Patient-specific modeling of atrial fibrosis increases the accuracy of sinus rhythm simulations and may explain maintenance of atrial fibrillation

Left atrial fibrosis is thought to contribute to the manifestation of atrial fibrillation (AF). Late Gadolinium enhancement (LGE) MRI has the potential to image regions of low perfusion, which can be related to fibrosis. We show that a simulation with a patient-specific model including left atrial regional fibrosis derived from LGE-MRI reproduces local activation in the left atrium more precisely than the regular simulation without fibrosis. AF simulations showed a spontaneous termination of the arrhythmia in the absence of fibrosis and a stable rotor center in the presence of fibrosis. The methodology may provide a tool for a deeper understanding of the mechanisms maintaining AF and eventually also for the planning of substrate-guided ablation procedures in the future.     

How to detect atrial fibrosis

In the last twenty years, new imaging techniques to assess atrial function and to predict the risk of recurrence of atrial fibrillation after treatment have been developed. The present review deals with the role of these techniques in the detection of structural and functional changes of the atrium and diagnosis of atrial remodeling, particularly atrial fibrosis. Echocardiography allows the detection of anatomical, functional changes and deformation of the atrial wall during the phases of the cardiac cycle. For this, adequate acquisition of atrial images is necessary using speckle tracking imaging and interpretation of the resulting strain and strain rate curves. This allows to predict new-onset atrial fibrillation and recurrences. Its main limitations are inter-observer variability, the existence of different software manufacturers, and the fact that the software used were originally developed for the evaluation of the ventricular function and are now applied to the atria. Cardiac magnetic resonance, using contrast enhancement with gadolinium, plays a key role in the visualization and quantification of atrial fibrosis. This is the established method for in vivo visualization of myocardial fibrotic tissue. The non-invasive evaluation of atrial fibrosis is associated with the risk of recurrence of atrial fibrillation and with electro-anatomical endocardial mapping. We discuss the limitations of these techniques, derived from the difficulty of demonstrating the correlation between fibrosis imaging and histology, and poor intra- and inter- observer reproducibility. The sources of discordance are described, mainly due to image acquisition and processing, and the challenges ahead in an attempt to eliminate differences between operators.     

Morphological remodeling in atrial fibrillation

In the recent years, a tremendous amount has been learned about the pathophysiology of atrial fibrillation (AF). AF induces electrophysiological changes in the atria causing a perpetuation of the arrhythmia ("electrical remodeling"). Besides such AF-induced electrophysiological changes, which involve the downregulation of L-type calcium channels and thereby the calcium inward current, AF induces structural and ultrastructural changes in atrial tissue ("structural remodeling"). Calcium-dependent tissue alterations are induced by proteases and phosphatases like calpain and calcineurin. Furthermore, cardiac diseases like hypertension, heart failure, etc. activate the atrial angiotensin II system, and thereby, a progressive pro-arrhythmogenic atrial fibrosis is induced. Besides first clinical trials assessing the antiarrhythmic effects of angiotensin II receptor blockers in patients with AF, experimental data suggest that viral gene transfer can be used to transform fibroblasts to electrically conducting cardiomyocytes. This highly interesting methodology may be helpful to restore electrical conduction in fibrotic cardiac tissue.     

Catheter ablation of persistent atrial fibrillation: The importance of substrate modification

Accumulating data have shown that elimination of atrial fibrillation (AF) sources should be the goal in persistent AF ablation. Pulmonary vein isolation, linear lesions and complex fractionated atrial electrograms (CFAEs) ablation have shown limited efficacy in patients with persistent AF. A combined approach using voltage, CFAEs and dominant frequency (DF) mapping may be helpful for the identification of AF sources and subsequent focal substrate modification. The fibrillatory activity is maintained by intramural reentry centered on fibrotic patches. Voltage mapping may assist in the identification of fibrotic areas. Stable rotors display the higher DF and possibly drive AF. Furthermore, the single rotor is usually consistent with organized AF electrograms without fractionation. It is therefore quite possible that rotors are located at relatively “healthy islands” within the patchy fibrosis. This is supported by the fact that high DF sites have been negatively correlated to the amount of fibrosis. CFAEs are located in areas adjacent to high DF. In conclusion, patchy fibrotic areas displaying the maximum DF along with high organization index and the lower fractionation index are potential targets of ablation. Prospective studies are required to validate the efficacy of substrate modification in left atrial ablation outcomes.     

Focal adhesion kinase mediates atrial fibrosis via the AKT/S6K signaling pathway in chronic atrial fibrillation patients with rheumatic mitral valve disease

Background

Atrial fibrosis, as a hallmark of atrial structural remodeling, plays a critical role in the maintenance of chronic atrial fibrillation (AF), but the mechanisms responsible for atrial fibrosis are still uncertain. Fibrogenesis represents a complex process in which focal adhesion kinase (FAK) plays an important role. Therefore, we investigated the role of FAK-mediated signaling in atrial fibrosis in patients with chronic AF related to rheumatic mitral valve disease (RMVD).

Methods

Atrial appendages were excised from 45 patients with RMVD and either chronic AF (n = 25, AF > 6 months) or sinus rhythm (n = 20). Fibrosis was assessed by histology, and FAK and its two downstream pathways (AKT/S6K and ERK1/2) were evaluated by western blotting. We further evaluated the role of FAK in fibrogenesis by culturing neonatal rat cardiac fibroblasts to determine the importance of FAK-regulated signaling in cardiac myofibroblast differentiation induced by transforming growth factor-β1 (TGFβ1).

Results

Our study revealed that FAK can regulate its downstream signaling to cause fibrosis in atrial tissue and activate isolated fibroblasts. Histology revealed a significant increase in atrial fibrosis in AF patients. The phosphorylation of FAK and its downstream AKT/S6K signaling was increased secondary to TGFβ1-induced high expression of α-SMA, a marker of myofibroblast activity. FAK and AKT inhibitors suppressed α-SMA expression in TGFβ1-induced fibroblasts. However, ERK1/2 signaling seemed to be unrelated to the fibrotic process in AF patients.

Conclusion

The FAK-mediated AKT/S6K signaling pathway participated in atrial fibrogenesis and this finding may contribute to the prevention of atrial fibrosis associated with chronic AF in patients with underlying cardiac disease.     

永久性心脏起搏器植入术中发生心房纤颤时心房电极导线定位经验

目的:研究永久性心脏起搏器植入术中心房纤颤(房颤)发作时以右心房波振幅最大处为右心房电极导线固定位置的可行性。方法:22例房颤发作时植入右心房电极导线的患者术中,测试右心房波振幅,术后随访恢复窦性心律(窦律)时测试右心房波振幅、起搏阈值,2者进行对比分析。结果:房颤心律时,所测得的右心房振幅与转为窦律后所测得的右心房波振幅有较好相关性,2者差异无统计学意义[(2.4±1.0)mv比(2.7±1.2)mv,P>0.05]。房颤时术中右心房波振幅平均(2.4±1.0)mv(1.6～3.7mv)者,在房颤转为窦律后所测定的心房感知和起搏功能良好。结论:在房颤发作时,右心房波振幅作为永久心脏起搏器合适的感知及起搏参数,有一定的临床实用价值。     

伊布利特转复心房颤动和心房扑动的疗效观察

目的观察和比较伊布利特和普罗帕酮终止心房颤动(房颤)/心房扑动(房扑)的疗效及其不良反应。方法 268例发作持续时间<90 d的房颤/房扑患者,随机分组,分别静脉应用(1～2次,每次10 min推注)伊布利特(1.0 mg和1.0 mg)和普罗帕酮(70.0 mg和70.0 mg)。结果伊布利特转复房颤/房扑的成功率分别为67.6%(46/68)和92.4%(61/66),普罗帕酮转复房颤/房扑的成功率分别为32.5%(26/80)和29.6%(16/54)。伊布利特组平均转复时间(27±13)min,转复窦性心律时平均使用量为(1.5±0.4)mg。普罗帕酮组平均转复时间(39±7)min,转复窦性心律时平均使用量为(134.1±6.4)mg。房颤的转复率与左心房直径呈负相关,左心房直径<4.0 cm患者的转复率明显高了左心房直径≥4.0 cm患者的转复率;房扑持续时间可作为房扑终止的预测因子。扑动波周长延长是伊布利特终止房扑的主要特征。结论伊布利特作为一种Ⅲ类的抗心律失常药,在监测的条件下,能迅速、安全、有效地终止房颤/房扑。     

Atrial fibrosis and substrate based characterization in atrial fibrillation: Time to move forwards

Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia in clinical practice. However, current therapeutic interventions for atrial fibrillation have limited clinical efficacy as a consequence of major knowledge gaps in the mechanisms sustaining atrial fibrillation. From a mechanistic perspective, there is increasing evidence that atrial fibrosis plays a central role in the maintenance and perpetuation of atrial fibrillation. Electrophysiologically, atrial fibrosis results in alterations in conduction velocity, cellular refractoriness, and produces conduction block promoting meandering, unstable wavelets and micro-reentrant circuits. Clinically, atrial fibrosis has also linked to poor clinical outcomes including AF-related thromboembolic complications and arrhythmia recurrences post catheter ablation. In this article, we review the pathophysiology behind the formation of fibrosis as AF progresses, the role of fibrosis in arrhythmogenesis, surrogate markers for detection of fibrosis using cardiac magnetic resonance imaging, echocardiography and electroanatomic mapping, along with their respective limitations. We then proceed to review the current evidence behind therapeutic interventions targeting atrial fibrosis, including drugs and substrate-based catheter ablation therapies followed by the potential future use of electro phenotyping for AF characterization to overcome the limitations of contemporary substrate-based methodologies.     

Extracellular matrix remodeling in atrial fibrosis: Mechanisms and implications in atrial fibrillation

Atrial fibrosis has been strongly associated with the presence of heart diseases/arrhythmias, including congestive heart failure (CHF) and atrial fibrillation (AF). Inducibility of AF as a result of atrial fibrosis has been the subject of intense recent investigation since it is the most commonly encountered arrhythmia in adults and can substantially increase the risk of premature death. Rhythm and rate control drugs as well as surgical interventions are used as therapies for AF; however, increased attention has been diverted to mineralocorticoid receptor (MR) antagonists including spironolactone as potential therapies for human AF because of their positive effects on reducing atrial fibrosis and associated AF in animal models. Spironolactone has been shown to exert positive effects in human patients with heart failure; however, the mechanisms and effects in human atrial fibrosis and AF remain undetermined. This review will discuss and highlight developments on (i) the relationship between atrial fibrosis and AF, (ii) spironolactone, as a drug targeted to atrial fibrosis and AF, as well as (iii) the distinct and common mechanisms important for regulating atrial and ventricular fibrosis, inclusive of the key extracellular matrix regulatory proteins involved.     

Primary Cardiac Sarcoidosis with Syncope and Refractory Atrial Arrhythmia: A Case Report and Review of the Literature

We discuss the case of a 38-year-old black man who presented at our hospital with his first episode of syncope, recently developed atrial arrhythmias refractory to pharmacologic therapy, and a left atrial thrombus. He was diagnosed with primary cardiac sarcoidosis characterized by predominant involvement of the epicardium that caused atrial fibrillation and atrial flutter. Histologic analysis of his epicardial lesions yielded a diagnosis of sarcoidosis. This patient''s atrial arrhythmia was successfully treated with a hybrid operation that involved resection of his atrial appendage, an Epicor maze procedure, and radiofrequency ablation during a catheter-based electrophysiologic study. The cardiac sarcoidosis was successfully managed with corticosteroid therapy.Our case report shows that sarcoidosis can initially manifest itself as syncope with new-onset atrial arrhythmia. Sarcoidosis is important in the differential diagnosis because of its progressive nature and its potential for treatment with pharmacologic, surgical, and catheter-based interventions.     

热休克蛋白47在心房颤动患者心肌中的表达

目的探讨热休克蛋白47(HSP47)在心房颤动(简称房颤)患者心房结构重构中所起的作用。方法 60例行心脏手术的患者分为窦性心律组、阵发性房颤组、持续性房颤组,各组20例,于手术中获取右心耳心房组织,采用实时荧光定量方法检测HSP47的mRNA表达;同时采用超声心动图测量心房内径,并研究其相关性。结果与窦性心律组比较,阵发性房颤组及持续性房颤组中HSP47mRNA水平明显增加(P<0.05),且持续性房颤组较阵发性房颤组增加更明显(P<0.05)。房颤患者HSP47mRNA水平与左房内径呈显著正相关(r=0.780,P<0.01)。结论房颤患者心房组织中HSP47基因表达显著增加,并与房颤的严重程度密切相关。     

白藜芦醇对快速起搏右心房诱发的持续性心房颤动猪心房结构重构的影响

目的 观察快速起搏猪右心房制备持续性心房颤动（AF）的效果,探讨白藜芦醇（RES）干预对持续性AF猪的心房结构重构的影响.方法 18只小家猪（雌雄不拘）按完全随机设计的分组方法（采用动物编号和随机分组表）分为起搏组（ATP组）、假手术组（Sham组）和RES干预组各6只,采用Seldinger血管穿刺技术送入双极电极至右心房并连接实验用起搏器（AOO）,ATP组和RES干预组的右心房快速起搏（500次/min）2周,制备持续性AF实验模型.3组猪分别于起搏前和起搏2周后进行电生理和经胸壁超声心动图检查,以检测AF的持续时间、左右心房大小及左心房收缩末面积.RES干预组猪于起搏前1周开始服用RES（2.5 mg·kg-1·d-1）.起搏2周后取各组猪的左右心房组织标本,观察心房组织形态学和间质纤维化的改变,用免疫组织化学分析软件计算胶原容积分数（CVF）来反映间质纤维化程度.结果 （1）起搏2周后,ATP组AF的发生率较RES干预组明显升高（100％比66.7％,x2=10,P＜0.01）、持续时间延长[（26.41±9.89）min比（9.56±1.36） min,F=10.7,P=0.01].（2）起搏2周后,ATP组和RES干预组猪的左右心房明显比起搏前增大;但RES干预组的左心房收缩末面积明显低于ATP组[（599.2±8.7） mm2比（744.3±29.9） mm2,F=130.61,P＜0.01].（3）RES干预组左右心房组织CVF明显低于ATP组（56％±6％比73％±7％;59％±6％比75％±7％,均为P＜0.01）.结论 快速起搏猪右心房可成功制备持续性AF模型;RES干预可以明显抑制快速起搏右心房诱发的持续性AF猪的心房结构重构,减少AF的发生.     

房颤心房纤维化相关研究的文献计量学分析

目的 分析近20年房颤心房纤维化相关领域的研究现状、热点及趋势。 方法 以Web of Science核心合集数据库为数据来源,利用可视化分析软件CiteSpace对近20年房颤心房纤维化相关研究进行可视化分析,探讨相关研究的作者、国家/机构分布、期刊分布状况以及对关键词进行分析。 结果 纳入1 468篇SCI文章,发文量最高的作者是Nattel S,引文量最高的是Burstein B。美国和中国为该领域研究的主要国家,美国犹他大学、约翰霍普金斯大学是房颤心房纤维化研究的重要机构,载文量最多的期刊是《Journal of cardiovascular electrophysiology》,被引频次最高的期刊是《Circulation》,主要的研究热点是①心力衰竭/心肌梗死并发心房颤动与心房纤维化研究;②心房纤维化评估在心房颤动导管消融/基质消融中的应用③炎症及氧化应激在房颤心房纤维化中的作用机制研究。研究的前沿方向主要有①关于房颤患者的患病率、复发率和死亡率的研究;②房颤患者中风的预防;③基于心肌成纤维细胞探讨房颤相关机制的研究;④房颤患者的管理;⑤通过延迟增强MRI评估心房组织纤维化程度。 结论 本研究为了解房颤心房纤维化相关研究提供了一个视角,为研究者识别潜在的合作者和合作机构、热点话题和研究前沿提供了有价值的信息。     

Minimally invasive pulmonary vein isolation and partial autonomic denervation for surgical treatment of atrial fibrillation

Objective It was our goal to determine the efficacy of a minimally invasive surgical approach to the treatment of atrial fibrillation that combines pulmonary vein antral isolation with targeted partial autonomic denervation. Methods Eighty-three patients underwent video-assisted bilateral pulmonary vein antral electrical isolation with confirmation of block and partial autonomic denervation. Sixty-two (41 paroxysmal, 21 persistent/long-standing persistent) patients had a follow-up of 6 months or greater. Fifty-seven of these patients had a long-term rhythm monitor at 6 months (39 paroxysmal, 18 persistent/long-standing persistent). Results Success was defined as no episodes of atrial fibrillation greater than 15 s duration on long-term monitoring. Treatment was successful in 32 of 39 (82.1%) patients with paroxysmal atrial fibrillation and 10 of 18 (55.6%) with persistent/long-standing persistent atrial fibrillation. Conclusion Early data suggest that pulmonary vein electrical isolation combined with targeted partial autonomic denervation is a safe and efficacious approach for the treatment of paroxysmal atrial fibrillation. Techniques are being developed for the minimally invasive surgical treatment of persistent and long-standing persistent atrial fibrillation from an epicardial approach.     

Increased lysyl oxidase expression and collagen cross-linking during atrial fibrillation

The aim of the study is to characterize the signal transduction leading to interstitial fibrosis in the pathogenesis of atrial fibrillation (AF) and atrial remodeling.Samples of the left atrial appendage (LA) from patients with AF showed higher collagen content (73 ± 5 vs. 38 ± 2 μg/mg protein) and 2.5-fold increased collagen crosslinking compared to patients with sinus rhythm (SR). Affymetrix-assays, RT-PCR and western Blot analysis revealed that LA of AF patients are characterized by increased lysyl oxidase (LOX) mRNA (218 ± 42%) and protein (253 ± 11%) expression. This was associated with increased expression of connective tissue growth factor (CTGF), fibronectin and Rac1 activity compared to SR. In neonatal cardiac fibroblasts, the Rac1 specific small molecule inhibitor NSC23766 prevented angiotensin II (AngII) induced upregulation of LOX (214 ± 16%) expression. Inhibition of CTGF by siRNA transfections completely inhibited AngII induced LOX expression. The LOX specific small molecule inhibitor BAPN prevented AngII and CTGF induced fibronectin expression. Left atria of transgenic mice with cardiac overexpression of Rac1 (RacET) that develop AF at high age exhibited upregulation of CTGF as well as LOX (187 ± 7%) and fibronectin (627 ± 146%) expression. Atria of RacET showed increased collagen content (28 ± 2 μg/mg protein) and crosslinking (10 ± 0.7) compared to wildtypes (20 ± 0.4 μg/mg protein; 5 ± 0.9).Left atrial myocardium of patients with atrial fibrillation is characterized by increased lysyl oxidase and fibronectin expression as well as collagen cross-linking. In cardiac fibroblasts, Rac1 GTPase mediates upregulation of fibronectin via LOX and CTGF. Inhibition of this signaling pathway may therefore represent a target for the prevention of fibrotic atrial remodeling.     

Dressler's syndrome following pulmonary vein isolation for atrial fibrillation

Dressler's syndrome, characterized by features of fever, pericarditis and pericardial effusion typically occurs in the weeks to months following a myocardial infarction. The syndrome has also been described following several other myocardial and pericardial pathologies, including two reports of Dressler's syndrome following radio-frequency ablation. We describe a case of Dressler's syndrome following a pulmonary vein isolation procedure, which is being performed with increasing frequency as a treatment strategy for atrial fibrillation.     

Incidence and predictive factors of atrial fibrillation after ablation of typical atrial flutter

Although cavotricuspid isthmus radiofrequency catheter ablation is considered curative therapy for typical atrial flutter, many patients develop an atrial fibrillation after ablation. The purpose of our study was to determine the incidence and the predictive factors of post-ablation atrial fibrillation. One hundred and forty eight consecutive patients underwent cavotricuspid isthmus ablation for the treatment of typical atrial flutter between January 2004 and December 2005 in our electrophysiological department. Complete cavotricuspid isthmus block was successfully obtained in 96.6% of the patients. At the end of the electrophysiological study a sustained atrial fibrillation was inducible in 20 patients (13.5%). During an average follow-up of 21.3 ± 8.2 months, atrial fibrillation occurred in 27% of the patients. Univariate analysis identified four parameters correlated with post-ablation atrial fibrillation among the 21 parameters tested: the young age of the patients, a prior history of atrial fibrillation, an inducible atrial fibrillation, and a paroxysmal atrial flutter. Only inducible atrial fibrillation and paroxysmal atrial flutter were independent factors linked to atrial fibrillation after ablation. In our study the incidence of atrial fibrillation after cavotricuspid isthmus radiofrequency catheter ablation is 152 per 1,000 patient-years, i.e. 25 times higher than the incidence of atrial fibrillation in the general population of the same age. Twenty five percent of the patients who had neither prior history of atrial fibrillation nor structural heart disease suffered from atrial fibrillation during a mean follow-up of 21.3 ± 8.2 months. All these results suggest that atrial flutter and fibrillation could be manifestations of a more general electrophysiologic disease. They emphasize the need for all these patients to benefit from regular, long-term cardiological follow-up after cavotricuspid isthmus ablation because of the high incidence of atrial fibrillation. Treatment with antiarrhythmic and antithrombotic agents should also be adapted to these factors.     

房颤伴高血压患者随诊间收缩压波动对预后的影响

目的 探讨收缩压波动对房颤伴高血压患者预后的预测意义 方法 选取2012-2014年于新疆维吾尔自治区人民医院确诊为心房颤动伴高血压的患者，随访其收缩压的变化及平均收缩压，并监测其心源性死亡、急性冠脉综合征、慢性心力衰竭、脑栓塞及外周血管栓塞的发生率。结果在随访的过程中，随着收缩压波动幅度的增加，其终点事件发生率也在不断的增加，收缩压波动最大的四分位组主要终点事件及次要终点事件的发生率是要明显高于收缩压波动最小的四分位组，且患者随诊次数越多，收缩压波动对房颤患者预后的预测意义就越大，这种预测意义在平均收缩压较高的患者中更为明显。结论 收缩压波动可影响房颤伴高血压患者的预后，且收缩压波动越大，房颤患者的预后越不佳。     

Atrial fibrosis – an obligatory component of arrhythmia mechanisms in atrial fibrillation?

Atrial fibrosis is common in atrial fibrillation (AF). Experimental studies have provided convincing evidence that fibrotic transformation of atrial myocardium results in deterioration of atrial conduction, increasing anisotropy of impulse propagation and building of boundaries that promote re-entry in the atrial walls that maybe directly relevant for the mechanisms responsible for maintaining AF. Whether or not fibrosis is a result of structural remodelling caused by persistent AF or a manifestation of occult myocardial process that leads to development of arrhythmia is less clear. Human data indicate the presence of association between persistency of AF and the extent of structural changes in atrial myocardium. The role atrial fibrosis plays in the mechanisms of AF, however, may differ between patients with structurally normal hearts, such as lone AF, and those with advanced cardiovascular comorbidities.     

Utility of postural change in differentiating sludge from thrombus in the left atrial appendage: A case report

We detected symptomatic atrial fibrillation in a 64‐year‐old man who had undergone mitral valvuloplasty. While performing transesophageal echocardiography (TEE) in the left lateral decubitus position, we detected an isoechoic mass lesion at the bottom of the left atrial appendage (LAA). After changing the patient's position from left to right, the mass lesion dropped down from the bottom of the LAA, spread out into the left atrium, and appeared as a spontaneous echocardiographic contrast with mobility. We therefore diagnosed the mass lesion as not a thrombus but sludge. Changing the patient's position during TEE is useful for distinguishing sludge from thrombi.