Yanhu Wu

Natriuretic peptides and right atrial fibrosis in patients with paroxysmal versus persistent atrial fibrillation

Natriuretic peptides (NPs) are excellent diagnostic and prognostic markers of heart failure, but their roles in atrial fibrillation (AF), particularly of isolated cardiac valvular origin, are unclear. We assessed the mRNA and protein content of pro-atrial natriuretic peptide (pro-ANP) and pro-brain natriuretic peptide (pro-BNP) in right atrial appendages (RAAs) and their N-terminal fragments (nt-proANP and nt-proBNP) in the plasma of 30 patients with paroxysmal AF (PaAF) and 40 patients with persistent AF (PeAF) matched with 34 patients in sinus rhythm (SR) undergoing isolated valvular replacement. To explore the underlying mechanism, fibrosis related examinations were simultaneously carried out in RAAs. Unexpectedly, atrial expression of pro-NPs mRNA was notably augmented in the PaAF subgroup, but not so pronounced in the PeAF subgroup. Atrial content of pro-NPs proteins and plasma nt-proNPs, between which surprisingly strong positive correlations were found (pro-ANP and nt-proANP: r=0.918, p<0.001; pro-BNP and nt-proBNP: r=0.913, p<0.001), were increased analogously in PaAF and PeAF subgroups. We identified significantly increasing gradients of atrial collagen volume fraction (CVF), levels of collagen I and III in the SR, PaAF and PeAF groups, and convincing negative linear correlations between CVF, levels of collagen I and III, and atrial transcripts of pro-NPs. These findings suggest that the discordance between transcripts and protein contents of pro-NPs was possibly due to the more outstanding atrial fibrosis in PeAF, and that circulating nt-proNPs levels could reflect the corresponding atrial pro-NPs contents in this report.

Calreticulin overexpression correlates with integrin-α5 and transforming growth factor-β1 expression in the atria of patients with rheumatic valvular disease and atrial fibrillation.

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 >6 months; 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.

OPG/RANK/RANKL Axis in Stabilization of Spontaneously Restored Sinus Rhythm in Permanent Atrial Fibrillation Patients after Mitral Valve Surgery

Objective: To investigate the expression of the osteoprotegerin (OPG)/receptor activator of nuclear factor-ĸB (RANK)/RANK ligand (RANKL) axis in the stabilization of spontaneously restored sinus rhythm (SR) in permanent atrial fibrillation (AF) patients after mitral valve (MV) surgery and study its clinical significance. Methods: Clinical data, biopsies of right atrial appendages were collected from 135 permanent AF patients who spontaneously restored SR after conventional isolated MV replacement. A comparison was made between patients who had recurrence of AF within 7 days and patients with persistent SR for more than 7 days. Results: AF patients had an increased expression of RANK, RANKL, and the RANKL/OPG ratio compared to SR patients, and the degree of fibrosis was lower in SR compared to AF in the atria. Moreover, the expressions of RANK, RANKL, and the RANKL/OPG ratio were positively correlated with the degree of fibrosis. Conclusion: These findings suggest that the OPG/RANK/RANKL axis plays important roles in the stabilization of restored SR after MV surgery by stimulating AF-related atrial remodeling in AF patients.

Intracellular lactate signaling cascade in atrial remodeling of mitral valvular patients with atrial fibrillation

BackgroundAtrial remodeling has emerged as the structural basis for the maintenance and recurrence of atrial fibrillation. Lactate signaling cascade was recently linked to some cardiovascular disorders for its regulatory functions to myocardial structural remodeling. It was hypothesized that lactate signaling cascade was involved in the maintenance and recurrence of atrial fibrillation by regulating atrial structural remodeling.MethodsBiopsies of right atrial appendage and clinical data were collected from sex- and age-matched 30 persistent atrial fibrillation, 30 paroxysmal atrial fibrillation, 30 sinus rhythm patients undergoing isolated mitral valve surgery and 10 healthy heart donors.ResultsAtrial fibrillation groups had higher atrial lactate expression and this upregulated expression was positively correlated with regulatory indicators of atrial structural remodeling as reflected by severe oxidative stress injury and mitochondrial control of apoptosis.ConclusionsThe present findings suggest a potential role for lactate signaling cascade in the maintenance and recurrence of atrial fibrillation and possibly represent new targets for therapeutic intervention in this disorder.

Essential role of STX6 in esophageal squamous cell carcinoma growth and migration.

Abnormalities in endosomes, or dysregulation in their trafficking, play an important role directly in many diseases including oncogenesis. Syntaxin-6 (STX6) is involved in diverse cellular functions in a variety of cell types and has been shown to regulate many intracellular membrane trafficking events such as endocytosis, recycling and anterograde and retrograde trafficking. However, its expression pattern and biological functions in esophageal squamous cell carcinoma (ESCC) remained unknown. Here, we have found that the expression of STX6 was up-regulated in ESCC samples, its expression was significantly correlated with tumor size, histological differentiation, lymph node metastasis and depth. On one hand, STX6 silencing inhibited ESCC cells viability and proliferation in a p53-dependent manner. On the other hand, STX6 effect integrin trafficking and regulate ESCC cells migration. Taken together, our study revealed the oncogenic roles of STX6 in the progression of ESCC, and it might be a valuable target for ESCC therapy.

Preoperative Serum Soluble Receptor Activator of Nuclear Factor-κB Ligand and Osteoprotegerin Predict Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Valve Surgery

BACKGROUND Postoperative atrial fibrillation (POAF), a frequent complication after cardiac surgery, causes morbidity and prolongs hospitalization. A significant association between circulating osteoprotegerin concentration and atrial fibrillation incidence had been identified. Osteoprotegerin/receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand (RANKL) axis may also contribute to the development and progression of AF. Herein we sought to determine whether preoperative serum soluble RANKL and osteoprotegerin and soluble RANKL/osteoprotegerin ratio are associated with the incidence of POAF in cardiac surgery patients. METHODS We enrolled 154 patients with preoperative sinus rhythm undergoing isolated cardiac valve surgery. Preoperative venous blood samples were obtained for measurement of serum soluble RANKL and osteoprotegerin. The POAF was defined as the characteristic arrhythmia lasting for at least 30 seconds before discharge. Comparison was made between patients without episode of POAF (sinus rhythm group, n=93) and patients experiencing POAF (atrial fibrillation group, n=61). RESULTS Serum levels of soluble RANKL and osteoprotegerin and soluble RANKL/osteoprotegerin ratio were significantly higher in the atrial fibrillation group than the sinus rhythm group. In multivariate survival regression, C-reactive protein, ejection fraction, left and right atrial diameters, preoperative use of beta-blocker, duration of ventilation, particularly serum soluble RANKL level, and soluble RANKL/osteoprotegerin ratio independently predicted POAF. According to receiver operating characteristic curve analysis, the best threshold values of serum soluble RANKL level and soluble RANKL/osteoprotegerin ratio for predicting POAF were 3.62 pmol/L and 0.51, respectively. CONCLUSIONS Elevated preoperative serum soluble RANKL level and soluble RANKL/osteoprotegerin ratio are independent predictors for POAF in patients undergoing cardiac valve surgery. These findings have important implications for identifying patients at higher risk of POAF who could be considered for prophylactic therapy.

Familial cardiac myxoma with multifocal recurrences: a case report and review of the literature.

We report a case of myxoma with multiple recurrences in both the atrium and ventricle in a 26-year-old woman five years after the surgical removal of left atrial myxoma. Her 52-year-old mother had a similar medical history. To our knowledge, this was the first familial case who suffered multifocal cardiac myxoma recurrences without any sign of the myxoma complex. Based on our understanding of the mechanism of recurrence, the approaches to prevent the recurrence, and markers to predict recurrence, we propose that multifocal recurrences, as reported herein, may result from a combination of familial predisposition and multifocal onset. The bi-atrial surgical approach and transesophageal echocardiography are preferred for patients with recurrent cardiac myxomas, especially for those with multiple recurrences and familial myxoma. Immunological and genetic screenings may help to identify family members at risk for developing this disease.

Interleukin 18 promotes myofibroblast activation of valvular interstitial cells

BACKGROUND Calcific aortic valve disease is the main heart valve disease in the elderly. Valvular interstitial cells (VICs) play an important role in the process of valve calcification. Interleukin 18 (IL-18) is expressed in stenosis aortic valves and is positively related with the clinical severity of aortic stenosis. However, the role of IL-18 in aortic valve calcification remains unclear. This study examined whether IL-18 promotes myofibroblast and/or osteoblast transdifferention of VICs. Porcine VICs were isolated and treated with recombinant porcine IL-18. METHODS Porcine VICs were cultured and treated with IL-18. Gene and protein expression of myofibroblastic and osteoblastic markers were tested and nuclear factor κB (NF-κB) phosphorylation was also analyzed. Alkaline phosphatase (ALP) staining and activity assay were also performed. RESULTS Our experiments demonstrated that IL-18 significantly enhanced alpha-smooth muscle actin (α-SMA) gene and protein expression. IL-18 treatment also promoted the expression of osteopontin (OPN) and runt-related transcription factor 2 (Runx2) mRNA, although OPN and Runx2 protein expressions were not changed. IL-18 could induce ALP activity in the presence of conditioning medium. We also demonstrated that IL-18 markedly enhanced NF-κB p65 phosphorylation in VICs. CONCLUSIONS Together these results suggest that IL-18 promotes the myofibroblast differentiation of VICs and accelerates calcification in the presence of conditioning medium via the NF-κB pathway.

Increased expression of NF-AT3 and NF-AT4 in the atria correlates with procollagen I carboxyl terminal peptide and TGF-β1 levels in serum of patients with atrial fibrillation

BackgroundAtrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Unfortunately, the precise mechanisms and sensitive serum biomarkers of atrial remodeling in AF remain unclear. The aim of this study was to determine whether the expression of the transcription factors NF-AT3 and NF-AT4 correlate with atrial structural remodeling of atrial fibrillation and serum markers for collagen I and III synthesis.MethodsRight and left atrial specimens were obtained from 90 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (n = 30), paroxysmal atrial fibrillation (n = 30), and persistent atrial fibrillation (n = 30) groups. NF-AT3, NF-AT4, and collagen I and III mRNA and protein expression in atria were measured. We also tested the levels of the carboxyl-terminal peptide from pro-collagen I, the N-terminal type I procollagen propeptides, the N-terminal type III procollagen propeptides, and TGF-β1 in serum using an enzyme immunosorbent assay.ResultsNF-AT3 and NF-AT4 mRNA and protein expression were increased in the AF groups, especially in the left atrium. NF-AT3 and NF-AT4 expression in the right atrium was increased in the persistent atrial fibrillation group compared the sinus rhythm group with similar valvular disease. In patients with AF, the expression levels of nuclear NF-AT3 and NF-AT4 correlated with those of collagens I and III in the atria and with PICP and TGF-β1 in blood.ConclusionsThese data support the hypothesis that nuclear NF-AT3 and NF-AT4 participates in atrial structural remodeling, and that PICP and TGF-β1 levels may be sensitive serum biomarkers to estimate atrial structural remodeling with atrial fibrillation.

MiR‐155 inhibits proliferation and invasion by directly targeting PDCD4 in non‐small cell lung cancer

MicroRNAs are often abnormally expressed in human non‐small cell lung cancer (NSCLC) and are thought to play a critical role in the emergence or maintenance of NSCLC by binding to its target messenger RNA. We assessed the effects of miR‐155 on cell proliferation and invasion to elucidate the role played by miR‐155/PDCD4 in NSCLC.