Tongguan capsule‐derived herb reduces susceptibility to atrial fibrillation by inhibiting left atrial fibrosis via modulating cardiac fibroblasts

Tongguan capsule is a compound Chinese medicine used to treat ischaemic heart diseases. This study aimed to investigate whether Tongguan capsule‐derived herb (TGD) has a preventive effect on atrial fibrillation (AF) in post‐myocardial infarction (MI) rats and to determine the underlying mechanisms. MI was induced by ligation of the left anterior descending coronary artery. TGD was administered to the post‐MI rats over a 4‐week period. The TGD‐treated rats had lower rates of AF inducibility and shorter AF durations than the MI rats. TGD improved the left atrial (LA) conduction velocity and homogeneity. It reduced the fibrosis‐positive areas and the protein levels of collagen types I and III in the left atrium. In vitro, it inhibited the expression of collagen types I and III by inhibiting the proliferation, migration, differentiation and cytokine secretion of cardiac fibroblasts (CFs). In conclusion, the current study demonstrated that TGD reduces susceptibility to AF and improves LA conduction function in rats with post‐MI by inhibiting left atrial fibrosis and modulating CFs. Targeting the CF population may be a novel antiarrhythmic therapeutic approach.     

MicroRNA-146b-5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4

Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR-146b-5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR-146b-5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR-146b-5p transfection in human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs)-fibroblast co-culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR-146b-5p downregulation on atrial fibrosis. The expression level of miR-146b-5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR-146b-5p transfection in hiPSC-aCMs-fibroblast co-culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR-146b-5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR-146b-5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR-146b-5p overexpressed co-culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR-146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR-146b-5p might become an effective therapeutic approach for preventing atrial fibrosis.     

高脂饮食引起小鼠心律失常及心肌纤维化

目的不良饮食方式导致的相关疾病,如肥胖和血脂异常是心律失常的(arrhythmia)重要因素。然而,这些疾病与心律失常的确切关系尚未得到充分确认。本研究中,我们通过高脂饮食(high fatty diet,HFD)动物模型评估了HFD与小鼠心律失常与心肌纤维化的关系。方法将成年雄性C57BL/6J小鼠分为标准饮食组(STD,12%脂肪)和高脂肪饮食组(HFD;50%脂肪)两组。10周后进行在体心电图测试,随后采集心脏组织进行生化及组织学测定。结果HFD可引起小鼠室性心动过速(ventricular tachycardia),QT间期(QT interval duration)显著延长,心房传导速度(atrial conduction velocity)显著降低,右心房动作电位持续时间(action potential duration)延长。组织学和生化分析表明,HFD增加小鼠心脏组织的纤维化程度,并导致炎症。结论HFD可导致小鼠心律失常和心肌纤维化。     

Inhibition of endoplasmic reticulum stress prevents high‐fat diet mediated atrial fibrosis and fibrillation

Obesity is a significant risk factor for atrial fibrillation (AF), which is the most common sustained arrhythmia with increased mortality and morbidity. High‐fat diet (HFD)‐induced obesity is associated with the activation of endoplasmic reticulum stress (ERS). However, the role of ERS in HFD‐induced AF remains elusive. Human atrium samples were examined for the ERS activation test. C57BL/6J mice were divided into four groups, including the control group, the HFD group, the 4‐phenylbutyric acid (4‐PBA) group, and the HFD + 4‐PBA group. At the age of 4 weeks, the HFD group and the HFD + 4‐PBA group were given HFD to construct the obesity model, while the other two groups were given a normal diet (ND). Transesophageal programmed electrical stimulation was conducted to evaluate the AF inducibility and duration. Atrial fibrosis and ERS activation were also investigated.We found that CHOP and GRP‐78 protein were significantly higher in overweight patients than the controls (both P < 0.05). AF inducibility and duration of the HFD group were significantly higher than the other groups (both P < 0.05), while there was no difference between those groups (P > 0.05). The mice of the HFD group had significantly higher collagen volume fraction (CVF%) than the other groups (P < 0.05). ERS marker protein of GRP78, p‐PERK, ATF6 and CHOP protein expression level was increased in the HFD group, which were significantly mitigated in the HFD + 4‐PBA group. In summary, HFD‐induced ERS activation facilitates atrial fibrosis and AF. The inhibition of ERS might alleviate atrial fibrosis and reduce the incidence of AF‐associated obesity.     

Airway-centered interstitial fibrosis: etiology,clinical findings and prognosis

Background

Airway-centered Interstitial Fibrosis (ACIF) is a common pathologic pattern observed in our practice.

Objectives

The objectives of this study are to describe the causes associated with ACIF in a large sample of patients and its effect on survival.

Methods

A retrospective study in three centers of interstitial lung disease in São Paulo, between January of 1995 and December of 2012. The surgical lung biopsy specimens were reviewed by three pathologists. The clinical, functional and tomographic findings were analyzed by a standardized protocol.

Results

There were 68 cases of ACIF, most of them women. The mean age was 57 ± 12 yr. Dyspnea, cough, restrictive pattern at spirometry and oxygen desaturation at exercise were common. A reticular pattern with peribronchovascular infiltrates was found in 79% of the cases. The etiologies of ACIF were hypersensitivity pneumonitis in 29 (42.6%), gastroesophageal reflux disease in 17 (25.0%), collagen vascular disease in 4 (5.9%), a combination of them in 15 cases and idiopathic in 3 (4.4%). The median survival was 116 months (95% CI = 58.5 – 173.5). Lower values of oxygen saturation at rest, presence of cough and some histological findings - organizing tissue in the airways, fibroblastic foci and microscopic honeycombing - were predictors of worse survival.

Conclusions

ACIF is an interstitial lung disease with a better survival when compared with IPF. The main etiologies are HP and GERD. The oxygen saturation at rest, the presence of cough and some histological findings are predictors of survival.     

Anatomical basis for the mobility of the esophagus: implications for catheter ablation of atrial fibrillation

We present autopsy data from a patient that illustrates the anatomical factors that allow the esophagus to be a mobile structure, especially with respect to the posterior left atrial wall.     

Atrial extracellular matrix remodelling in patients with atrial fibrillation

Atrial fibrillation (AF) is the most frequent clinical arrhythmia. Atrial fibrosis is an important factor in initiating and maintaining AF. However, the collagen turnover and its regulation in AF has not been completely elucidated. We tested the hypothesis that the extracellular matrix changes are more severe in patients with permanent AF in comparison with those in patients in sinus rhythm (SR). Intraoperative biopsies from the right atrial appendages (RAA) and free walls (RFW) from 24 patients with AF undergoing a mini-Maze procedure and 24 patients in SR were investigated with qualitative and quantitative immunofluorescent and Western blot analyses. As compared with SR, all patients with AF exhibited dysregulations in collagen type I and type III synthesis/degradation. Tissue inhibitors of metalloproteinases (TIMP2) was significantly enhanced only in RAA-AF. As compared with SR, collagen VI, matrix metalloproteinases MMP2, MMP9 and TIMP1 were significantly increased while TIMP3 and TIMP4 remained unchanged in all AF groups. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a newly discovered MMPs inhibitor, was elevated in RFW as compared to RAA-AF (P<0.05) and RFW-SR (P<0.05). The level of transforming growth factor (TGF)-beta1 was higher in AF than SR. Smad2 and phosphorylated Smad2 showed an elevation in RFW-AF as compared to RFW-SR, RAA-AF, and RAA-SR groups (P<0.05). CONCLUSIONS: Atrial fibrosis in AF is characterized by severe alterations in collagen I and III synthesis/degradation associated with disturbed MMP/TIMP systems and increased levels of RECK. TGF-beta1 contributes to atrial fibrosis via TGF-beta1-Smad pathway by phosphorylating Smad2. These processes culminate in accumulations of fibrillar and non-fibrillar collagens leading to excessive atrial fibrosis and maintainance of AF.     

囊性纤维化跨膜电导调节体:ATP结合和水解门控Cl-通道

囊性纤维化跨膜电导调节体（cystic fibrosis transmembrane conductance regulator,CFTR）是一种Cl^-通道,属于ATP结合（ATP-binding cassette,ABC）转运体超家族。CFTR功能缺陷是高加索人种中普遍存在的致死性常染色体隐性遗传疾病囊性纤维化（cystic fibrosis,CF）发生的主要原因。这种疾病患者各组织上皮细胞内Cl^-转运失调。目前,与CF相关的不同突变超过1400种。CFTR调节（regulatory,R）域负责调控,核苷酸结合域（nucleotide-binding domains,NBDs）NBD1和NBD2负责ATP结合和水解门控。近期研究发现CFFR的NBDs与其它ABC蛋白一样可以二聚化。二聚化过程中,NBD1和NBD2首-尾相连,一个NBD上的WalkerA和B模块与另一个NBD提供的标签序列（signature sequence）形成ATP结合袋（ATP-binding pockets,ABPs）ABP1和ABP2。ABPs中与ATP结合相关的氨基酸突变实验揭示,ABP1和ABP2在CFTR的ATP依赖门控中发挥不同作用。ABP2由NBD2上的WalkA和B模块与NBD1提供的标签序列形成,它与ATP结合催化通道开放,而ABP1单独与ATP结合不能促进通道开放,只能稳定通道构象。有一些CFrR突变相关疾病的特征就是门控失调,进一步深入研究CFTR的NBD1和NBD2如何通过相互作用而达到通道门控,将为药理学研究提供更多所需的机制信息,有利于为CF治疗的药物设计铺平道路。     

Mechanisms of perpetuation of atrial fibrillation in chronically dilated atria

The progressive nature of atrial fibrillation (AF) has been demonstrated in numerous experimental as well as clinical investigations. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to the increase in stability of the arrhythmia. However, "domestication of AF" must also depend on other mechanisms since the stability of AF continues to increase after electrical remodeling has been completed. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electro-anatomical substrate is characterized by increased non-uniform anisotropy and local conduction heterogeneities facilitating reentry in the dilated atria. Atrial fibrosis may lead to disruption of the electrical side-to-side junctions between muscle bundles. This can result in electrical dissociation between neighboring muscle bundles, i.e. they become activated out-of-phase. Recent mapping studies in goats with persistent AF showed that electrical dissociation can not only occur between neighboring muscle bundles but also in the third dimension, i.e. between the epicardial layer and the endocardial bundle network. Such endo-epicardial dissociation will significantly increase the number of wavefronts which can simultaneously be present in the atrial wall. This article reviews data suggesting a role of endo-epicardial dissociation in dilated and fibrillating atria, for the self-perpetuating nature of AF as well as its possible implications for therapeutic interventions.     

高血压房颤与孤立性房颤的临床对比分析

目的：分析高血压房颤（HAF）与孤立性房颤（LAF）的临床特征及其对预后的影响。方法：高血压房颤患者106例,孤立性房颤患者102例,分别对其性别,年龄,家族史,并发症,持续性房颤发生情况,超声心动图等临床特征进行分析。结果：二者相比,LAF组发病年龄轻,左房增大者少,持续性房颤者少;两组中左房增大均与持续性房颤者,并发症呈正相关。高血压程度与持续性房颤者,并发症呈正相关。结论左房增大是房颤发生的主要机制,左房是否增大是判断愈后的一个重要指标。     

Necroptosis is required for atrial fibrillation and involved in aerobic exercise-conferred cardioprotection

Necroptosis, a novel programmed cell death, plays a critical role in the development of fibrosis, yet its role in atrial fibrillation (AF) remains elusive. Mounting evidence demonstrates that aerobic exercise improves AF-related symptoms and quality of life. Therefore, we explored the role of necroptosis in AF pathogenesis and exercise-conferred cardioprotection. A mouse AF model was established either by calcium chloride and acetylcholine (CaCl₂-Ach) administration for 3 weeks or high-fat diet (HFD) feeding for 12 weeks, whereas swim training was conducted 60 min/day, for 3-week duration. AF susceptibility, heart morphology and function and atrial fibrosis were assessed by electrophysiological examinations, echocardiography and Masson's trichrome staining, respectively. Both CaCl₂-Ach administration and HFD feeding significantly enhanced AF susceptibility (including frequency and duration of episodes), left atrial enlargement and fibrosis. Moreover, protein levels of necroptotic signaling (receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, mixed lineage kinase domain-like protein and calcium/calmodulin-dependent protein kinase II or their phosphorylated forms) were markedly elevated in the atria of AF mice. However, inhibiting necroptosis with necrostatin-1 partly attenuated CaCl₂-Ach (or HFD)-induced fibrosis and AF susceptibility, implicating necroptosis as contributing to AF pathogenesis. Finally, we found 3-week swim training inhibited necroptotic signaling, consequently decreasing CaCl₂-Ach-induced AF susceptibility and atrial structural remodeling. Our findings identify necroptosis as a novel mechanism in AF pathogenesis and highlight that aerobic exercise may confer benefits on AF via inhibiting cardiac necroptosis.     

Mesoscopic fluorescence lifetime imaging: Fundamental principles,clinical applications and future directions

Fluorescence lifetime imaging (FLIm) is an optical spectroscopic imaging technique capable of real-time assessments of tissue properties in clinical settings. Label-free FLIm is sensitive to changes in tissue structure and biochemistry resulting from pathological conditions, thus providing optical contrast to identify and monitor the progression of disease. Technical and methodological advances over the last two decades have enabled the development of FLIm instrumentation for real-time, in situ, mesoscopic imaging compatible with standard clinical workflows. Herein, we review the fundamental working principles of mesoscopic FLIm, discuss the technical characteristics of current clinical FLIm instrumentation, highlight the most commonly used analytical methods to interpret fluorescence lifetime data and discuss the recent applications of FLIm in surgical oncology and cardiovascular diagnostics. Finally, we conclude with an outlook on the future directions of clinical FLIm.     

Plasma zinc in adults with cystic fibrosis: Correlations with clinical outcomes

BackgroundZinc status has been previously documented in cystic fibrosis (CF) infants, children and adolescents. However, despite the increasing life expectancy observed in CF populations, data regarding zinc status of CF adults are surprisingly lacking. The objectives of this study were to (1) characterize zinc status and (2) explore associations between zinc status and clinical outcomes of CF adult patients.MethodsA retrospective chart review was performed for patients who had their plasma zinc measured between 2009 and 2012. Data included demographics, clinical characteristics, biochemical parameters and co-morbid conditions.ResultsA total of 304 CF patients were included in the study. These patients displayed a good nutritional status (mean BMI ± SD: 22.7 ± 3.5) and moderate lung disease (mean FEV₁ ± SD: 66.3 ± 22.2). Low plasma zinc concentration (<9.2 μmol/L) was found in 68 out of 304 CF patients (22.4%). Compared to patients with normal zinc, those with low zinc had significantly lower forced vital capacity and forced expiratory volume in one second. 72% of CF adults with low zinc suffered from bone disease (vs 49% with normal zinc, p = 0.037) and 79% had impaired glycemic status (vs 58%, p = 0.016). Accordingly, negative correlations were found between plasma zinc and glucose (r = −0.139, p = 0.0001), HbA1c (r = −0.237, p = 0.0001) and fructosamine (r = −0.134, p = 0.034). In multiple linear regression, albumin and glycemic status were significant predictors of plasma zinc.ConclusionOur data indicated that nearly one quarter of CF adults with good nutritional status and moderate lung disease had low plasma zinc concentration and that low zinc status was associated with worse clinical outcomes.     

山羊房颤模型中左心房与肺静脉外膜碎裂电位的动态比较

目的:比较在持续性房颤发生、发展过程中,房颤模型山羊左心房与肺静脉外膜碎裂电位(CFAEs)的变 化,以期探讨肺静脉外膜碎裂电位(CFAEs)在持续性房颤中的作用.方法:选取10只雌性山羊,使用左心房快速刺激,发送输出电压为6 V、周长为20 ms的脉冲1 s,间隔2 s后重复发放,以此方法建立持续性房颤模型(房颤持续...     

Mechanisms of pulmonary fibrosis induced by core fucosylation in pericytes

Pulmonary fibrosis is a common outcome of a variety of pulmonary interstitial diseases, and myofibroblasts are the main culprit for this process. Recent studies have found that pericytes are one of the major sources of myofibroblasts; the transformation of which involves a complex process of activation of TGF-β/Smad2/3 and PDGFβ/Erk signaling pathways. We have reported that the transforming growth factor-β receptor and platelet-derived growth factor-β receptor (TGF-βR I and PDGFβR, respectively) are modified by glycosylation. Thus, we hope to regulate the above-mentioned signal pathways through core fucosylation (CF) catalyzed by α-1,6-fucosyltransferase (FUT8). Previous work has confirmed that TGF-β1 can induce the transformation of pericytes into myofibroblasts, while FUT8siRNA can inhibit such transformation. In the present study, we used an adenovirus packaging FUT8 shRNA to infect a bleomycin-induced pulmonary fibrosis mouse model and determined the effect of CF on pulmonary fibrosis by analyzing the mechanism of CF-mediated pericyte transformation. Our findings may shed new light on the mechanism of pulmonary interstitial fibrosis and provide a novel therapeutic target for clinical applications.     

Mechanisms of atrial fibrillation in athletes: what we know and what we do not know

Exercise is an emerging cause of atrial fibrillation (AF) in young individuals without coexisting cardiovascular risk factors. The causes of exercise-induced atrial fibrillation remain largely unknown, and conclusions are jeopardised by apparently conflicting data. Some components of the athlete’s heart are known to be arrhythmogenic in other settings. Bradycardia, atrial dilatation and, possibly, atrial premature beats are therefore biologically plausible contributors to exercise-induced AF. Challenging findings in an animal model suggest that exercise might also prompt the development of atrial fibrosis, possibly due to cumulative minor structural damage after each exercise bout. However, there is very limited, indirect data supporting this hypothesis in athletes. Age, sex, the presence of comorbidities and cardiovascular risk factors, and genetic individual variability might serve to flag those athletes who are at the higher risk of exercise-induced AF. In this review, we will critically address current knowledge on the mechanisms of exercise-induced AF.