Renal Denervation Suppresses Atrial Fibrillation in a Model of Renal Impairment

BackgroundA close association exists between renal impairment (RI) and atrial fibrillation (AF) occurrence. Increased activity of the sympathetic nervous system (SNS) may contribute to the development of AF associated with RI. Renal denervation (RDN) decreases central sympathetic activity.ObjectiveThe main objective of the study was to explore the effects of RDN on AF occurrence and its possible mechanisms in beagles with RI.MethodsUnilateral RI was induced in beagles by embolization of small branches of the renal artery in the right kidney using gelatin sponge granules in Model (n = 6) and RDN group (n = 6). The Sham group (n = 6) underwent the same procedure, except for embolization. Then animals in RDN group underwent radiofrequency ablation of the renal sympathetic nerve. Cardiac electrophysiological parameters, blood pressure, left ventricular end-diastolic pressure, and AF inducibility were investigated. The activity of the SNS, renin-angiotensin-aldosterone system (RAAS), inflammation and atrial interstitial fibrosis were measured.ResultsEmbolization of small branches of the renal artery in the right kidney led to ischemic RI. Heart rate, P wave duration and BP were increased by RI, which were prevented or attenuated by RDN. Atrial effective refractory period was shortened and AF inducibility was increased by RI, which were prevented by RDN. Antegrade Wenckebach point was shortened, atrial and ventricular rates during AF were increased by RI, which were attenuated or prevented by RDN. Levels of norepinephrine, renin and aldosterone in plasma, norepinephrine, angiotensin II, aldosterone, interleukin-6 and high sensitivity C-reactive protein in atrial tissue were elevated, and atrial interstitial fibrosis was enhanced by RI, which were attenuated by RDN.ConclusionsRDN significantly reduced AF inducibility, prevented the atrial electrophysiological changes in a model of RI by combined reduction of sympathetic drive and RAAS activity, and inhibition of inflammation activity and fibrotic pathway in atrial tissue.     

Periatrial Epicardial Fat Is Associated with Markers of Endothelial Dysfunction in Patients with Atrial Fibrillation

Background

Epicardial adipose tissue (EAT) is associated to atrial fibrillation (AF) burden and outcome after AF ablation. We intended to determine whether global or local EAT is associated with systemic and/or left atrial (LA) inflammation and markers of endothelial dysfunction in AF patients.

Methods and Results

Total, atrial, and ventricular EAT volume (EATtotal, EATatrial, EATventricular) were measured by multislice cardiac CT in 49 patients with paroxysmal (PAF, n=25) or persistent AF (PeF, n=24). Periatrial epicardial fat thickness at the esophagus (LA-ESO) and thoracic aorta (LA-ThA) were also measured. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), soluble intercellular adhesion molecule 1 (sICAM-1), transforming growth factor-β1 (TGF-β1), and von Willebrand Factor (vWF) levels were measured in peripheral and LA blood samples obtained during catheterization during AF ablation. Patients with PeF had higher EATatrial (P<0.05) and LA-ESO (P=0.04) than patients with PAF. VEGF, IL-8, and TGF-β1 were not associated with EAT. In contrast, after adjusting for LA volume and body mass index, higher LA-ThA was significantly associated with higher sICAM-1 and vWF levels, both in peripheral blood (P<0.05) and in LA (P<0.05). Similar results were found with LA-ESO. Body mass index, EATtotal and EATventricular were not associated with sICAM-1 and vWF.

Conclusions

Periatrial epicardial fat showed a significant positive association with increased levels of sICAM-1 and vWF, which are biomarkers of endothelial dysfunction. No such associations were found when considering body mass index or EATtotal. These results suggest that local EAT rather than regional or total adiposity may modulate endothelial dysfunction in patients with AF.     

Computational Mapping Identifies Localized Mechanisms for Ablation of Atrial Fibrillation

Atrial fibrillation (AF) is the most common heart rhythm disorder in the Western world and a common cause of hospitalization and death. Pharmacologic and non-pharmacologic therapies have met with limited success, in part due to an incomplete understanding of the underlying mechanisms for AF. AF is traditionally characterized by spatiotemporally disorganized electrical activation and, although initiating triggers for AF are described, it is unclear whether AF is sustained by spatially meandering continuous excitation (re-entrant waves), localized electrical sources within the atria, or some other mechanism. This has limited therapeutic options for this condition. Here we show that human AF is predominantly caused by a small number (1.8±0.9) of localized re-entrant waves or repetitive focal beats, that remain stable with limited spatial migration over prolonged periods of time. Radiofrequency ablation that selectively targeted the sites of these sources was able to immediately terminate fibrillation and eliminate the arrhythmia with high success. Our results show that human AF, despite apparent spatiotemporal disorganization, is often perpetuated by a few spatially-constrained and temporally conserved sources whose targeted ablation can eliminate this complex rhythm disorder.     

A Canine Model of Sustained Atrial Fibrillation Induced by Rapid Atrial Pacing and Phenylephrine

Atrial fibrillation is a common arrhythmia with considerable morbidity and mortality. Limitations in studying both the mechanisms and therapy of atrial fibrillation arise due to the paucity of models that yield sufficiently high-quality data, are not costly, and in which atrial fibrillation is sustained long enough to make the necessary observations. The canine model we present is based on the hypothesis that atrial fibrillation requires heterogeneity of repolarization, that distribution of vagal fibers is heterogeneous in the atria, and that atrial fibrillation will persist after reflex stimulation of vagal efferents by increased systemic arterial pressure. Dogs were anesthetized with morphine–chloralose because this combination maintains nearly intact autonomic control. Systemic arterial pressure was elevated approximately 75 mm Hg during infusion of phenylephrine (2 μg/kg · min⁻¹). The right atrium was paced for 20 min at 40 Hz. Atrial fibrillation was sustained after cessation of atrial pacing in dogs receiving phenylephrine, but terminated within seconds in normotensive animals. In conclusion, atrial fibrillation can be maintained for at least 40 min after cessation of rapid atrial pacing in dogs with phenylephrine-induced hypertension.Atrial fibrillation is a common arrhythmia that affects more than 2 million persons in the United States.¹ This condition is characterized by chaotic asynchronous activation and contraction of hundreds of regions of the atria, resulting in both absence of active atrial transport of blood and a rapid ventricular response. With chronic atrial fibrillation, patients can develop thromboembolism and stroke;²² and 15% of strokes in the United States occur in patients with atrial fibrillation.¹ Despite prodigious efforts to understand the mechanism of this condition and to prevent and remediate it, atrial fibrillation leads to enormous morbidity and mortality.³ One factor hindering studies of atrial fibrillation is the absence of a model in which fibrillation can be sustained for more than several seconds, although the arrhythmia can be sustained nearly permanently after weeks of rapid atrial pacing in animals with either heart failure or physical injury to the left atrium.⁸Rapid atrial pacing decreases the atrial effective refractory period, slows atrial conduction, and increases electrophysiologic heterogeneity.^10,11,20 Recently, phenylephrine was shown to increase the difference between left and right atrial and intraatrial refractory periods, thus creating heterogeneity of atrial refractoriness.¹⁶ We therefore postulated that rapid atrial pacing together with phenylephrine infusion would induce relatively sustained atrial fibrillation for at least 40 min in dogs—a duration likely to be sufficient for testing of agents with potential to convert atrial fibrillation. This report describes a simple canine model using rapid atrial pacing in which atrial fibrillation was sustained for at least 40 min.     

Dynamic Approximate Entropy Electroanatomic Maps Detect Rotors in a Simulated Atrial Fibrillation Model

There is evidence that rotors could be drivers that maintain atrial fibrillation. Complex fractionated atrial electrograms have been located in rotor tip areas. However, the concept of electrogram fractionation, defined using time intervals, is still controversial as a tool for locating target sites for ablation. We hypothesize that the fractionation phenomenon is better described using non-linear dynamic measures, such as approximate entropy, and that this tool could be used for locating the rotor tip. The aim of this work has been to determine the relationship between approximate entropy and fractionated electrograms, and to develop a new tool for rotor mapping based on fractionation levels. Two episodes of chronic atrial fibrillation were simulated in a 3D human atrial model, in which rotors were observed. Dynamic approximate entropy maps were calculated using unipolar electrogram signals generated over the whole surface of the 3D atrial model. In addition, we optimized the approximate entropy calculation using two real multi-center databases of fractionated electrogram signals, labeled in 4 levels of fractionation. We found that the values of approximate entropy and the levels of fractionation are positively correlated. This allows the dynamic approximate entropy maps to localize the tips from stable and meandering rotors. Furthermore, we assessed the optimized approximate entropy using bipolar electrograms generated over a vicinity enclosing a rotor, achieving rotor detection. Our results suggest that high approximate entropy values are able to detect a high level of fractionation and to locate rotor tips in simulated atrial fibrillation episodes. We suggest that dynamic approximate entropy maps could become a tool for atrial fibrillation rotor mapping.     

消融右肺动脉神经节丛对肾上腺素能刺激和胆碱能刺激诱发房颤的影响

目的：探讨右肺动脉神经节丛（RPVGP）消融对胆碱能及儿茶酚胺诱发房颤的影响。方法：20只犬麻醉开胸后,暴露RPVGP,分别在消融RPVGP前后,经股静脉静滴乙酰胆碱（ACh）及儿茶酚胺。测量房颤诱发率及两类递质诱发房颤的阈浓度。结果：RPVGP消融前,静滴Ach和异丙基肾上腺素（IPA）及肾上腺素（EPI）（1～100μmol/l）均可诱发AF,诱发率100%。Ach、IPA和EPI的诱发阈浓度分别为2.6±0.3μmol/l,3.3±0.2μmol/l,5.6±0.2μmol/l。RPVGP消融后,Ach及儿茶酚胺的AF诱发率分别降至10%及35%,且三种递质的诱发阈浓度分别提高至2.6±0.3μmol/l、22.5±2.4μmol/l和26.±2.6μmol/（lP〈0.05）。结论：消融RPVGP使乙酰胆碱和儿茶酚胺诱发房颤的阈浓度增高,并降低此二类介质的房颤诱发率。     

Multivariate Analysis of Correspondence between Left Atrial Volumes Assessed by Echocardiography and 3-Dimensional Electroanatomic Mapping in Patients with Atrial Fibrillation

Background

Left atrial (LA) enlargement is a predictor of worse outcome after catheter ablation for atrial fibrillation (AF). Widely used two-dimensional (2D)-echocardiography is inaccurate and underestimates real LA volume (LAV). We hypothesized that baseline clinical characteristics of patients can be used to adjust 2D-ECHO indices of LAV in order to minimize this disagreement.

Methods

The study enrolled 535 patients (59 ± 9 years; 67% males; 43% paroxysmal AF) who underwent catheter ablation for AF in three specialized centers. We investigated multivariately the relationship between 2D-echocardiographic indices of LA size, specifically LA diameter in M-mode in the parasternal long-axis view (LAD), LAV assessed by the prolate-ellipsoid method (LAV_Ellipsoid), LAV by the planimetric method (LAV_Planimetry), and LAV derived from 3D-electroanatomic mapping (LAV_CARTO).

Results

Cubed LAD of 106 ± 45 ml, LAV_Ellipsoid of 72 ± 24 ml and LAV_Planimetry of 88 ± 30 ml correlated only modestly (r = 0.60, 0.69, and 0.53, respectively) with LAV_CARTO of 137 ± 46 ml, which was significantly underestimated with a bias (±1.96 standard deviation) of -31 (-111; +49) ml, -64 (-132; +2) ml, and -49 (-125; +27) ml, respectively; p < 0.0001 for their mutual difference. LA enlargement itself, age, gender, type of AF, and the presence of structural heart disease were independent confounders of measurement error of 2D-echocardiographic LAV.

Conclusion

Accuracy and precision of all 2D-echocardiographic LAV indices are poor. Their agreement with true LAV can be significantly improved by multivariate adjustment to clinical characteristics of patients.     

心房重构与心房纤颤的病理学机制研究进展

目前,发生率最高的心率失常被认为是心房纤颤,且该病的发生率随着年龄的增长而上升。伴随着我国人口年龄结构的变化,心房纤颤在我国的发病率逐渐增加。了解该病的发生和发展的机制十分迫切。已经证明,心房重构是该病的重要发生机制。随着研究的加深,研究人员对心房重构与该病的病理学机制有了更加深刻的了解。现就心房纤颤和重构在发病中的机制进行回顾。     

Epicardial Ablation of Focal Atrial Tachycardia Arising From Left Atrial Appendage in Children

Focal left atrial tachycardia (FLAT) although a common cause of supraventricular tachycardia(SVT) among children, the one''s arising from left atrial appendage (LAA) present a unique challenge for successful ablation because of anatomical location. We present two children with FLAT arising from the epicardial LAA, successfully mapped and ablated through percutaneuous epicardial approach.     

Fluoroscopy-Free Pulmonary Vein Isolation in Patients with Atrial Fibrillation and a Patent Foramen Ovale Using Solely an Electroanatomic Mapping System

Introduction

The advent of electroanatomical mapping (EAM) systems for pulmonary vein isolation (PVI) has dramatically decreased radiation exposure. However, the need for some fluoroscopy remains for obtaining left atrial (LA) access. The aim was to test the feasibility of fluoroscopy-free PVI in patients with atrial fibrillation (AF) and a patent foramen ovale (PFO) guided solely by an EAM system.

Methods

Consecutive patients with AF undergoing PVI and documented PFO were studied. An EAM-guided approach without fluoroscopy and ultrasound was used. After completing the map of the right atrium, the superior vena cava and the coronary sinus, a catheter pull-down to the PFO was performed allowing LA access. The map of the LA and subsequent PVI was also performed without fluoroscopy.

Results

30 patients [age 61±12 years, 73% male, ejection fraction 0.64 (0.53–0.65), LA size in parasternal long axis 38±7 mm] undergoing PVI were included. The time required for right atrial mapping including transseptal crossing was 9±4 minutes. Total procedure time was 127±37 minutes. Fluoroscopy-free PVI was feasible in 26/30 (87%) patients. In four patients, fluoroscopy was needed to access (n = 3) or to re-access (n = 1) the LA. In these four patients, total fluoroscopy time was 5±3 min and the DAP was 14.9±13.4 Gy*cm². Single-procedure success rate was 80% (24/30) after a median follow-up of 12 months.

Conclusion

In patients with a documented PFO, completely fluoroscopy-free PVI is feasible in the vast majority of cases.     

Atrial Fibrillation and Colonic Neoplasia in African Americans

Background

Colorectal cancer (CRC) and atrial fibrillation/flutter (AF) share several risk factors including increasing age and obesity. However, the association between CRC and AF has not been thoroughly examined, especially in African Americans. In this study we aimed to assess the prevalence of AF and its risk factors in colorectal neoplasia in an African American.

Methods

We reviewed records of 527 African American patients diagnosed with CRC and 1008 patients diagnosed with benign colonic lesions at Howard University Hospital from January 2000 to December 2012. A control group of 731 hospitalized patients without any cancer or colonic lesion were randomly selected from the same time and age range, excluding patients who had diagnosis of both CRC and/or adenoma. The presence or absence of AF was based upon ICD-9 code documentation. The prevalence of AF in these three groups was compared by multivariate logistic regression.

Results

The prevalence of AF was highest among CRC patients (10%) followed by adenoma patients (7.2%) then the control group (5.4%, P for trend = 0.002). In the three groups of participants, older age (P<0.008) and heart failure (P<0.001) were significantly associated with higher risk of AF. After adjusting for these risk factors, CRC (OR: 1.4(95%CI):0.9–2.2, P = 0.2) and adenoma (OR: 1.1(95%CI):0.7–1.6, P = 0.7) were not significantly associated AF compared to control group.

Conclusions

AF is highly prevalent among CRC patients; 1 in 10 patients had AF in our study. The predictors of AF in CRC was similar to that in adenoma and other patients after adjustment for potential confounders suggesting that the increased AF risk in CRC is explained by higher prevalence of AF risk factors.     

Measurement of Left Atrial Pressure is a Good Predictor of Freedom From Atrial Fibrillation

Background

It is suggested that an elevated left atrial pressure (LAP) promotes ectopic beats emanating in the pulmonary veins (PVs) and that LAP might be a marker for structural remodeling. This study aimed to identify if the quantification of LAP correlates with structural changes of the LA and may therefore be associated with outcomes following pulmonary vein isolation (PVI).

Methods

We analysed data from 120 patients, referred to PVI due to drug-refractory atrial fibrillation (AF) (age 63±8; 57% men). The maximum (mLAP) and mean LAP (meLAP) were measured after transseptal puncture.

Results and Conclusions

Within a mean follow-up of 303±95 days, 60% of the patients maintained in sinus rhythm after the initial procedure and 78% after repeated PVI. Performing univariate Cox-regression analysis, type of AF, LA-volume (LAV), mLAP and the meLAP were significant predictors of recurrence after PVI (p=0.03; p=0.001; p=0.01). In multivariate analysis mLAP>18mmHg, LAV>100 ml and the presence of persistent AF were significant predictors (p=0.001; p=0.019; p=0.017). The mLAP >18 mmHg was associated with a hazard ratio of 3.8. Analyzing receiver-operator characteristics, the area under the curve for mLAP was 0.75 (p<0.01). mLAP >18 mmHg predicts recurrence with a sensitivity of 77 % and specificity of 60 %. There was a linear correlation between the LAV from MDCT and mLAP (p = 0.01, R2 = 0.61). The mLAP measured invasively displays a significant predictor for AF recurrence after PVI. There is a good correlation between LAP and LAV and both factors may be useful to quantify LA remodeling.     

128道心外膜电位标测系统的设计

心外膜电位标测是一种重要的心脏电生理研究方法,特别适用于房颤等复杂心律失常电生理机制的研究。128道心外膜电位标测系统由柔性电极、放大器、数据采集卡以及相应的软件组成,可用于心外膜实时标测。通过对标测结果的分析可以确定心律失常的起源部位和传导路径,为临床诊断、治疗提供重要依据。     

房颤患者心房肌细胞的原代培养与应用

探索成功培养房颤(atrial fibrillation,AF)患者原代心房肌细胞的方法,能够为房颤发病机制的研究奠定实验基础。取心胸外科行迷宫手术患者的左心耳,利用I型胶原蛋白酶消化法培养房颤患者的原代心房肌细胞,通过免疫组化进行鉴定,同时对培养的心房肌细胞进行初步研究。与动物实验相反,房颤患者心房肌细胞缝隙连接蛋白40(connexin40,Cx40)及Kv1.5钾离子通道蛋白的表达量均降低。由此可见直接研究成人房颤患者的心房肌细胞具有更高的可靠性,同时也证明了房颤患者心房肌细胞的培养是研究其发病机制的基础。     

Aortic and Cardiac Structure and Function Using High-Resolution Echocardiography and Optical Coherence Tomography in a Mouse Model of Marfan Syndrome

Marfan syndrome (MFS) is an autosomal-dominant disorder of connective tissue caused by mutations in the fibrillin-1 (FBN1) gene. Mortality is often due to aortic dissection and rupture. We investigated the structural and functional properties of the heart and aorta in a [Fbn1^C1039G/+] MFS mouse using high-resolution ultrasound (echo) and optical coherence tomography (OCT). Echo was performed on 6- and 12-month old wild type (WT) and MFS mice (n = 8). In vivo pulse wave velocity (PWV), aortic root diameter, ejection fraction, stroke volume, left ventricular (LV) wall thickness, LV mass and mitral valve early and atrial velocities (E/A) ratio were measured by high resolution echocardiography. OCT was performed on 12-month old WT and MFS fixed mouse hearts to measure ventricular volume and mass. The PWV was significantly increased in 6-mo MFS vs. WT (366.6 ± 19.9 vs. 205.2 ± 18.1 cm/s; p = 0.003) and 12-mo MFS vs. WT (459.5 ± 42.3 vs. 205.3 ± 30.3 cm/s; p< 0.0001). PWV increased with age in MFS mice only. We also found a significantly enlarged aortic root and decreased E/A ratio in MFS mice compared with WT for both age groups. The [Fbn1^C1039G/+] mouse model of MFS replicates many of the anomalies of Marfan patients including significant aortic dilation, central aortic stiffness, LV systolic and diastolic dysfunction. This is the first demonstration of the direct measurement in vivo of pulse wave velocity non-invasively in the aortic arch of MFS mice, a robust measure of aortic stiffness and a critical clinical parameter for the assessment of pathology in the Marfan syndrome.     

人类心房纤维性颤动变化的分子机制

近年来确认了心房纤维性颤动(AF)以促进心房的发生和维持的方式修饰了心房的电特征.并确立了节律紊乱发生的电生理变化.主要描述了功能的快变化和蛋白质表达的慢变化的分子机制,这种慢变化会引起心房纤维性颤动的电改变和收缩异常.心房纤维性颤动的一个重要分子特征是L型钙离子通道功能和蛋白质表达的减少.这种减少可能有助于保护细胞抵制由于心房纤维性颤动的激活率增加产生的潜在致死钙离子超载.对蛋白水解系统的可能作用也进行了讨论,其中重点讨论了钙蛋白酶作为一种与钙离子超载导致蛋白表达减少相联系的机制.