old. The associated intracardiac abnormality included 3 aortic root aneurysms, 3 aortic insufficiency, 1 aortic stenosis, 3 mitral regurgitation (MR), 1 coronary artery disease (CAD), 1 patent ductus arteriosus (PDA) and 1 ventricular septal defect (VSD). All patients received extra-anatomic aortic bypass approach to tackle complex COA. The extra-anatomic aortic bypasses comprised 4 ascending-descending aortic bypass grafting and 2 ascending-abdominal aortic bypass grafting. Simultaneous intracardiac abnormality repair procedures comprised 3 Bentall procedures, 1 aortic valve replacement, 3 mitral valve repairs, 1 coronary artery bypass grafting, 1 PDA repair and 1 VSD repair.There was no early or late mortality. None of the patients suffered from stroke or paraplegia. Only 1 patient received reexploration for hemostasis because of post-pericardial anastomosis bleeding. The same patient suffered from acute renal failure, but completely recovered after 7-day hemodialysis. All other patients had uneventful post-operative recoveries. The follow-up (mean 37±22.9 months) showed that all patients survived and all patients' blood pressures significantly decreased (pre-operative 165.8±16.3mmHg versus post-operative 121.5±10.8 mmHg, P0.05). All patients have significantly reduced ankle-brachial pressure gradients (pre-operative 63.3±17.2 mmHg versus post-operative 29.1±4.3 mmHg, P0.05). All aortic grafts maintained patent flow.Simultaneous management of complex COA concomitant with intracardiac abnormality is a safe and reliable surgical method.

Chronic intermittent hypoxia (CIH) is key pathological mechanism of obstructive sleep apnea (OSA), which induced cardiac dysfunction. Filamin c (FLNC) is a muscle-restricted isoform and predominantly expressed in muscle tissue. In this study, we utilized a recently developed CIH rat model to mimic OSA, investigated the expression of FLNC in cardiomyocytes, and examined the correlations of FLNC with active caspase-3 to ascertain whether FLNC regulates the survival of cardiomyocytes. Forty Sprague-Dawley rats were randomly divided into normoxia and CIH groups. All rats were exposed either to normoxia or CIH 8 h daily for 6 weeks. Echocardiogram and HE staining were used to examine cardiac pathology, structure, and function. Body weight, heart weight, and blood gas values were recorded, respectively. The FLNC, Bax, Bcl-2, BNIP 3, and active caspase-3 proteins were detected by western blot; FLNC was examined by immunohistochemistry and immunofluorescence. Association of FLNC with cardiomyocyte apoptosis was detected by immunofluorescence. CIH induced cardiac injuries and caused arterial blood gas disorder. FLNC significantly increased in CIH-induced cardiomyocytes than that in normoxia tissues. Pro-apoptotic BNIP 3 and Bax proteins were significantly increased in CIH, whereas anti-apoptotic member Bcl-2 was decreased. Active caspase-3, a universal marker of apoptosis, was significantly increased in CIH group. Co-localizations of FLNC and active caspase-3 were observed in CIH group. These results suggested FLNC is implicated in the pathogenesis of CIH-induced cardiomyocyte apoptosis, and FLNC may serve as a novel cardioprotective target for OSA patients.

The surgical treatment for aortic diseases remains a challenge for any cardiac surgeon. The use of sutureless ring connector in aortic anastomosis can simplify the procedure and shorten anastomosis time. Therefore, we developed a novel device for sutureless aortic anastomosis. A series of experiments were carried out for tensile and leakproof-capacity assessments to verify the feasibility of the ring connector by using fresh swine aorta samples. In in vivo test, the ring connector was implanted in 6 swine with follow-up of 6 months. Radiographic and pathological studies of the aorta were performed. In the tensile tests, the strength was 32.7±5.9 Newton (N) in the sutureless anastomosis group, compared with 73.3±12.5 N in the control group by traditional manual suture. In the leakproof-capacity assessment, no sign of either leakage or bursting was evident at 280 mmHg of internal pressure in the aorta samples. In in vivo tests, it took 9.47±0.3 minutes for the sutureless anastomosis, compared with 15.58±1.39 minutes for hand-sewn suturing. Insertion was easy and rapid. Radiographic and pathological studies were performed at first month, third month and sixth month after surgery, each time obtained from the two swine, showed patency of the anastomosis and no signs of stenosis, blood leakage, migration or pseudoaneurysm formation, except one paralyzed swine developed of thrombo-occlusion at the site of the sutureless anastomosis. The result indicates that this novel ring connector offers considerable promise for sutureless aortic anastomosis.

Background: Risk factors for healthcare associated infections (HAIs) following surgical repair of acute type A aortic dissection (TAAD) has not been well defined. Methods: This was a retrospective study of patients treated between Jan 2013 and May 2016 at the large tertiary teaching hospital in Jiangsu, China. Logistic regression analysis was performed to investigate the association patients with acute TAAD who underwent ascending aortic and arch replacement under deep hypothermic circulatory arrest (DHCA) and healthcare associated infections during hospitalization. Results: Of the final 210 patients with aortic dissection (AD) admitted to our hospital, 100 patients had TAAD (100/210, 47.62%), which were then allocated to the HAIs group (n=36) and Non-HAIs group (n=64). We found that DCHA >29 min [odds ratio (OR) =2.60, 95% confidential interval (CI), 1.01–6.80, P=0.048], preoperative PLT 9 /L (OR =3.62; 95% CI, 1.33–9.79; P=0.011) and D-dimer >4.25 mg/L (OR =2.83; 95% CI, 1.07–7.47; P=0.035) were independently associated with the occurrence of HAIs for the patients with TAAD following surgical repair. Hosmer-Lemeshow statistic of the model suggested perfect model discrimination from a perfect fit (χ 2 =4.77, P=0.6883). Logistic model was verified when the area under receiver operating characteristic (ROC) curve was equal to 0.7665. Conclusions: TAAD patients with longer DHCA time, lower preoperative PLT, higher serum D-dimer would significantly increase the risks after surgical repair of arch replacement.

The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), whereas the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participates in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification. Immunostaining, quantitative PCR, and Western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to a low-level increase of p53 mRNA and protein in both pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNA-mediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification, and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.

With the wide application of RNA-Seq technology, thousands of circular RNAs (circRNAs) have been identified in different type of tissues and cells in many organisms, but little is known on the human aortic valve expressed circRNAs. In this study, we identified all circRNAs in two calcified human aortic valves, and characterized the features of all circRNAs. A total of 5476 circRNAs were identified in human aortic valves, including 1412 (25.79%) aortic valve specific circRNAs. Next, we showed that most aortic valve specific circRNAs were derived from the exonic regions of their host genes, and majority of the host genes contained less than three circRNAs. To predict the potential function of aortic valve specific circRNAs, we performed the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for the host genes, and identified both microRNA (miRNA) and RNA binding protein (RBP) binding sites inside aortic valve specific circRNAs. Results showed that these host genes were involved in some aortic valve related function pathways, such as ECM-receptor interaction pathway, ErbB signaling pathway, and vascular smooth muscle contraction pathway. We also found that most aortic valve specific circRNAs harbored abundant miRNA response elements (MREs), and some aortic valve specific circRNAs could bind to RBP of interest. Functional analysis suggested that these aortic valve specific circRNAs could act as post-transcriptional regulators.

Aims Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial cardiomyopathy (ACM) underlies this rhythm disorder. This study was aimed to characterize the underlying substrate and to explore the aetiology of this unexplained scar-related AT. Methods and results Twenty-six (11 men, aged 46 ± 13 years) of 52 non-surgical scar-related AT patients identified by three-dimensional voltage mapping were enrolled in this prospective observational study. Multimodality image examinations (echocardiography, cardiac magnetic resonance, 99Tc single-photon emission computed tomography), ventricular voltage mapping, and intracardiac pressure curve recording ruled out ventricular involvement. Catheter ablation was acutely successful for all the patients, and pacemaker implantation was performed in seven patients who presented sinus node dysfunction or atrial standstill after termination of the AT. In three patients with multiple AT recurrences, the diseased areas of the right atrium were resected and dechannelled via mini-invasive surgical interventions. Histological examinations revealed profound fibrosis without amyloidosis or adipose deposition. Viral and familial investigations yielded negative results. Fibrosis progression over a median of 45 (5-109) months of follow-up manifested as atrial arrhythmia recurrence in seven patients and atrial lead non-capture due to newly developed atrial standstill in two patients. Two patients suffered four ischaemic stroke events before receiving anticoagulation treatment. Conclusion Isolated, fibrotic ACM may underlie the idiopathic scar-related ATs. This novel cardiomyopathy has unique clinical characteristics with high morbidity including stroke and warrants specific therapeutic strategies. Further investigations are required to determine the aetiology and mechanism.

In our aging world, increasing numbers of people are suffering from calcific aortic valve disease (CAVD). In this study, we used integrated bioinformatics analysis to predict several key genes that are involved in the initiation and progression of CAVD. Expression profiles of 15 calcific and 14 normal human aortic valve samples were generated from two gene expression datasets (GSE12644 and GSE51472). Dataset GSE26953 from the human aortic valve fibrosa-derived endothelial cells cultured under laminar or oscillatory shear stress was also evaluated. Related R packages were used to process the data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for functional annotation. Hub genes were identified based on the protein-protein interaction network. CAVD-related gene modules were identified by Weighted Gene Co-expression Network Analysis (WGCNA). The predicted key genes were manually reviewed. In our present work, complex connections among mechano-response, oxidative stress, inflammation and extracellular remodeling pathways in the etiology of CAVD were revealed. The key genes, thus identified, encode a transcription factor KLF2 and phospholipid phosphatase 3 (PLPP3) that are involved in mechano-responses; eNOS involved in oxidative stress; IL-8 involved in inflammation; and collagen triple helix repeat containing 1 (CTHRC1) and secretogranin II (SCG2) involved in extracellular remodeling. These gene products are predicted to play critical roles in CAVD development and progression. The present study provides valuable information for future research and drug development.

Background/Aims: Aortic stenosis caused by leaflet calcification in the bicuspid aortic valve (BAV) is more accelerative than that in the tricuspid aortic valve (TAV). MicroRNA-195 (miR-195) is downregulated more in stenotic than in insufficient BAVs, but its expression in BAVs compared with TAVs is unclear. We aimed to investigate the roles of miR-195 and its calcification-related target SMAD7 in stenotic BAVs compared with those in TAVs. Methods: Twenty-one stenotic BAV and 29 TAV samples were collected from surgical patients and examined for the expression of miR-195 and SMAD7 by RT-PCR. The samples were also assessed by western blotting and immunohistochemistry for the functional protein alteration associated with calcification. Dual-luciferase assay was performed to determine the putative target of miR-195 before the effects of miR-195 expression on osteogenic progression was demonstrated in cultured porcine valve interstitial cells (VICs). Results: Compared with TAV, the expression of miR-195 was remarkably lower in the BAV leaflet with higher expression of SMAD7, which was then validated as a direct target of miR-195. Their negative correlation was then confirmed in cultured VICs. Under an osteogenic environment, the cellular calcification was promoted in miR-195-repressed VICs expressing higher BMP-2 and Runx2 and higher activity of MMP-2 compared with the controls. Finally, higher MMP-2 and MMP-9 expression and more collagen distribution were observed in BAV than TAV samples. Conclusions: miR-195 is downregulated more in stenotic BAV than TAV in this study. The downregulation of miR-195 is associated with valvular calcification via targeting SMAD7, which promotes the remodeling of the extracellular matrix.

Background We aimed to develop and validate a prediction model for in‐hospital complications in children with tetralogy of Fallot repaired at an older age. Methods and Results A total of 513 pediatric patients from the Tianjin data set formed a derivation cohort, and 158 pediatric patients from the Hefei and Xiamen data sets formed validation cohorts. We applied least absolute shrinkage and selection operator analysis for variable selection and logistic regression coefficients for risk scoring. We classified patients into different risk categorizations by threshold analysis and investigated the association with in‐hospital complications using logistic regression. In‐hospital complications were defined as death, need for extensive pharmacologic support (vasoactive‐inotrope score of ≥20), and need for mechanical circulatory support. We developed a nomogram based on risk classifier and independent baseline variables using a multivariable logistic model. Based on risk scores weighted by 11 preoperative and 4 intraoperative selected variables, we classified patients as low, intermediate, and high risk in the derivation cohort. With reference to the low‐risk group, the intermediate‐ and high‐risk groups conferred significantly higher in‐hospital complication risks (adjusted odds ratio: 2.721 [95% CI, 1.267–5.841], P =0.0102; 9.297 [95% CI, 4.601–18.786], P ARIAR ‐Risk classifier (absolute and relative low risk, intermediate risk, and aggressive and refractory high risk) with age and mean blood pressure showed good discrimination and goodness‐of‐fit for derivation (area under the receiver operating characteristic curve: 0.785 [95% CI , 0.731–0.839]; Hosmer‐Lemeshow test, P =0.544) and external validation (area under the receiver operating characteristic curve: 0.759 [95% CI , 0.636–0.881]; Hosmer‐Lemeshow test, P =0.508). Conclusions A risk‐classifier–oriented nomogram is a reliable prediction model for in‐hospital complications in children with tetralogy of Fallot repaired at an older age, and strengthens risk/benefit–based decision‐making.

The human induced pluripotent stem cell line HELPi001-A was derived from peripheral blood mononuclear cells (PBMC) of a 35-year-old female Beals syndrome patient carrying a heterozygous FBN2c.728 T > C mutation. HELPi001-A were positive for pluripotent stem cell markers, had a normal karyotype and the ability to differentiate into cells representing all three germ layers. The patient not only demonstrated typical characteristics of Beals syndrome such as joint contractures and crumpled ears, but also demonstrated aortic dissection. HELPi001-A could serve as a platform for exploring the pathogenesis of cardiovascular and connective tissue disorders related to FBN2 mutation.

Background Chronic intermittent hypoxia ( CIH ) is a distinct pathological mechanism of obstructive sleep apnea ( OSA ), which is recognized as an independent risk factor for cardiovascular diseases. The aims of this study were to ascertain whether CIH induces atrial fibrillation ( AF ), to determine whether cardiac sympathetic denervation ( CSD ) can prevent it and suppress blood pressure, and to explore the potential molecular mechanisms involved. Methods and Results Sixty Sprague‐Dawley male rats were randomly divided into 4 groups: sham, CSD , CIH , CIH + CSD . The rats were exposed either to CIH 8 hours daily or normoxia for 6 weeks. Cardiac pathology and structure were analyzed by hematoxylin and eosin staining and echocardiogram. ECG, blood pressure, body weight, and blood gas were recorded. Connexin 43 and tyrosine hydroxylase were detected by western blot, immunohistochemistry, and immunofluorescence. CIH induced atrial remodeling, and increased AF inducibility. CSD treatment reduced postapneic blood pressure rises and AF susceptibility, which could attenuate CIH ‐associated structural atrial arrhythmogenic remodeling. In addition, CIH ‐induced sympathetic nerve hyperinnervation and CSD treatment reduced sympathetic innervation, which may affect CIH ‐induced AF ‐associated sympathovagal imbalance. Connexin 43 was specifically downregulated in CIH , whereas CSD treatment increased its expression. Conclusions These results suggested CIH induces atrial remodeling, increases AF inducibility, results in sympathetic nerve hyperinnervation, and decreases connexin 43 expression, but CSD treatment reduces AF susceptibility, postapneic blood pressure increase, sympathetic innervation, and the alteration of Cx43, which may be a key point in the genesis of CIH ‐induced AF .

Background Bicuspid aortic valve is a heritable heart valve disease with characteristic early onset of valve calcification and stenosis with rapid progression compared with tricuspid aortic valve. Strong evidence indicates that many miRNAs and their target genes are involved in the development of BAV calcification. This study was designed to investigate miR-15a and Smad7 expressions in BAV and their mechanism of regulating calcification. Methods Immunohistochemistry and western blotting were used to explore the expression levels of Smad7 and Runx2 in human aortic valve tissue. The expression of miR-15a, Smad7 and Runx2 were detected by RT-PCR. The relationship between miR-15a and Smad7 was assessed by dual-luciferase assay. MiR-15a was overexpressed in cultured porcine valve interstitial cells (PVICs) and the variations of Smad7 and Runx2 mRNA were evaluated by RT-PCR, as well as the changes of Smad7 and Runx2 protein. Alizarin reds staining was used to verify the calcification inhibition effect of miR-15a in cultured PVICs under calcification induction. Results Compared with calcified TAV, remarkable higher expression of Smad7 and Runx2 were found in calcified BAV, significantly lower expressions of miR-15a and higher expressions of Smad7 and Runx2 mRNA, along with negative correlation between expressions of miR-15a and mRNA level of Smad7. MiR-15a-overexpressed PVICs shown upregulation of miR-15a, downregulation of Smad7 and Runx2 expression. PVICs under calcification induction shown significantly reduced calcification in miR-15a-overexpressed group. Conclusions The lower miR-15a expression in BAV results in the high expression of Smad7, thereby reducing antagonism of Smad2/3–Smad4 complex to runx2 and promoting the progress of BAV calcification.

Concomitant occurrence of atrial myxoma and esophageal carcinoma is an extremely rare entity. Here we present two cases of synchronously suffered left atrial myxoma and esophageal carcinoma. Both patients underwent simultaneous resection of two tumors via the right thoraco-abdominal approach and recovered well.

Objectives: To identify risk factors associated with cardiac valve calcification that is easily detectable through routine blood tests in patients who received valve replacement therapy. Methods: Four hundred patients with valvular heart disease who underwent valve replacement surgery between December 2009 and January 2013 were enrolled in this study. Of these, 77 had valve calcification; the other 323 did not. Multivariate logistic regression analysis was used to assess for risk factors associated with valve calcification. Results: In our study population, rheumatic valve lesions were the most common reason for valve replacement. Degenerative nonstenotic valve lesion was a protective factor and degenerative stenotic valve lesion was a strong risk factor for valve calcification. Serum levels of gamma-glutamyl transferase (GGT) of between 30 and 46 IU/l and >90 IU/l and total bilirubin (TBIL) of between 15 and 20 μmol/l were positively correlated with valve calcification. Meanwhile, serum calcium (Ca2+) levels of between 2.3 and 2.4 mmol/l were negatively correlated with rheumatic valve calcification. Conclusions: Degenerative stenotic lesion is a risk factor and degenerative nonstenotic lesion a protective factor for cardiac valve calcification. Serum GGT and TBIL levels are positively correlated and serum Ca2+ levels negatively correlated with rheumatic cardiac valve calcification.

Left ventricular rupture is an infrequent but potentially fatal complication of mitral valve replacement. Here, we report a case of large posterior mid-ventricular rupture following mitral valve replacement, which was successfully treated by a sandwich style repair and autotransplantation.

Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery. Increased acetylation of histones 3 and 4 is present in interstitial cells from human calcific aortic valves, but whether it is involved in aortic valve calcification has not been studied. In this study, we found that treating cultured porcine aortic valve interstitial cells with a high-calcium/high-phosphate medium induced calcium deposition, apoptosis, and expression of osteogenic marker genes, producing a phenotype resembling valve calcification in vivo. These phenotypic changes were attenuated by the histone acetyltransferase inhibitor C646. C646 treatment increased the levels of class I histone deacetylase members and decreased the acetylation of histones 3 and 4 induced by the high-calcium/high-phosphate treatment. Conversely, the histone deacetylase inhibitor suberoylanilide hydroxamic acid promoted valve interstitial cell calcification. In a mouse model of aortic valve calcification induced by adenine and vitamin D treatment, the levels of acetylated histones 3 and 4 were increased in the calcified aortic valves. Treatment of the models with C646 attenuated aortic valve calcification by restoring the levels of acetylated histones 3 and 4. These observations suggest that increased acetylation of histones 3 and 4 is part of the pathogenesis of aortic valve calcification associated with calcium and phosphate metabolic disorders. Targeting acetylated histones 3 and 4 may be a potential therapy for inoperable aortic valve calcification in chronic kidney disease patients., Cardiovascular disease: Averting a calcium catastrophe A therapeutic strategy for preventing calcium build-up in the heart could protect chronic kidney disease (CKD) patients from lethal cardiovascular complications. This accumulation is a common feature of late-stage CKD, resulting in obstruction of the aortic valve that can ultimately cause heart failure. A team led by Wei Sun and Xiangqing Kong of The First Affiliated Hospital of Nanjing Medical University in China has demonstrated that specific chemical modifications to histone proteins contribute to this process. Histones organize chromosomal DNA and can thereby regulate gene expression, and the researchers showed that a drug that inhibits histone-modifying acetyltransferase enzymes switches off biochemical pathways that promote calcium accumulation in cultured heart valve cells. They subsequently confirmed these protective effects in a mouse model of aortic valve calcification, indicating a potentially promising avenue for treating CKD.

Aims Inadequate autophagy contributed to endothelial dysfunction in diabetic patients. We aimed to investigate the relationship between inadequate autophagy and endothelial cells (ECs) apoptosis in diabetes and its underlying mechanism. Methods and results Aortic intima and ECs were isolated from diabetic patients. Cultured human aortic endothelial cells (HAECs) were stimulated with advanced glycation end products (AGEs). The expression of autophagy and apoptosis-related proteins were determined by western blotting. Autophagosomes were observed by electron microscopy. The fusion of autophagosome and lysosomes was detected by immunofluorescence. Compared with non-diabetic subjects, the levels of LC3-II, p62, FoxO1, and Ac-FoxO1 were increased in ECs from diabetic patients, accompanied by the decreased expressions of Atg14, STX17, and co-localization of LC3-II/LAMP2 and Atg14/STX17. Long-term stimulation with AGEs up-regulated LC3-II and p62 expression and the number of autophagosomes with decreased level of Atg14, STX17, Ras-related protein 7 (Rab7), and co-localization of LC3-II/LAMP2 and Atg14/STX17 in HAECs. The apoptosis rates were increased with elevated cleaved-caspase-3 and declined Bcl-2 expression. Inhibition of autophagy with 3-methyladenine could reduce long-term AGEs-induced apoptosis. Higher levels of FoxO1, Ac-FoxO1, and Ac-FoxO1 binding to Atg7 were detected in AGEs-treated HAECs. AGEs-induced FoxO1 enhanced Akt activity, decreased SIRT1-deacetylase activity by phosphorylation and elevated Ac-FoxO1. Knockout of FoxO1 reduced AGEs-induced autophagy and promoted the expression of Atg14 and the co-localization of LC3-II/LAMP 2 and Atg14/STX17. Conclusion Inadequate autophagy with impaired autophagosome-lysosomal fusion exists in aortic intima and ECs from diabetic patients. FoxO1 mediates AGEs-induced ECs autophagic apoptosis through impairing autophagosome-lysosomes fusion by inhibiting Atg14 expression.

Autophagy regulates the metabolism, survival and function of numerous types of cell, including cells that comprise the cardiovascular system. The dysfunction of autophagy has been demonstrated in atherosclerosis, restenotic lesions and hypertensive vessels. As a member of the Ras GTPase superfamily, Rab7 serves a significant role in the regulation of autophagy. The present study evaluated how Rab7 affects the proliferation and invasion, and phenotypic transformations of aortic dissection (AD) smooth muscle cells (SMCs) via autophagy. Rab7 was overexpressed in AD tissues and the percentage of synthetic human aortic SMCs (HASMCs) was higher in AD tissues compared with NAD tissues. Downregulation of Rab7 decreased cell growth, reduced the number of invasive cells and decreased the percentage cells in the G1 phase. Autophagy of HASMCs was inhibited following Rab7 knockdown. Inhibition of autophagy with 3‑methyladenine or Rab7 knockdown suppressed the phenotypic conversion of contractile to synthetic HASMCs. The action of Rab7 may be mediated by inhibiting the Ras/Raf/mitogen‑activated protein kinase (MAPK) kinase (MEK)/extracellular signal related kinase (ERK) signaling pathway. In conclusion, the results revealed that Rab7‑mediated autophagy regulated the behavior of SMCs and the phenotypic transformations in AD via activation of the Ras/Raf/MEK/ERK signaling pathway. The findings of the present study may improve understanding of the role Rab7 in the molecular etiology of AD and suggests the application of Rab7 as a novel therapeutic target in the treatment of human AD.

Background Radical nephrectomy with inferior vena cava (IVC) thrombectomy is the preferred treatment for renal cell carcinoma (RCC) with IVC thrombus. However, IVC thrombectomy using a laparoscopic approach has not been reported for high-level thrombi. Objective To describe the surgical technique for laparoscopic IVC thrombectomy in patients with different thrombus levels and to assess its safety and feasibility. Design, setting, and participants Retrospective review of medical records for 11 patients with right-side RCC, including six patients with level II IVC thrombus and five patients with level IV thrombus. Surgical procedure Laparoscopic thrombectomy for level II thrombus was performed after clamping the infrarenal IVC, left renal vein, and infrahepatic IVC. Laparoscopic thrombectomy and thoracoscope-assisted open atriotomy for level IV thrombus were performed after establishing cardiopulmonary bypass and clamping the infrarenal IVC, left renal vein, and hepatoduodenal ligament. Measurements The intraoperative variables, postoperative complications, and surgical outcomes were assessed. Results and limitations The median operative time was 210min. The median IVC clamping time for patients with level II and level IV thrombus was 16.5 and 31min, respectively. The median estimated blood loss was 510ml, and no major intraoperative or postoperative complications occurred. One patient with level IV thrombus died of brain metastasis 6 mo after the operation, and the remaining ten patients had no local recurrence or distant metastasis during a median follow-up period of 31 mo. Conclusions Laparoscopic IVC thrombectomy for level II thrombus and well-selected level IV thrombus may be a safe and technically feasible alternative to open surgery. Patient summary We studied the treatment of patients with an inferior vena cava thrombus at different levels using a laparoscopic approach. This technique was safe and feasible in well-selected patients.

Aims Aortic dissection (AD) represents one of the most common aortic emergencies with high incidence of morbidity and mortality. Clinical studies have shown that the increased excitability of the sympathetic nerve may be associated with the formation of AD. In this study, we examined the effects of bilateral superior cervical sympathectomy (SCGx) on the progression of β-aminopropionitrile (BAPN)-induced AD in rats. Main methods Sprague–Dawley rats were randomly divided into three groups, including BAPN, BAPN + SCGx and control groups. For terminal measurements, the mean arterial pressure (MAP) and heart rate (HR) were monitored and the basal sympathetic nerve activity (SNA) was assessed through recording the variation in arterial pressure in response to hexamethonium application. Pathological changes in the aortic wall were observed by histological staining. Matrix metalloproteinase-2 (MMP-2) and MMP-9 concentrations within the aortic wall were analyzed by western blot. Key findings The results show that BAPN administration could elevate SNA and cause the formation of AD in rats with a high incidence (67.7%), while SCGx treatment inhibited the elevation of SNA and significantly reduced the incidence (20%). SCGx may suppress the formation of BAPN-induced AD via restraining the rise of HR and reducing the MMP-9 concentration in aortic wall. Significance These results indicate that surgical techniques such as sympathetic nerve block may be a potentially useful therapy for the prevention of AD.

The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), whereas the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participates in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification. Immunostaining, quantitative PCR, and Western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to a low-level increase of p53 mRNA and protein in both pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNA-mediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification, and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.

Oxidative stress is a key contributor to endothelial dysfunction and associated cardiovascular pathogenesis. Hydrogen sulfide (H2S) is an antioxidant gasotransmitter that protects endothelial cells against oxidative stress. Sirtuin3 (SIRT3), which belongs to the silent information regulator 2 (SIR2) family, is an important deacetylase under oxidative stress. H2S is able to regulate the activity of several sirtuins. The present study aims to investigate the role of SIRT3 in the antioxidant effect of H2S in endothelial cells. Results: Cultured EA.hy926 endothelial cells were exposed to hydrogen peroxide (H2O2) as a model of oxidative stress-induced cell injury. GYY4137, a slow-releasing H2S donor, improved cell viability, reduced oxidative stress and apoptosis, and improved mitochondrial function following H2O2 treatment. H2S reversed the stimulation of MAPK phosphorylation, downregulation of SIRT3 mRNA and reduction of the superoxide dismutase 2 and isocitrate dehydrogenase 2 expression which were induced by H2O2. H2S also increased activator protein 1 (AP-1) binding activity with SIRT3 promoter and this effect was absent in the presence of the specific AP-1 inhibitor, SR11302 or curcumin. Paraquat administration to mice induced a defected endothelium-dependent aortic vasodilatation and increased oxidative stress in both mouse aorta and small mesenteric artery, which were alleviated by GYY4137 treatment. This vasoprotective effect of H2S was absent in SIRT3 knockout mice. Innovation: The present results highlight a novel role for SIRT3 in the protective effect of H2S against oxidant damage in the endothelium both in vitro and in vivo. Conclusion: H2S enhances AP-1 binding activity with the SIRT3 promoter, thereby upregulating SIRT3 expression and ultimately reducing oxidant-provoked vascular endothelial dysfunction.

Background/Aims: To evaluate the long-term outcomes of Chinese patients with cardiac surgery-associated acute kidney injury (CSA-AKI). Methods: Patients who underwent cardiac surgery with a median 3-year follow-up were enrolled. The long-term survival rate and the incidence of chronic kidney disease (CKD) were recorded, and related risk factors were analyzed. Results: Of all 1,363 patients, 457 (33.5%) developed CSA-AKI. The AKI patients had a lower 3-year survival rate (88.8 vs. 97.2%, respectively, p < 0.001) and a higher incidence of CKD stages 3-5 (9.9 vs. 2.3%, respectively, p < 0.001) than the non-AKI patients. Cox regression analysis showed that AKI, atrial fibrillation, chronic cardiac insufficiency, longer surgical duration, respiratory failure after surgery, and longer mechanical ventilation time were associated with long-term mortality, while AKI, older age, and lower baseline kidney function were associated with incident CKD stages 3-5. Conclusion: CSA-AKI increased the risk of 3-year mortality and incident CKD stages 3-5.

Chronic heart failure (CHF) is responsible for significant morbidity and mortality worldwide, mainly as a result of neurohumoral activation. Acupuncture has been used to treat a wide range of diseases and conditions. In this study, we investigated the effects of electroacupuncture (EA) on the sympathetic nerve activity, heart function, and remodeling in CHF rats after ligation of the left anterior descending coronary artery. CHF rats were randomly selected to EA and control groups for acute and chronic experiments. In the acute experiment, both the renal sympathetic nerve activity and cardiac sympathetic afferent reflex elicited by epicardial application of capsaicin were recorded. In the chronic experiment, we performed EA for 30 min once a day for 1 wk to test the long-term EA effects on heart function, remodeling, as well as infarct size in CHF rats. The results show EA significantly decreased the renal sympathetic nerve activity effectively, inhibited cardiac sympathetic afferent reflex, and lowered the blood pressure of CHF rats. Treating CHF rats with EA for 1 wk dramatically increased left ventricular ejection fraction and left ventricular fraction shortening, reversed the enlargement of left ventricular end-systolic dimension and left ventricular end-diastolic dimension, and shrunk the infarct size. In this experiment, we demonstrated EA attenuates sympathetic overactivity. Additionally, long-term EA improves cardiac function and remodeling and reduces infarct size in CHF rats. EA is a novel and potentially useful therapy for treating CHF.

Background and purpose Periostin, a matricellular protein, plays an important role in cardiac development and remodeling. Its expression profile and the association with myocardial fibrosis have not been investigated in human failing hearts. This work aimed to explore the behavior and pathologic significance of periostin in signifying collagen fibrogenesis in human hearts from patients with end-stage heart failure. Methods and subjects Tissues were collected from heart transplant recipients and the control hearts were from unmatched donors. Periostin mRNA and protein were detected using quantitative real-time polymerase chain reaction and Western blotting. Immunohistochemistry staining was employed to directly detect the protein level and distribution of periostin in heart tissues. The extent of myocardial fibrosis was expressed by the percentage of Masson's trichrome staining. Gelatin zymography was used to detect the activities of matrix metalloproteinase (MMP)2 and MMP9. Results A low level of periostin mRNA expression was found in control hearts while not detectable at the protein level. Periostin mRNA was increased significantly in failing myocardium compared to that of controls. Periostin was distributed extensively in left ventricle and interventricular septum of the failing hearts. Correlation analysis showed periostin protein expression was positively associated with myocardial fibrosis as well as left ventricular diastolic dimension. The distribution and extent of periostin was consistent with that of myocardial fibrosis. MMP2 activity has an obvious increase about fourfold in heart tissues from HF patients. But there is no quantitative association with the expression of periostin. Conclusions Periostin, the distribution and expression of which were consistent with the extent of myocardial fibrosis, might be a potential biomarker of cardiac remodeling in heart failure patients.

Lung cancer is the most common malignancy and exhibits significant morbidity and mortality worldwide. Among all lung cancer subtypes, non-small-cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Although there have been intensive investigations on the underlying mechanism of NSCLC development and progression, the exact molecular basis is not well understood. Further insights on important molecular regulators of lung cancer are needed for development of novel therapeutics. The heat shock protein (HSP) family is a group of molecular chaperones that assist in protein folding, modification, and transportation. Different HSPs are essential for tumor cell survival by binding diverse client proteins and regulating homeostasis. In the current study, we sought to characterize HSP70 and HSP90 as potent regulators of NSCLC growth. Our results indicate that differential expression of HSP70 is associated with the malignant phenotype of NSCLC cell lines and plays an important regulatory role in NSCLC cell proliferation. Moreover, a specific inhibitor of HSP70, VER-155008 significantly inhibits NSCLC proliferation and cell cycle progression. We showed that this effect is largely abolished by HSP70 overexpression, indicating that the inhibitory effect of VER-155008 on cell growth is specifically through HSP70 inhibition. In addition, 17-AAD, an inhibitor of HSP90, exerts a potent synergistic effect on NSCLC proliferation with VER-155008. We also observed that inhibition of HSP70 by VER-155008 can sensitize A549 cells to ionizing radiation. These data provide proof-of-principle that VER-155008 can be a good candidate for NSCLC treatment and HSP machinery is a good target for developing NSCLC therapeutics.

ABSTRACT: Aims: To examine the relationship between the expression levels of miR-1 and PIK3CA in resected non-small-cell lung cancer (NSCLC) tissues and clinical characteristics and prognosis. Materials & methods: Levels of miR-1 and PIK3CA in cancerous and normal tissues obtained from 55 patients with NSCLC were measured by real-time PCR and western blot assays, and their associations with clinicopathological features were evaluated. Results: A total of 69.1% of the NSCLC tissue samples showed low miR-1 expression (p < 0.05) and 70.9% showed high PIK3CA expression (p < 0.05). Patients with low miR-1 expression and those with high PIK3CA expression had significantly higher incidences of lymph node metastases and postoperative recurrences within 1 year after surgery than those with moderate miR-1 expression and moderate PIK3CA expression (p < 0.05 for both). Conclusion: Low expression of miR-1 and overexpression of PIK3CA in NSCLC tissues may be useful predictors of lymph node metastasis and postoperative recurrence in patients with NSCLC.

Background Despite the successful creation of complex lesion sets during hybrid ablation (HA), reoccurrence of atrial fibrillation (AF), and/or atrial arrhythmia and procedural complications still occur. The main objective of this study was to compare the efficacy and safety between HA and transcatheter ablation (TA). Methods We searched Pubmed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) database up to October 2017. Studies that satisfied our predefined inclusion criteria were included. Of the 894 records, 4 studies encompassing 331 patients were included in our study. We assessed pooled data using random-effect or fixed-effect model. The main endpoint was freedom of atrial arrhythmia after follow-up duration, secondary results were procedure time and intraoperative and postoperative adverse events. Similarly, tertiary outcomes were endocardial time, fluoroscopy time, and postoperative hospitalization. Results Compared with TA, HA treatment through mini-thoracotomy access improved superiority in freedom of atrial arrhythmia after follow-up duration (odds ratio [OR] = 6.67, 95% confidence interval [CI]: 2.63-16.90), but HA increased the incidence of intraoperative and postoperative adverse events for AF patients (OR = 2.98, 95% CI: 1.30-6.83). HA through either mini-thoracotomy or transdiaphragmatic/subxiphoid access had longer procedure time and postoperative hospitalization than TA. However, endocardial time was shorter than TA. Conclusions For AF patients, HA possessed of an overall superior outcome using mini-thoracotomy way to TA. Although HA had longer procedure time, it yielded a reduction in endocardial time. Meanwhile, we should pay attention to the significantly high risk of intraoperative and postoperative adverse events that the HA generated.

Objectives The aim of this study was to determine whether altered calreticulin expression and distribution contribute to the pathogenesis of atrial fibrillation (AF) associated with valvular heart disease (VHD). Background AF affects electrophysiological and structural changes that exacerbate AF. Atrial remodeling reportedly underlies AF generation, but the precise mechanism of atrial remodeling in AF remains unclear. Methods Right and left atrial specimens were obtained from 68 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (SR; n =25), paroxysmal AF (PaAF; n =11), and persistent AF (PeAF; AF lasting >6months; n =32) groups. Calreticulin, integrin-α5, and transforming growth factor-β1 (TGF-β1) mRNA and protein expression were measured. We also performed immunoprecipitation for calreticulin with either calcineurin B or integrin-α5. Results Calreticulin, integrin-α5, and TGF-β1 mRNA and protein expression were increased in the AF groups, especially in the left atrium in patients with mitral valve disease. Calreticulin interacted with both calcineurin B and integrin-α5. Integrin-α5 expression correlated with TGF-β1 expression, while calreticulin expression correlated with integrin-α5 and TGF-β1 expression. Despite similar cardiac function classifications, calreticulin expression was greater in the PeAF group than in the SR group. Conclusions Calreticulin, integrin-α5, and TGF-β1 expression was increased in atrial tissue in patients with AF and was related to AF type, suggesting that calreticulin is involved in the pathogenesis of AF in VHD patients.

Amplification and overexpression of human epidermal growth factor receptor-2 (HER-2) has been shown in subgroups of gastric cancer, correlated to more aggressive disease and predictive for the treatment with HER-2 antibodies. In this study, we examined the prognostic value of HER-2 expression in primary gastric cancer and in associated lymph node metastases and confirmed the role of HER-2 in tumor angiogenesis by examining vascular endothelial growth factor (VEGF) expression.Immunohistochemistry was used to detect HER-2 and VEGF expression in 110 gastric cancer specimens and associated lymph node metastases and in 96 specimens of normal gastric mucosa.The expression level of HER-2 in gastric tissues was significantly higher than in normal tissues (19.1 % vs. 8.3 %; P0.05). HER-2 overexpression was homogeneous in primary gastric cancer and metastatic lymph nodes (P = 0.607). There was a significant positive correlation of HER-2 expression and VEGF expression (P = 0.007). HER-2 overexpression in primary tumor correlated with lymph node metastasis, distant metastasis, and American Joint Committee on Cancer (AJCC) stage. Cox regression multivariate analyses confirmed that tumor size, histological grade, lymph node ratio, AJCC stage, chemotherapy, and HER-2 expression were all prognostic factors. Patients with HER-2 positivity in both primary and metastatic tissues (+/+) had the poorest survival (OS, 12.5 months; DFS, 11.0 months) (P0.01).HER-2 was significantly overexpressed in gastric cancer versus normal tissue and correlated with VEGF expression. HER-2 in tumor or lymph nodes was an independent negative prognostic factor.

Platinum-based chemotherapy is the most common treatment for patients with advanced non-small cell lung cancer (NSCLC). Genetic polymorphisms in the base excision repair (BER) pathway are suspected to influence the response of patients to this type of therapy. In this study, we investigated whether nonsynonymous single nucleotide polymorphisms (SNPs) in the BER pathway were associated with the response, progression-free survival (PFS) and overall survival (OS) of NSCLC patients following platinum-based chemotherapy. We used TaqMan to genotype four SNPs (APE1 Asp148Glu, PARP1 Va1762Ala, XRCC1 Arg194Trp and XRCC1 Arg399Gln) in 147 patients with advanced NSCLC who had undergone routine platinum-based chemotherapy. Logistic regression analysis showed that subjects with the XRCC1-399 A allele had a significantly better response to platinum-based chemotherapy than those with the XRCC1-399 GG genotype (AA/AG vs. GG: adjusted OR = 2.35, 95 % CI = 1.11–5.00). Furthermore, multivariate Cox proportional hazard regression analysis showed that the PARP1-762 CC genotype was a significantly unfavorable prognostic factor for PFS (CC vs. CT/TT: adjusted HR = 1.90, 95 % CI = 1.02–3.52). In contrast, the APE1-148 GG genotype was a significantly protective prognostic factor for OS (GG vs. TT: adjusted HR = 0.33, 95 % CI = 0.12–0.92). We found that XRCC1 Arg399Gln, PARP1 Va1762Ala and APE1 Asp148Glu SNPs in the BER pathway may influence the prognosis of advanced NSCLC patients following platinum-based chemotherapy.

There is controversy regarding the impact of different depths of submucosal invasion on lymph node metastasis (LNM) and overall survival (OS). We evaluated the impact of depth of submucosal invasion on the presence of metastatic lymphadenopathy and survival in a Chinese population with esophageal squamous cell carcinoma (ESCC).A total of 258 patients who underwent esophagectomy from November 2009 to March 2014 were studied. Demographics of patients, tumor characteristics, and surgical information were retrospectively collected through medical records. Submucosal invasion was equally categorized into inner one-third (sm1), middle one-third (sm2), and deep one-third (sm3) invasion by pathologists. The patients were observed at the outpatient department in accordance with appointed time and recurrence, and deaths were recorded. The median follow-up duration was 26 months and the deadline was April 2015. Cancer characteristics and its association with LNM and OS were analyzed.The study included 75 (29.1%) sm1, 73 (28.3%) sm2, and 110 (42.6%) sm3 patients, and the rates of LNM were 12% (9/75), 11% (8/73), and 20.9% (23/110), respectively. sm3 might be associated with regional LNM (univariate analysis, P=0.041). Tumor volume1.856 cm(3) (P=0.022) and lymphovascular invasion (LVI) (P=0.004) predicted LNM using multivariate analysis. No significant differences in distant metastases were observed according to the depth of invasion. Only metastatic lymph nodes predicted OS (P0.001) rather than the depth of invasion.Submucosal ESCC showed a substantial rate of LNM. In T1b ESCC, after adjusting for possible covariates, depth of invasion does not predict LNM or OS.

RNA sequencing (RNA-seq) has revolutionary roles in transcriptome identification and quantification of different types of tissues and cells in many organisms. Although numerous RNA-seq data derived from many types of human tissues and cell lines, little is known on the transcriptome repertoire of human aortic valve. In this study, we sequenced the total RNA prepared from two calcified human aortic valves and reported the whole transcriptome of human aortic valve. Integrating RNA-seq data of 13 human tissues from Human Body Map 2 Project, we constructed a transcriptome repertoire of human tissues, including 19,505 protein-coding genes and 4,948 long intergenic noncoding RNAs (lincRNAs). Among them, 263 lincRNAs were identified as novel noncoding transcripts in our data. By comparing transcriptome data among different human tissues, we observed substantial tissue specificity of RNA transcripts, both protein-coding genes and lincRNAs, in human aortic valve. Further analysis revealed that aortic valve-specific lincRNAs were more likely to be recently derived from repetitive elements in the primate lineage, but were less likely to be conserved at the nucleotide level. Expression profiling analysis showed significant lower expression levels of aortic valve-specific protein-coding genes and lincRNA genes, when compared with genes that were universally expressed in various tissues. Isoform-level expression analysis also showed that a majority of mRNA genes had a major isoform expressed in the human aortic valve. To our knowledge, this is the first comparative transcriptome analysis between human aortic valve and other human tissues. Our results are helpful to understand the transcriptome diversity of human tissues and the underlying mechanisms that drive tissue specificity of protein-coding genes and lincRNAs in human aortic valve.

Intimal sarcoma of pulmonary artery (PAIS) is a rare disease with no characteristic symptoms. No standard therapeutic guidelines have been established so far. A 55-year-old woman who underwent pulmonary endarterectomy in 2005 with a pathological and immunohistochemical result of PAIS was re-admitted to our hospital on August 24, 2009, presenting with cough and dyspnea. The thoracic computed tomography (CT) scan revealed a 12.5 cm × 9 cm well-defined mass in the right lobe, considered a local neoplasm recurrence after a 44 month symptom-free period. As surgical resection was not proposed, she received combined chemotherapy consisting of doxorubicin, cisplatin, and ifosfamide for two cycles. Because of intolerable side effects, she received vinorelbine and cisplatin for the next four cycles. CT scans after six cycles showed remarkable regression of the tumor. After that, she began to take oral cyclophosphamide (50 mg t.i.d) everyday as a maintenance therapy. As of the time of writing, 19 months after the onset of the recurrence, she remains stable. Several antineoplastic drugs have been reported to be used in PAIS, with poor effects in most cases. To our knowledge, this is the first case of PAIS that has been successfully treated by a vinorelbine-based regimen used as second-line chemotherapy. Vinorelbine is a promising drug that may be relatively well tolerated in heavily pretreated patients with PAIS.

The human epidermal growth factor receptor 2 (HER-2) and leptin/OB-R system have been reported to be intertwined in several cancer types. However, limited research has been conducted with regard to this interaction in lung cancers. In this study, we investigated the relationship between the expression levels of these proteins and the development, progression and prognosis of non-small-cell lung cancer (NSCLC). The expression of leptin, OB-Rb and HER-2 was evaluated in 100 NSCLC specimens by immunohistochemistry, with normal lung tissue as controls. The relationships between their expression levels and clinicopathological factors were evaluated by correlation analysis. Univariate and multivariate analyses were used to determine the associations between the expression levels of these proteins and the survival of NSCLC patients. Leptin was expressed in 71 and 25% (P