New approach for atrial fibrillation by suppression of renin-angiotensin system

Several studies have shown that activation of the renin-angiotensin system is associated with the mechanism of atrial fibrillation (AF). We have studied the effects of the angiotensin II type 1 receptor blocker(ARB) on electrical and structural remodeling. Although the degree of the shortening of the atrial effective refractory period was similar between ARB and a control, ARB significantly decreased the conduction delay by suppressing interstitial fibrosis. These results indicate that angiotensin II may be involved in the mechanism of structural remodeling in chronic AF, and may lead to therapies to prevent both electrical and structural substrate development. Thus, ARB may constitute a novel therapeutic approach to preventing AF.     

Pharmacological prevention of atrial tachycardia induced atrial remodeling as a potential therapeutic strategy

Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring medical therapy, and present treatment modalities are inadequate. Over the past few years, we have learned a great deal about the phenomenon of electrical remodeling, by which rapid atrial activation leads to changes in atrial electrical properties that promote AF initiation and maintenance. This knowledge opens up the possibility that electrical remodeling may itself be a novel therapeutic target in AF. The present paper reviews what is known about the basic mechanisms of atrial electrical remodeling and then discusses the experimental and clinical evidence that remodeling can be prevented by drug therapy. Despite great potential value, the development of pharmacological interventions to prevent atrial electrical remodeling is still in its infancy.     

房颤中心房钾离子通道重构机制及相关药物的研究进展

心房颤动(简称房颤)是临床上最常见的持续性快速心律失常之一,可以引起心房内血栓、脑栓塞等严重并发症,是我国70岁以上老年人发病率较高、致死率较高的一种疾病。房颤的发生机制较为复杂,大量研究表明,心脏离子钾通道重构在房颤的发生和持续存在中发挥极其重要的作用。作用靶点位于钾离子通道的药物已应用于心房颤动,虽有一定的疗效但仍存在效果欠佳,并发症较多等缺点,现阶段关于心房钾离子通道重构及新型钾离子通道药物已经成为房颤研究中的热点之一。     

Upstream therapy of atrial fibrillation

Failure of current pharmacological therapy for atrial fibrillation in maintaining sinus rhythm may be due to structural atrial remodeling caused by inflammation and fibrosis. Upstream therapy that interferes in the structural remodeling process may be effective in maintaining sinus rhythm. This article reviews upstream therapy in atrial fibrillation. Various prospective and retrospective studies demonstrate that upstream therapy, consisting of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, fish oils, glucocorticoids, or moderate physical activity, is associated with a reduced incidence of new-onset atrial fibrillation (i.e., primary prevention) and with a reduced recurrence of atrial fibrillation (i.e., secondary prevention). Larger clinical trials are required to further elucidate the position of upstream therapy in the primary and secondary prevention of atrial fibrillation.     

Enhancement of myocardial vulnerability by atrial fibrillation

Certain groups are known to have an increased risk for sudden cardiac death. Epidemiologic studies have suggested that patients with atrial fibrillation may be at higher risk. The authors hypothesize that atrial fibrillation may increase myocardial vulnerability. To test this hypothesis, 37 dogs were studied using programmed electrical stimulation techniques to determine myocardial vulnerability as assessed by the ability to provoke ventricular tachycardia. Prior to atrial fibrillation, programmed electrical stimulation did not induce ventricular tachycardia. Aconitine was then topically applied to the right atrial appendage with care taken not to make contact with the ventricle. Application of aconitine caused atrial fibrillation with an increase in ventricular rate, but did not affect arterial blood pressure. Ventricular tachycardia was induced by programmed electrical stimulation studies in 25 of 26 dogs in atrial fibrillation. The enhanced vulnerability was noted following atrial fibrillation, not after aconitine application to the great veins, which did not cause atrial fibrillation. To further exclude the possibility that aconitine application may cause changes in ventricular threshold, atrial fibrillation was induced by pacing techniques in five dogs. Prior to atrial fibrillation induction, programmed electrical stimulation did not induce ventricular tachycardia. Following atrial fibrillation, ventricular tachycardia could be repeatedly induced. Mean heart rate following atrial fibrillation increased, while pacing animals at this increment in rate did not change the noninducibility of dogs in sinus rhythm. Six patients with a history of atrial fibrillation and ventricular tachycardia were studied to determine if AF lowered myocardial threshold to VT induction. Ventricular tachycardia could only be induced by PES techniques in four of five patients when the patients' rhythm was AF (P < 0.05). This study suggests that atrial fibrillation lowers myocardial threshold for ventricular tachycardia induction and thus enhances myocardial vulnerability. The association of AF with a higher incidence of sudden death may be due to an enhanced electrical instability.     

Atrial electrophysiology and mechanisms of atrial fibrillation

Atrial fibrillation is the most common cardiac arrhythmia in clinical practice, and its management remains challenging. A solid understanding of the scientific basis for atrial fibrillation therapy requires insight into the mechanisms underlying the arrhythmia, about which an enormous amount has been learned over the past 10 years. The basic information presently available about atrial fibrillation mechanisms is reviewed. The particular properties of normal atrial electrophysiology are discussed, including salient ionic determinants of the atrial action potential and key anatomic features. Reviewed are three crucial arrhythmia mechanisms long held to be involved in atrial fibrillation: 1) rapid ectopic activity, 2) single-circuit reentry with fibrillatory conduction, and 3) multiple-circuit reentry. The determinants of each and the evidence for their involvement in clinical and/or experimental atrial fibrillation are noted. The physiological consequences, various contributing mechanisms, and clinical implications of the role of atrial-tachycardia remodeling are analyzed. Atrial-tachycardia remodeling links the potential mechanisms of atrial fibrillation, since atrial fibrillation beginning by any mechanism is likely to cause tachycardia-remodeling and thus promote the maintenance of atrial fibrillation by multiple-circuit reentry. Atrial structural remodeling is discussed as a paradigm of atrial fibrillation in which the classic features required for reentry (reduced refractory period and reentrant wavelength) may be lacking. Finally, the importance of recent insights into potential genetic determinants of atrial fibrillation is reviewed. The classic understanding of atrial fibrillation pathophysiology saw the different possible mechanisms as being alternative and opposing hypotheses. We now consider the multiple potential mechanisms as contributing to the pathophysiology of the arrhythmia to a different extent in different clinical settings and interacting with each other in a dynamic way at various stages of the natural history in many patients. It is hoped that this improved mechanistic understanding will lead to the development of improved therapeutic options.     

Down-regulation of sarcolipin mRNA expression in chronic atrial fibrillation

BACKGROUND: Abnormal intracellular Ca2+ homeostasis is an important modulator of chronic atrial fibrillation. Sarcolipin, a homologue of phospholamban, is specifically expressed in the atria, and may play an important role in modulating intracellular Ca2+ homeostasis in the atria. The aim of this study was to investigate the expression of sarcolipin mRNA in the atrial myocardium of patients with chronic atrial fibrillation. METHODS: We analyzed the expression of sarcolipin, phospholamban, cardiac calsequestrin and sodium calcium exchanger mRNAs in the right atrial myocardium from nine patients with mitral valvular disease with atrial fibrillation (MVD/AF), nine patients with MVD who had normal sinus rhythm (MVD/NSR), and 10 control patients with normal sinus rhythm who received open heart surgery (controls). The expression of mRNA was measured using the ABI PRISM 7700 Sequence Detection System (Applied Biosystems, Foster City, CA). RESULTS: Relative expression levels of sarcolipin mRNA were significantly lower in MVD/AF (0.60 +/- 0.11) than in either MVD/NSR (1.28 +/- 0.17, P < 0.01) or controls (1.10 +/- 0.10, P < 0.05). The expression levels of sarcolipin mRNA were significantly lower in the group with high values for right atrial pressure. The expression levels of phospholamban, cardiac calsequestrin and sodium calcium exchanger mRNAs were comparable among all three groups. CONCLUSIONS: Chronic electrical and mechanical overload decreased the expression of sarcolipin mRNA in the right atrial myocardium in patients with chronic atrial fibrillation. Down-regulation of sarcolipin mRNA may be part of atrial fibrillation-induced atrial remodelling.     

电重构对肺静脉内电位的影响

目的：探讨电重构对肺静脉内电位的影响。方法：窦性心律下，标测左心房和左上肺静脉的电位。在人工电刺激条件下，使左心房和左上肺静脉发生电重构，再次标测左心房和左上肺静脉的电位。结果：窦性心律下，左心房未测到尖峰电位，部分肺静脉内记录到尖峰电位，但不能驱动房颤的发生；电重构后，人工刺激，肺静脉内尖峰电位即提前且能驱动房颤的发生。结论：左上肺静脉更易于发生电重构；电重构后，左上肺静脉内尖峰电位即可提前且能驱动房颤的发生。     

Heart failure complicated by atrial fibrillation: mechanistic,prognostic, and therapeutic implications

Atrial fibrillation and congestive heart failure are two distinct clinical entities that are responsible for significant morbidity and mortality in the Western world. Hypertension, coronary artery disease, and nonischemic cardiomyopathy represent the most prevalent underlying pathologies of both diseases, implying a coincidence of both in many patients. The prevalence of atrial fibrillation with a progressive degree of congestive heart failure is increasing, as judged by New York Heart Association functional class. Moreover, the presence of congestive heart failure has been identified as one of the most powerful independent predictors of atrial fibrillation, with a sixfold increase in relative risk of its development. On the other hand, atrial fibrillation can cause or significantly aggravate symptoms of congestive heart failure in previously asymptomatic or well-compensated patients. In some patients, symptomatic dilated cardiomyopathy may develop over time entirely due to atrial fibrillation with rapid ventricular rates. Upon restoration of sinus rhythm, this type of "tachymyopathy" has been shown to be often reversible. Recent investigations of the physiologic and structural changes of the atrial myocardium ("electrical and structural remodeling") have shown that neurohumoral activation, fibrosis, and apoptosis are demonstrable with both diseases. On the other hand, experimental data suggest that the substrates of atrial fibrillation in congestive heart failure are different from those of pure atrial tachycardia-related forms of atrial fibrillation. This review highlights the clinical and pathophysiologic similarities and differences of atrial fibrillation and congestive heart failure relevant to the understanding, treatment, and prevention of these diseases in the population at risk.     

Verapamil suppresses the inhomogeneity of electrical remodeling in a canine long-term rapid atrial stimulation model

Verapamil is known to suppress shortening of the atrial effective refractory period (AERP) during relatively short-term atrial pacing, although the effect of a long-term stimulation model is unclear. The effect of verapamil on electrical remodeling was evaluated in a canine rapid atrial stimulation model. The right atrial appendage (RAA) was continuously paced (400 beats/min) for 2 weeks. Four pairs of electrodes were sutured at four atrial sites; the RAA, right atrium close to the inferior vena cava, Bachmann's bundle, and LA. AERP, AERP dispersion (AERPd), conduction time, and inducibility of AF were evaluated during the pacing phase and the recovery phase. The same protocol was performed under the administration of verapamil. In five control dogs, the AERP shortening was inhomogeneous and the shortening of the AERP was most prominent in the LA. AERPd increased during the rapid pacing phase by 5 +/- 2 ms, but recovered quickly in the recovery phase. The max AERPd was 46 +/- 4 ms in the control group and was larger than that in the verapamil group (31 +/- 3 ms, P = 0.001). At the LA site, the shortening of the AERP was decreased by verapamil administration (-19 +/- 3 vs -5 +/- 2 ms, P = 0.04). However, the AF inducibility was not significantly different between the two groups. The effect of verapamil on electrical remodeling was inhomogeneous, depending on the anatomic portion. As a result, AERPd widening during the rapid pacing phase was suppressed by verapamil, while the AF inducibility was unchanged.     

Left atrial appendage-flow velocity predicts cardioversion success in atrial fibrillation

Restoration of sinus rhythm by electrical cardioversion is a therapeutic option in appropriately selected patients with atrial fibrillation. It is important to determine predictors of electrical cardioversion outcome in patients with atrial fibrillation. Predictive value of clinical and conventional echocardiographic parameters for predicting cardioversion outcome is limited. The role of left atrial appendage (LAA) function, which may reflect left atrial contractile function, for prediction of cardioversion outcome remains unclear. We conducted a single center prospective study to evaluate the role of LAA function for prediction of cardioversion success in patients with atrial fibrillation. One hundred sixty three patients with atrial fibrillation underwent transthoracic and transesophageal echocardiography (TEE) before electrical cardioversion. LAA functions, including LAA peak flow velocity, LAA area and LAA ejection fraction, were examined. Cardioversion was successful in 133 patients and unsuccessful in 30 patients. Mean LAA peak emptying flow velocity was significantly higher in the patients with successful cardioversion than in those with unsuccessful cardioversion (0.34 +/- 0.14 vs 0.27 +/- 0.1 m/sec; p = 0.013). At multivariate logistic regression analysis, only LAA flow velocity (> 0.28 m/sec, odds ratio = 2.8 ; p = 0.03) proved to be an independent predictor of cardioversion success. LAA area (p = 0.18) and LAA ejection fraction (p = 0.52) were not different between successful and unsuccessful cardioversion groups. Therefore, measurement of LAA flow velocity provides valuable information for prediction of cardioversion outcome in patients with atrial fibrillation before TEE guided cardioversion.     

超声心动图评价左心房重构的应用

目的 左心房重构是心房颤动和心力衰竭等心血管疾病的重要机制,也是疾病进展的主要病理生理学基础。本文主要对超声心动图在早期诊断左心房重构,并对其进行危险分层,及有效评价左心房重构逆转程度等方面的应用进行综述。     

Upstream Effect for Atrial Fibrillation: Still a Dilemma?

Atrial fibrillation is the most common arrhythmia in clinical practice. Ion channel blocking agents are often characterized by limited long-term efficacy and several side effects. In addition, ablative invasive procedures are neither easily accessible nor always efficacious. The "upstream therapy," which includes angiotensin-converting enzyme inhibitors, aldosterone receptor antagonists, statins, glucocorticoids, and ω-3 poly-unsaturated fatty acids, targets arrhythmia substrate, influencing atrial structural and electrical remodeling that play an essential role in atrial fibrillation induction and maintenance. The mechanisms involved and the most important clinical evidence regarding the upstream therapy influence on atrial fibrillation are presented in this review. Some open questions are also proposed.     

Indices of electrical and contractile remodeling during atrial fibrillation in man

BACKGROUND: Atrial electrical and contractile remodeling have been demonstrated to coincide during atrial fibrillation (AF) in experimental studies. We explored whether electrical and contractile remodeling correlate in man and explored its clinical implications. METHODS: Forty-nine patients with persistent AF were studied. Electrical remodeling was assessed noninvasively using spectral analysis to estimate the average fibrillatory rate (AFR). Atrial contractility was assessed by transesophageal echocardiography (TEE) measurement of left atrial appendage outflow velocity (LAAOV). RESULTS: The AFR was 403+/-43 fibrillations per minute (fpm) and the LAAOV was 0.27+/-0.14 m/s. A significant correlation was found between AFR and LAAOV (r=-0.47, P=0.001). In patients with a LAAOV>or=0.25 m/s, the AFR was 387+/-48 fpm compared to 419+/-31 fpm among patients with LAAOV<0.25 m/s (P<0.01). CONCLUSIONS: This study demonstrates that indices of electrical and contractile remodeling are strongly correlated in persistent AF in man. The interindividual overlap, however, is too large to allow predictions of LAAOV based on fibrillatory frequency alone.     

Broad complex atrial fibrillation

The management of broad complex atrial fibrillation is complex and may be a source of morbidity and mortality if not correctly recognized and treated appropriately. We present a case series of 3 patients who were managed in our emergency department after complaints of palpitations. They presented with varying forms of rapid atrial fibrillation that had broad complexes on the 12-lead electrocardiogram. The first 2 patients were treated with calcium channel blockers for rate control, and treatment was complicated by rapid arrhythmia that required cardioversion. The final patient was correctly treated with intravenous procainamide. The diagnosis of Wolff-Parkinson-White syndrome was eventually made in all these patients. Broad complex atrial fibrillation must be treated with respect. Cases with rapid ventricular rate can decompensate from mismanagement due to poor ability to recognize the possibility of Wolff-Parkinson-White syndrome in such patients. Procainamide forms the cornerstone of treatment in hemodynamically stable rapid broad complex atrial fibrillation of unknown origin.     

Left atrial appendage electrical isolation for persistent atrial fibrillation

Left atrial appendage (LAA) may be the source for initiation and maintenance of atrial fibrillation (AF). This report shows restoration of sinus rhythm in the atria during radiofrequency wide‐area LAA electrical isolation, whereas AF persists in the LAA.     

Deglutition induced atrial tachycardia and atrial fibrillation

Deglutition induced supraventricular tachycardia is an uncommon condition postulated to be a vagally mediated phenomenon due to mechanical stimulation. Patients usually present with mild symptoms or may have severe debilitating symptoms. Treatment with Class I agents, beta blockers, calcium channel blockers, amiodarone and radiofrquency catheter ablation has shown to be successful in the majority of reported cases. We report the case of a 46-year-old healthy woman presenting with palpitations on swallowing that was documented to be transient atrial tachycardia with aberrant ventricular conduction as well as transient atrial fibrillation. She was successfully treated with propafenone with no induction of swallowing-induced tachycardia after treatment. This is also the first case to show swallowing-induced atrial tachycardia and atrial fibrillation in the same patient.     

大蒜素对血管紧张素Ⅱ诱发人心房肌细胞钙电流和游离钙离子浓度的影响

背景近年来发现血管紧张素Ⅱ可诱发心房电重构,而大蒜素具有相应的拮抗作用,可阻止或减轻心房电重构的发生.目的观察大蒜素对血管紧张素Ⅱ诱发人心房肌细胞膜钙通道电流和细胞内游离钙离子浓度的影响.设计以急性分离的人的心房肌细胞为实验对象,随机对照设计.单位一所军医大学医院心内科. 方法实验于2003-06/2004-06在第四军医大学西京医院心脏内科实验室完成.选择在此期间接受心脏体外循环手术的先天性心脏病患者10例;男6例,女4例,平均年龄(15±6)岁.术中取患者右心耳标本送至实验室后,急性分离单个人心房肌细胞,实验分4组对照组(不加任何干预措施);血管紧张素Ⅱ组加入终浓度为0.1μmol/L的血管紧张素Ⅱ;大蒜素组加入终浓度为50 μmol/L的大蒜素;血管紧张素Ⅱ+大蒜素组大蒜素50 μmol/L与血管紧张素Ⅱ0.1 μmol/L同时加入.采用全细胞膜片钳方法记录L型钙电流;以钙荧光探针荧光指示剂负载,应用激光共聚焦显微镜技术,分别于加入干预药物后即刻与15 min检测游离钙离子浓度变化.主要观察指标各组人心房肌细胞L型钙电流峰值电流密度及钙离子游离钙离子的荧光强度变化率.结果①血管紧张素Ⅱ组人心房肌细胞膜L型钙电流峰值电流密度明显高于对照组[(-12.77±1.61),(-5.78±0.81)pA/pF,P＜0.05).②大蒜素组人心房肌细胞膜L型钙电流峰值电流密度与对照组比较,无明显差异[(-5.69±0.83)pA/pF,P＞0.05].③血管紧张素Ⅱ+大蒜素组人心房肌细胞膜L型钙电流峰值电流密度明显低于血管紧张素Ⅱ组[(-8.75±0.97)pA/pF,P＜0.05).④血管紧张素Ⅱ组人心房肌细胞内游离钙离子荧光强度和游离钙离子荧光强度变化率明显高于对照组和大蒜素组[(2610.1±112.6,(299.2±27.3)%;653.9±42.5,0;639.5±44.7,(-2.2±0.6)%,P＜0.05].血管紧张素Ⅱ+大蒜素组人心房肌细胞游离钙离子荧光强度和游离钙离子荧光强度变化率明显低于血管紧张素Ⅱ组[(1284.9±85.2,(96.5±8.4)%,P＜0.05].结论大蒜素可拮抗血管紧张素Ⅱ致人心房肌细胞膜L型钙电流峰值电流密度的增加,拮抗人心房肌细胞内钙超载,产生减轻心房肌细胞电重构的作用.     

Differential atrial stunning after electrical cardioversion: an echo tissue Doppler case study.

Left atrial stunning after cardioversion is a well-known phenomenon. It has been associated with higher risk of postcardioversion thromboemboli and increased risk of recurrence of atrial fibrillation. We present a case of differential atrial stunning after electrical cardioversion for atrial fibrillation. Diagnosis was made by pulsed wave Doppler of mitral, tricuspid, and pulmonary vein inflow and mitral and tricuspid annuli. Differential mechanical atrial stunning may be a common phenomenon after cardioversion and may suggest difference in right and left atrial transport function. Its prevalence needs to be determined by a large study. Doppler tissue imaging might be routinely used in patients after cardioversion for atrial fibrillation to detect atrial stunning.     

Postoperative atrial fibrillation

Atrial fibrillation is a common arrhythmia after cardiac surgery. It is associated with an increase in morbidity, length of hospital stay, and mortality. Patients who are at higher risk of postoperative atrial fibrillation should receive prophylactic treatment. Atrial fibrillation usually resolves spontaneously after heart rate is controlled; however, if patients are highly symptomatic or hemodynamically unstable, sinus rhythm should be restored by electrical or pharmacologic cardioversion. Patients with atrial fibrillation of more than 48 hours should receive antithrombotic therapy for thromboembolism prevention.