Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability

Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF‐dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6‐week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP‐induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa‐B (NF‐κB) phosphorylation; up‐regulated interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and transforming growth factor‐β1 (TGF‐β1) levels in LA and EAT; decreased peroxisome proliferator‐activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL‐6, TNF‐α and TGF‐β1 expression and decreased PPARγ/APN expression in 3T3‐L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL‐1 cells with LPS‐stimulated 3T3‐L1 conditioned medium (CM) significantly increased IL‐6, TNF‐α and TGF‐β1 expression and decreased SERCA2a and p‐PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca²⁺ handling dysfunction. MET attenuated the RAP‐induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF‐dependent EAT remodelling and AF vulnerability by MET.     

Inflammatory and lipid regulation by cholinergic activity in epicardial stromal cells from patients who underwent open‐heart surgery

The modulation of acetylcholine (ACh) release by botulinum toxin injection into epicardial fat diminishes atrial fibrillation (AF) recurrence. These results suggest an interaction between autonomic imbalance and epicardial fat as risk factors of AF. Our aim was to study the inflammatory, lipidic and fibroblastic profile of epicardial stroma from patients who underwent open‐heart surgery, their regulation by cholinergic activity and its association with AF. We performed in vitro and ex vivo assays from paired subcutaneous and epicardial stromal cells or explants from 33 patients. Acute ACh effects in inflammation and lipid‐related genes were analysed by qPCR, in intracellular calcium mobilization were performed by Fluo‐4 AM staining and in neutrophil migration by trans‐well assays. Chronic ACh effects on lipid accumulation were visualized by AdipoRed. Plasma protein regulation by parasympathetic denervation was studied in vagotomized rats. Our results showed a higher pro‐inflammatory profile in epicardial regarding subcutaneous stromal cells. Acute ACh treatment up‐regulated monocyte chemoattractant protein 1 levels. Chronic ACh treatment improved lipid accumulation within epicardial stromal cells (60.50% [22.82‐85.13] vs 13.85% [6.17‐23.16], P < .001). Additionally, patients with AF had higher levels of fatty acid‐binding protein 4 (1.54 ± 0.01 vs 1.47 ± 0.01, P = .005). Its plasma levels were pronouncedly declined in vagotomized rats (2.02 ± 0.21 ng/mL vs 0.65 ± 0.23 ng/mL, P < .001). Our findings support the characterization of acute or chronic cholinergic activity on epicardial stroma and its association with AF.     

Volumetric assessment of epicardial adipose tissue with cardiovascular magnetic resonance imaging

Objective: Previous studies determined the amount of epicardial fat by measuring the right ventricular epicardial fat thickness. However, it is not proven whether this one‐dimensional method correlates well with the absolute amount of epicardial fat. In this prospective study, a new cardiovascular magnetic resonance imaging (CMR) method using the three‐dimensional summation of slices method was introduced to assess the total amount of epicardial fat. Research Methods and Procedures: CMR was performed in 43 patients with congestive heart failure and in 28 healthy controls. The absolute amount of epicardial fat was assessed volumetrically in consecutive short‐axis views by means of the modified Simpson's rule. Additionally, the right ventricular epicardial fat thickness was measured in two different imaging planes: long‐axis view (EFT‐4CV) and consecutive short‐axis views (EFT‐SAX). Results: Using the volumetric approach, patients with congestive heart failure had less epicardial fat mass than controls (51 g vs. 65 g, p = 0.01). This finding was supported by EFT‐SAX (2.9 mm vs. 4.3 mm, p < 0.0001) but not by EFT‐4CV (3.5 mm vs. 3.8 mm, p = not significant). Epicardial fat mass correlated moderately with EFT‐SAX in both groups (r = 0.466, p = 0.012 in controls and r = 0.590, p < 0.0001 in patients) and with EFT‐4CV in controls (r = 0.387, p = 0.042). There were no significant differences between EFT‐4CV and EFT‐SAX in controls (4.3 mm vs. 3.8 mm, p = 0.240). However, in the heart failure group, EFT‐4CV was significantly higher compared with EFT‐SAX (3.5 mm vs. 2.9 mm, p = 0.003). Interobserver variability and reproducibility were superior for the volumetric approach compared with thickness measurements. Discussion: Quantitative assessment of epicardial fat mass using the CMR‐based volumetric approach is feasible and yields superior reproducibility compared with conventional methods.     

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...     

Trimethylamine N‐oxide as a risk marker for ischemic stroke in patients with atrial fibrillation

Trimethylamine N‐oxide (TMAO) is an independent risk factor of cardiovascular disease. Our objective was to explore the relation between TMAO and ischemic stroke (IS) in patients with atrial fibrillation (AF). A total of 68 patients with AF with IS and 111 ones without IS were enrolled. The plasma levels of TMAO remarkably increased in IS‐AF patients (8.25 ± 1.58 µM) compared with patients with AF (2.22 ± 0.09 µM, P < 0.01). The receiver operating characteristic analysis revealed that the best cutoff value of TMAO to predict IS in patients with AF was 3.53 µM with 75.0% sensitivity and 92.8% specificity (area under the curve: 0.917, 95% confidence intervals: 0.877‐0.957). Univariate and multivariate logistic regression analysis showed that TMAO was an independent predictor in IS. The level of TMAO was correlated with the CHA2DS2‐VASc score. In conclusion, TMAO was an independent predictor of IS, which could potentially refine stroke stratification in patients with AF.     

Identification of functional lncRNAs in atrial fibrillation by integrative analysis of the lncRNA-mRNA network based on competing endogenous RNAs hypothesis

A mounting body of evidence has suggested that long noncoding RNAs (lncRNAs) play critical roles in human diseases by acting as competing endogenous RNAs (ceRNAs). However, the functions and ceRNA mechanisms of lncRNAs in atrial fibrillation (AF) remain to date unclear. In this study, we constructed an AF-related lncRNA-mRNA network (AFLMN) based on ceRNA theory, by integrating probe reannotation pipeline and microRNA (miRNA)-target regulatory interactions. Two lncRNAs with central topological properties in the AFLMN were first obtained. By using bidirectional hierarchical clustering, we identified two modules containing four lncRNAs, which were significantly enriched in many known pathways of AF. To elucidate the ceRNA interactions in certain disease or normal condition, the dysregulated lncRNA-mRNA crosstalks in AF were further analyzed, and six hub lncRNAs were obtained from the network. Furthermore, random walk analysis of the AFLMN suggested that lncRNA RP11-296O14.3 may function importantly in the pathological process of AF. All these eight lncRNAs that were identified from previous steps (RP11-363E7.4, GAS5, RP11-410L14.2, HAGLR, RP11-421L21.3, RP11-111K18.2, HOTAIRM1, and RP11-296O14.3) exhibited a strong diagnostic power for AF. The results of our study provide new insights into the functional roles and regulatory mechanisms of lncRNAs in AF, and facilitate the discovery of novel diagnostic biomarkers or therapeutic targets.     

Concomitant epicardial left atrial appendage ligation and left atrial ablation of atrial fibrillation: Safety,feasibility and outcome

IntroductionWe present initial results of patients undergoing a combined procedure of epicardial LAA ligation in addition to left atrial ablation for AF.Methods9 patients were included for additional use of LARIAT as an individual treatment approach for AF. First an epicardial LAA ligation was performed, in the same procedure left atrial ablations consisting of PVI and additional substrate based modifying ablations were performed. Follow–up at 3 months and 12 months was performed.ResultsThere was only 1 minor procedural complication (11%) involving epicardial bleeding and 2 late adverse events of pericardial tamponade and stroke. At the final follow-up (median 20 months) 7 patients were in stable sinus rhythm (78%) and 2 pts had reduced AF burden.ConclusionConcomitant epicardial LAA ligation and ablation is feasible in selected patients with a reasonable risk profile. More prospective data are required to validate the safety and efficacy.     

Proteomics of epicardial adipose tissue in patients with heart failure

Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot closely linked to the pathogenesis of heart failure (HF). But the molecular signatures related to the mechanism of HF have not been systematically explored. Here, we present comprehensive proteomic analysis of EAT in HF patients and non‐HF patients as controls. A total of 771 proteins were identified in liquid chromatography‐tandem mass spectrometry experiments. Amongst them, 17 increased in abundance in HF and seven decreased. They were involved in HF‐related processes including inflammation and oxidative stress response and lipid metabolism. Of these proteins, serine proteinase inhibitor A3 (Serpina3) levels in EAT were highly up‐regulated in HF, with HF/non‐HF ratio of 4.63 (P = .0047). Gene expression of Serpina3 via quantitative polymerase chain reaction was significantly increased in the HF group. ELISA analysis confirmed a significant increase in circulating plasma Serpina3 levels in the HF group (P = .004). In summary, for the first time, we describe that parts of EAT proteome may be reactive and work as modulators of HF. Our profiling provides a comprehensive basis for linking EAT with pathogenesis of HF. Understanding the role of EAT may offer new insights into the treatment of HF.     

超敏C反应蛋白与阵发性房颤射频消融术后早期复发的关系

目的：前瞻性研究超敏C反应蛋白（hsCRP）与阵发性心房颤动射频消融术后早期复发的关系。方法：接受CARTO指导房颤射频消融术的非瓣膜性阵发性房颤患者57例,平均年龄（53.32±9.98）岁,其中男42例,女15例。术前及术后5 d连续测定外周血hsCRP和高敏肌钙蛋白T （hs-cTnT）水平,记录体表心电图,行24 h动态心电图检查。术后5 d内,32名患者（56.14%）为窦性心律,为未复发组,25名（43.86%）复发房颤,为复发组。结果：未复发组与复发组患者的hsCRP与hs-cTnT日均升高量显著正相关,P=0.044,r=0.268。而两组间基线临床特征、手术前后血浆hsCRP、hs-cTnT水平、血浆hsCRP及hs-cTnT的总升高量（峰值水平-术前水平）、日均升高量（总升高量/达到峰值所用天数）无明显统计学差异（P均>0.05）。结论：房颤射频消融术后hsCRP升高变化与心肌损伤程度相关,与早期复发无直接关系,尚不能作为预测房颤术后早期复发的高危因子。     

Clinical outcome of ablation for long-standing persistent atrial fibrillation with or without defragmentation

Objective

To assess the outcome and associated risks of atrial defragmentation for the treatment of long-standing persistent atrial fibrillation (LSP-AF).

Methods

Thirty-seven consecutive patients (60.4 ± 7.3 years; 28 male) suffering from LSP-AF who underwent pulmonary vein isolation (PVI) and linear ablation were compared. All patients were treated with the Stereotaxis magnetic navigation system (MNS). Two groups were distinguished: patients with (n = 20) and without (n = 17) defragmentation. The primary endpoint of the study was freedom of AF after 12 months. Secondary endpoints were AF termination, procedure time, fluoroscopy time and procedural complications. Complications were divided into two groups: major (infarction, stroke, major bleeding and tamponade) and minor (fever, pericarditis and inguinal haematoma).

Results

No difference was seen in freedom of AF between the defragmentation and the non-defragmentation group (56.2 % vs. 40.0 %, P = 0.344). Procedure times in the defragmentation group were longer; no differences in fluoroscopy times were observed. No major complications occurred. A higher number of minor complications occurred in the defragmentation group (45.0 % vs. 5.9 %, P = 0.009). Mean hospital stay was comparable (4.7 ± 2.2 vs. 3.4 ± 0.8 days, P = 0.06).

Conclusion

Our study suggests that complete defragmentation using MNS is associated with a higher number of minor complications and longer procedure times and thus compromises efficiency without improving efficacy.     

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.     

左房增大对起搏器术后的老年阵发性房颤患者再发房颤的影响

目的：探讨植入心脏起搏器的老年阵发性房颤患者再发房颤（包括无症状性房颤）发生率及左房容积指数对再发房颤的影响。方法：收集2012年1月-2013年12月在我院起搏器门诊长期随访且未服用抗心律失常药物的起搏器术后老年阵发性房颤患者148例,记录基线特征、超声心动图参数及随访期间内房颤发生情况。分别根据左房容积指数及房颤负荷进行分组,应用Cox回归分析探讨起搏器检测的再发房颤及房颤高负荷的危险因素。结果：患者平均随访时间为22.79个月,期间57.43%的患者再发房颤,22.97%的患者为房颤高负荷,15.54%的患者为无症状房颤。多因素Cox回归分析发现左房增大分别是再发房颤及房颤高负荷的独立危险因素。结论：左房容积指数是预测起搏器术后老年阵发性房颤患者房颤复发及房颤高负荷的独立危险因素。     

Autonomic denervation for the treatment of atrial fibrillation

The influence of the autonomic nervous system (ANS) on triggering and perpetuation of atrial fibrillation (AF) is well established. Ganglionated plexi (GP) ablation achieves autonomic denervation by affecting both the parasympathetic and sympathetic components of the ANS. An anatomic approach for GP ablation at relevant atrial sites appears to be safe, and improves the results of PV isolation in patients with paroxysmal and persistent AF. GP ablation can be accomplished endocardially or epicardially, ie, during the maze procedure or thoracoscopic approaches. Further experience is needed to assess the clinical value of this promising technique.     

The effect of ranolazine on maintaining sinus rhythm in patients with resistant atrial fibrillation

Background

Atrial fibrillation (AF) may arise out of anomalous impulse activity at atrial venous junctions. Triggered activity may be a source of abnormal impulse activity. Ranolazine is an anti-anginal agent, which inhibits normal and abnormal late Na+ channel current in the ventricle and peak Na+ channel current in the atrium. This produces an energy sparing effect and stabilizes cardiac membranes. Ranolazine is a potent inhibitor of triggered activity. The purpose of this report is to describe our initial experience with ranolazine used in patients with resistant AF.

Methods

Seven patients (4 males, 3 females, 67 ± 9 years) who developed recurrent AF within hours to a few days of restoring sinus rhythm despite AF ablation and /or failing one or more anti-arrhythmic agents were started on ranolazine (500-1000 mg/twice/day) after stopping all other anti-arrhythmic therapy. All but one patient had some form of associated structural heart disease.

Results

Two patients received no apparent benefit from ranolazine developing recurrent AF within 2 days. All other patients derived significant benefit. Four patients have experienced no recurrent AF. The other patient relapsed at 3 months and again at 6 months. The mean time in sinus rhythm to date, or to the first relapse, for the five responders was 27 ± 11 weeks. No clinically evident pro-arrhythmic episodes occurred.

Conclusion

Ranolazine was helpful in maintaining sinus rhythm in the majority of patients in which more established measures had failed. A controlled prospective trial is warranted to further investigate the efficacy of ranolazine in AF.     

Evaluating the novel parameters for assessing the LAA function and thrombus formation with nonvalvular atrial fibrillation

The dysfunction of left atrial appendage (LAA) is prone to form thrombus when atrial fibrillation (AF) sustained more than 48 h. Traditional 2D-TEE (transesophageal echocardiography) can not accurate evaluate the function of LAA. The purpose of this study is to analyze the relationship of LAA function parameters and thrombus formation in patients with non-valvular atrial fibrillation (NVAF) by real-time three-dimensional transesophageal echocardiography (RT-3D-TEE). High risk patients can be identified according to the characteristics of ultrasonic index in patients with left atrial appendage thrombosis, which has important clinical value and significance in the risk assessment, guiding treatment and judging prognosis. We examined the relationship between the echocardiographic parameters of LAA function and the incidence of thrombus in 102 NVAF patients. They underwent RT-3D-TEE and left atrial appendage thrombus (LAAT)/severe spontaneous echocardiographic contrast (SSEC) was found in 67 patients (thrombus group) but absent in the remaining 35 patients (non-thrombus group). After measured by QLAB software, the LAA functional parameters were significantly associated with LAAT/SEC formation. Univariate analysis indicated that AF time, LAD, LVEF, LAA-OAmax, LAAVmax, LAAVI and LAAEF demonstrated a positive association (P < 0.05). However, logistic regression analysis identified that AF time (OR:1.73, P < 0.05)、LAAEF (OR:4.09, P < 0.01)and LAAVI (OR:3.28, P < 0.01) were independent predictors of LAAT/SSEC. In patients with nonvalvular atrial fibrillation, echocardiographic parameters of LAA function are significantly associated with LAAT/SSEC.     

Increased inpatient mortality in patients hospitalized for atrial fibrillation and atrial flutter with concomitant amyloidosis: Insight from National Inpatient Sample (NIS) 2016-2017

PurposeUsing National Inpatient Database (NIS), comparison of clinical outcomes for patients primarily admitted for atrial fibrillation/flutter with and without a secondary diagnosis of amyloidosis was done. Inpatient mortality was the primary outcome and hospital length of stay (LOS), mean total hospital charges, odds of undergoing cardiac ablation, pharmacologic cardioversion, having a secondary discharge diagnosis of heart block, cardiogenic shock and cardiac arrest were secondary outcomes.MethodsNIS database of 2016, 2017 was used for only adult hospitalizations with atrial fibrillation/flutter as principal diagnosis with and without amyloidosis as secondary diagnosis using ICD-10 codes. Multivariate logistic with linear regression analysis was used to adjust for confounders.Results932,054 hospitalizations were for adult patients with a principal discharge diagnosis of atrial fibrillation/flutter. 830 (0.09%) of these hospitalizations had amyloidosis.Atrial fibrillation/flutter hospitalizations with co-existing amyloidosis have higher inpatient mortality (4.22% vs 0.88%, AOR: 3.92, 95% CI 1.81–8.51, p = 0.001) and likelihood of having a secondary discharge diagnosis of cardiac arrest (2.40% vs 0.51%, AOR: 4.80, 95% CI 1.89–12.20, p = 0.001) compared to those without amyloidosis.ConclusionsHospitalizations of atrial fibrillation/flutter with co-existing amyloidosis have higher inpatient mortality and odds of having a secondary discharge diagnosis of cardiac arrest compared to those without amyloidosis. However, LOS, total hospital charges, likelihood of undergoing cardiac ablation, pharmacologic cardioversion, having a secondary discharge diagnosis of heart block and cardiogenic shock were similar between both groups.     

The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease

Obesity, insulin resistance and the metabolic syndrome, are characterized by expansion and inflammation of adipose tissue, including the depots surrounding the heart and the blood vessels. Epicardial adipose tissue (EAT) is a visceral thoracic fat depot located along the large coronary arteries and on the surface of the ventricles and the apex of the heart, whereas perivascular adipose tissue (PVAT) surrounds the arteries. Both fat depots are not separated by a fascia from the underlying tissue. Therefore, factors secreted from epicardial and PVAT, like free fatty acids and adipokines, can directly affect the function of the heart and blood vessels. In this review, we describe the alterations found in EAT and PVAT in pathological states like obesity, type 2 diabetes, the metabolic syndrome and coronary artery disease. Furthermore, we discuss how changes in adipokine expression and secretion associated with these pathological states could contribute to the pathogenesis of cardiac contractile and vascular dysfunction.     

Outcome of stand-alone thoracoscopic epicardial left atrial posterior box isolation with bipolar radiofrequency energy for longstanding persistent atrial fibrillation

Introduction

Catheter ablation of longstanding (> 1 year) persistent atrial fibrillation (AF) is associated with poor outcome. This might be due to remodelling and fibrosis formation, mainly located in the posterior left atrial (LA) wall. Therefore, we adopted a thoracoscopic epicardial box isolation of the posterior left atrium using bipolar RF energy with intraoperative testing of conduction block.

Methods and results

Bilateral thoracoscopic box isolation was performed with a bipolar RF clamp. Entrance block was defined as absence of a conducted electrogram within the box, while exit block was confirmed by pacing at 10.0 V/2 ms. Ablation outcome was evaluated after 3, 6, 12 and 24 months with 12-lead ECGs and 24-hour Holter recordings.Twenty-five consecutive patients were included (58 ± 7 years, persistent AF duration 1.8 ± 0.9 years). Entrance block was achieved in all patients and exit block confirmed if sinus rhythm was achieved. After 17 ± 7 months, 76 % of the patients (n = 19) were free of AF recurrence. One patient died within 1 month and was considered an ablation failure. Four patients with AF recurrences regained sinus rhythm with additional catheter ablation or antiarrhythmic drugs.

Conclusions

Treatment of longstanding persistent AF with thoracoscopic epicardial LA posterior box isolation using bipolar RF energy with intraoperative testing of conduction block is feasible and highly effective.