Journal of Applied Physiology Journal of Applied Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 105: 293-298, 2008. First published May 1, 2008; doi:10.1152/japplphysiol.01270.2007
8750-7587/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
105/1/293    most recent
01270.2007v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Liang, L.
Right arrow Articles by Chen, Y.-H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liang, L.
Right arrow Articles by Chen, Y.-H.

High sensitivity of the sheep pulmonary vein antrum to acetylcholine stimulation

Lei Liang,1,2,* Qin Pan,3,* Yi Liu,3,* Huaizhi Chen,1,3,* Jun Li,1,2 Ramon Brugada,4 Pedro Brugada,5 Kui Hong,6 Guillermo J. Perez,7 Cuimei Zhao,1,2 Jie Qi,1,2 Yangyang Zhang,1 Luying Peng,3 Li Li,3 and Yi-Han Chen1,2,3

1Department of Cardiology, Tongji Hospital, 2Heart Rhythm Research Center, and 3Institute of Medical Genetics, Tongji University, Shanghai, China; 4Montreal Heart Institute, Montreal, Quebec, Canada; 5Heart Rhythm Management Center, Cardiovascular Center, UZ Brussel-VUB, Brussels, Belgium; 6Department of Cardiology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; and 7Masonic Medical Research Laboratory, Utica, New York

Submitted 4 December 2007 ; accepted in final form 23 April 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Isolation of the pulmonary vein antrum can terminate atrial fibrillation, but the rationale has not been elucidated. In the present study, we show that sheep atrial effective refractory period (ERP) was heterogeneously shortened by acetylcholine administration. After perfusion with 15 µM acetylcholine, the shortest ERP occurred in the pulmonary vein antrum, which was recorded with the standard intracellular microelectrode technique (the ERP results in the pulmonary vein antrum, left atrial posterior wall, roof, free wall and appendage, and right atrial free wall were 52.0 ± 1.6, 75.1 ± 2.0, 77.2 ± 1.7, 85.6 ± 1.7, 64.3 ± 2.1, and 90.5 ± 1.3 ms, respectively; P < 0.05). Immunofluorescent staining revealed that muscarinic type 2 receptors (M2R) were also distributed heterogeneously in the atrial myocardium, with the highest density in the antrum (the relative fluorescent intensity results of the M2R in the pulmonary vein antrum, left atrial posterior wall, roof, free wall and appendage, and right atrial free wall were 62.64 ± 2.56, 53.12 ± 2.76, 51.83 ± 2.45, 47.90 ± 2.33, 55.27 ± 2.08, and 45.53 ± 2.02, respectively; P < 0.05), which was in accordance with the heterogeneity of ERP distribution. Thus the pulmonary vein antrum is a unique electrophysiological region with high sensitivity to acetylcholine, and its intensive response to acetylcholine is most likely associated with the dense M2R distribution of this region. Such an acetylcholine-induced ERP heterogeneity is possibly a substrate for atrial fibrillation and hence one of the potential electrophysiological bases for the isolation therapy.

atrial fibrillation; pulmonary vein antrum; effective refractory period; muscarinic type 2 receptor

ATRIAL FIBRILLATION IS THE most common arrhythmia encountered in clinical practice. It can cause complications such as congestive heart failure and stroke (7, 24). Catheter ablation is thought to be a breakthrough in the history of the treatment of the arrhythmia (30). Although the technique has been modified, its critical point is isolation of the pulmonary vein antrum (4, 8, 25–27). Association of cholinergic nerves with atrial fibrillation has been well documented in, for example, humans, canine, and sheep (17, 19, 27, 32). In human heart, cholinergic nerve fibers distribute mainly in the left atrial posterior wall (LAPW), especially in the pulmonary vein antrum or the vicinity (5, 29). Cholinergic denervation achieved by catheter ablation can effectively reduce the recurrence of the arrhythmia (27). We hypothesize that cholinergic nerves may alter the electrophysiological activity of the pulmonary vein antrum via muscarinic type 2 receptors (M2R). The activation of the receptor produces an electrophysiological substrate involved in the initiation or maintenance of the arrhythmia, whereas isolation of the pulmonary vein antrum may block the interaction of the electrophysiological substrate with other parts of the atria. In this study, we investigated the electrophysiological response of the sheep pulmonary vein antrum to cholinergic agonists and found that its effective refractory period (ERP) was reduced more than in other locations of the atrium. This heterogeneity in electrophysiological response is correlated with the distribution of the M2R. These results are consistent with our hypothesis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
All procedures for animals were approved by the Animal Ethics and Experimentation Committee of the Tongji University, Shanghai, China, and were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (publication no. 85-23, revised 1996). The research protocol for humans was reviewed and approved by the Ethical Committee at the Tongji University School of Medicine, Shanghai, China, and conformed to the guidelines of the World Medical Assembly (the Declaration of Helsinki).

Tissue preparation.   Young sheep weighing 13–17 kg were anesthetized with pentobarbital sodium. Mechanical ventilation was applied with an incubated endotracheal tube. Thoracotomy was performed on all animals via the sternum. For the immunofluorescent staining of M2R, sheep hearts were continuously perfused with a Langendorff apparatus with 36.5°C Tyrode solution (in mM: 145 NaCl, 4.5 KCl, 2. 5 CaCl2, 1.0 MgCl2, 20 HEPES, 11.1 glucose, pH 7.35, 95% O2-5% CO2) through the coronary artery for 5–10 min. For the intracellular microelectrode recording, sheep hearts were quickly excised and stored in oxygenated (95% O2-5% CO2) cold above Tyrode solution. The sheep pulmonary vein antrum, LAPW, left atrial roof, left atrial free wall (LAFW), left atrium appendage (LAA), and right atrial free wall (RAFW) were isolated under a stereoscopic microscope, respectively. The isolation procedure took no longer than 15 min.

The research also included the pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW of human hearts of both sexes (4 women, 2 men) from 10 to 40 years of age, which were taken from cadavers without basal heart disease.

Intracellular microelectrode recordings.   Standard intracellular microelectrode recording techniques were used (16). The voltage signal was amplified with a DC preamplifier and head stage (NL102; Digitimer, Welwyn Garden City, UK) and analyzed by a PowerLab/8SP data-acquisition system (Chart software, version 5.0; AD Instruments, Colorado Springs, CO). All samples were stimulated at 1 Hz with square-wave pulses of 1 ms in duration and with the amplitude at two times the threshold. Glass capillary microelectrodes with tip resistances of 10–20 M{Omega} and filled with 3 M KCl were used to impale into endocardial surface. Experiments were started after 2 h of perfusion in 36.5°C Tyrode solution as mentioned above. After the sample was perfused with 15 µM acetylcholine for 30 min, resting membrane potential, action potential amplitude, action potential duration (APD) at 50% and 90% of repolarization (APD50 and APD90, respectively), and ERP were acquired. One cell was recorded at each of the following sites: the pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW (one cell each site from one sheep). The ERP was measured with 15 basic (S1) stimuli followed by a premature (S2) stimulus at an S1S2 interval that was decreased by 1- to 10-ms decrements from the basic cycle length, with the ERP defined as the longest S1S2 interval failing to produce a new, propagated action potential. The ERP was determined twice at each basic cycle length, and the mean of the ERP values was used for data analysis.

Pharmacological studies.   To examine the EC50, tissues from pulmonary vein antrum and other atrial regions were discretely perfused with different doses of acetylcholine for ~10 min and then washed out for 5 min. With the increase of acetylcholine concentration, the ERP did not further shorten, and a plateau response was achieved. As for the determination of IC50, with 15 µM acetylcholine preadministered for 10 min and subsequent constant administration, tissues from pulmonary vein antrum and other atrial regions were perfused with different muscarinic receptor blockers for ~10 min and then washed out for 5 min. The dose-response curves were acquired via logistic equation.

Immunofluorescent staining for M2R in the atrium.   We analyzed the distribution of the M2R in the pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW in sheep (n = 6) and humans (n = 6) by immnunohistochemistry and confocal laser scanning biological microscopy, following modifications to previous methods (6). After the pericardium and fatty tissue were eliminated from the surface of the atrium, the atrium specimens were fixed by 4% paraformaldehyde in PBS for 24 h and embedded in paraffin. Five-micrometer-thick sections were then sliced from each block. After samples were immersed in dimethylbenzene and graded ethanol successively, slides of the pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW were sequentially treated as follows: 1) exposure to 0.01 mol/l citrate buffer (pH 6.0) at 95°C for 15 min, 2) blocking nonspecific antigen by 10% normal rabbit serum for 10 min, 3) incubation overnight at 4°C with M2R (Sigma-Aldrich), muscarinic type 3 receptors (M3R; MBL), muscarinic type 4 receptors (M4R; MBL), GIRK3.1 (US Biological), GIRK3.4 polyclonal antibody (1:100; Santa Cruz Biotechnology), and distilled water (negative control). Rat hippocampus was used as a positive control. Slides of different sites were treated with the same antibody at the same time. Thereafter, slides were reacted with goat anti-rabbit IgG-FITC (1:100; Santa Cruz Biotechnology) for 45 min at room temperature. Signals were visualized at 500–550 nm by FV1000 confocal laser-scanning biological microscope (Olympus). Immunofluorescence was analyzed from 50 cardiomyocytes of each slide in five slides of each atrial site. Moreover, the fluorescence of slides on the same sample was measured three times over 3 days. The cellular fluorescent intensity was evaluated by ImageJ 1.34 software (National Institutes of Health) (1, 20).

Statistics.   Data are expressed as means ± SE. Statistical analysis of data was performed by applying one-way ANOVA followed by Student-Newman-Keuls post hoc test. A P value of <0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Electrophysiological response of the pulmonary vein antrum to M2R agonist.   We examined the effect of acetylcholine, an M2R agonist, on the parameters of action potential and ERP of the sheep atrial myocardium using the standard intracellular microelectrode recording technique. Figure 1 displays the backsides of the atrium and the pulmonary vein antrum in the sheep. Figure 2 shows a dose-response curve and a time dependence of the effect of acetylcholine on the ERP in cardiomyocytes of sheep pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW. In the present study, we used the data from the left superior pulmonary vein antrum to represent the different pulmonary vein antrums. The data from the left superior pulmonary vein antrum were similar to those from the other pulmonary vein antrums. The pulmonary vein antrum displayed a maximum response to acetylcholine stimulation. The ERP stayed stable, without significant changes for 30 min after application of 15 µM acetylcholine. Without treatment of acetylcholine, no significant difference in the ERP was observed among the pulmonary vein antrum, LAPW, roof, LAFW, and LAA (P > 0.05), except that the RAFW showed a longer ERP than the left atrium (the pulmonary vein antrum, LAPW, roof, LAFW, and LAA) (P < 0.05). After perfusion with 15 µM acetylcholine, ERP results in pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW were 52.0 ± 1.6, 75.1 ± 2.0, 77.2 ± 1.7, 85.6 ± 1.7, 64.3 ± 2.1, and 90.5 ± 1.3 ms, respectively. Acetylcholine obviously shortened the ERP in the atrial myocytes, especially in the pulmonary vein antrum (from 104.0 ± 2.1 to 52.0 ± 1.6 ms), resulting in a pronounced heterogeneity in the ERP among different sites of the atrial myocardium. Similarly, resting membrane potential, action potential amplitude, APD50, and APD90 also showed heterogeneity in spatial distribution (Fig. 3 and Table 1).


Figure 1
View larger version (99K):
[in this window]
[in a new window]

  		Fig. 1. A: backside of the atrium. LSPV and RSPV, left and right superior pulmonary veins; LIPV and RIPV, left and right inferior pulmonary veins; SVC, superior vena cava; IVC, inferior vena cava; LAA and RAA, left and right atrial appendage. B: pulmonary vein antrum. Two inferior pulmonary veins share a common antrum in sheep.

 

Figure 2
View larger version (18K):
[in this window]
[in a new window]

  		Fig. 2. A: dose-response curves of effect of ACh on effective refractory period (ERP) of cardiomyocytes in the pulmonary vein antrum, left atrial posterior wall (LAPW), left atrial roof, left atrial free wall (LAFW), LAA, and right atrial free wall (RAFW); n = 5 sheep. B: time-effect curves of ACh on ERP of the pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW (1 cell each site from 1 sheep; n = 5 sheep). Antrum indicates the left superior pulmonary vein antrum. *P < 0.05, antrum vs. LAA, roof, and LAPW; **P < 0.01, antrum vs. RAFW and LAFW.

 

Figure 3
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 3. Representative action potential configurations of atrial cardiomyocytes in the left superior pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW. Black lines represent AP before ACh application, and red lines represent AP after 15 µM ACh application.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Electrophysiological changes of atrial cardiomyocytes before and after acetylcholine application

 
We also noted that, after acetylcholine was washed out, action potential parameters and ERP of sheep atrial cardiomyocytes returned to original levels before treatment with acetylcholine. Another M2R agonist, carbachol (1 µM), also produced an effect (Table 2) similar to acetylcholine, whereas the M2R blocker methoctramine (1 µM) and the selective blocker of the acetylcholine-activated potassium current (IK-ACh) tertiapin-Q (0.15 µM) abolished the effect of acetylcholine (15 µM) (data not shown).


View this table:
[in this window]
[in a new window]

  		Table 2. Electrophysiological changes of atrial cardiomyocytes before and after carbachol application

 
To further test which type of muscarinic receptors is responsible for the effects of acetylcholine, we used the M2R, M3R, and M4R blockers to inhibit the acetylcholine-induced ERP shortening. The results showed that IC50 values for methoctramine, an M2R blocker, 4-diphenylacetoxy-N-methylpiperidine, an M3R blocker, and tropicamide, an M4R blocker, were 0.151, 1.063, and 2.497 µM (Fig. 4), respectively. These results indicate that M2R plays a major role in the response of atrial myocytes to acetylcholine stimulation.


Figure 4
View larger version (12K):
[in this window]
[in a new window]

  		Fig. 4. Dose-response curves of the effect of different types of muscarinic receptors (M2R, M3R, and M4R) on ACh-induced electrophysiological parameter changes of cardiomyocytes in the pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW; n = 5 sheep (1 cell each site from 1 sheep). M2RB, M3RB, and M4RB represent M2R, M3R and M4R blockers [methoctramine, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), and tropicamide], respectively. {Delta}ERPMRB/{Delta}ERPMRBMax refers to (ERPMRB – ERPACh)/(ERPMRBMax – ERPACh). ERPMRB represents the ERP under different dose of muscarinic receptor blockers in the presence of 15 µM ACh. ERPMRBMax represents the ERP under different muscarinic receptor blockers (with maximum response) in the presence of 15 µM ACh.

 
M2R distribution in the atrial myocardium.   Our results revealed that the M2R widely distributed in the atrial myocardium, but the distribution was not homogenous. The relative fluorescent intensities of the receptors in the pulmonary vein antrum, LAPW, roof, LAFW, LAA, and RAFW were 62.64 ± 2.56, 53.12 ± 2.76, 51.83 ± 2.45, 47.90 ± 2.33, 55.27 ± 2.08, and 45.53 ± 2.02, respectively. The pulmonary vein antrum displayed the highest M2R density (Fig. 5, A–G). A similar distribution of the M2R was also found in human hearts (Fig. 5, H–N). The coefficient of variation of the fluorescence was 5.07–12.31% for the same sample. In contrast, the expression of M3R, M4R, GIRK3.1, and GIRK3.4 showed no significant difference among different sites (data not shown).


Figure 5
View larger version (39K):
[in this window]
[in a new window]

  		Fig. 5. Representative sections of M2R distribution in sheep left superior pulmonary vein antrum (A), LAPW (B), roof (C), LAFW (D), LAA (E), and RAFW (F) and in the human left superior pulmonary vein antrum (H), LAPW (I), roof (J), LAFW (K), LAA (L), and RAFW (M). G and N are the negative controls. M2R relative fluorescent intensity in the different regions of the atria is also shown (O: sheep; P: humans). #P < 0.05, antrum vs. LAPW, roof, and LAA; §P < 0.01, antrum vs. LAFW and RAFW. n = 6 sheep.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, we for the first time demonstrated that atrial ERP was heterogeneously shortened by cholinergic agonist administration, with the shortest ERP occurring in the pulmonary vein antrum. In conformity with the heterogeneity of ERP distribution, M2R also heterogeneously distributed in the atrial myocardium, and the highest density of M2R was found in the pulmonary vein antrum, indicating that acetylcholine-induced heterogeneous ERP distribution may be a consequence of heterogeneous distribution of M2R. However, other muscarinic receptors, M3R and M4R, and IK-Ach channel subunits, GIRK3.1 and GIRK3.4, demonstrated no significant differences of spatial distribution in the atrium.

The heterogeneous shortening of ERP by acetylcholine as a consequence of the heterogeneity of M2R distribution is also supported by the following results. First, the M2R agonist carbachol could produce an effect similar to that of acetylcholine. Second, the effect of acetylcholine was inhibited by the M2R blocker methoctramine with a much higher sensitivity than by the M3R or M4R blockers 4-diphenylacetoxy-N-methylpiperidine or tropicamide. Third, the inhibition of IK-Ach channel, which is activated by the M2R signaling pathway, by tertiapin-Q also effectively abolished the effect of acetylcholine. These results were supported by the present findings on muscarinic expression, left atrial refractory period, and IK-Ach channel blockade (2, 9, 10).

Recently, Mansour et al. (22) identified sequential wave fronts with similar spatial patterns of propagation and temporal periodicity during atrial fibrillation in the isolated sheep heart by combining high-resolution video imaging, electrocardiographic recordings, and spectral analyses. These results showed a high degree of spatiotemporal periodicity accompanying atrial fibrillation, which thereby led to the hypothesis that atrial fibrillation maintenance depends on the uninterrupted periodic activity of a single or small number of reentrant sources to give rise to fibrillatory conduction through interactions with anatomic and/or functional obstacles (24, 15). Increasing studies of animals and humans have demonstrated that the pulmonary vein antrum or junction of pulmonary vein left atrium is the leading reentrant source (7, 12, 17, 21). Most of the clinical catheter ablation practices, such as circumferential pulmonary vein ablation and electrogram-guided ablation, also target substructures in the pulmonary vein antrum or junction of pulmonary vein and left atrium (3, 4, 8, 14, 18, 23, 26, 31). The pulmonary vein antrum apparently plays an important role in atrial fibrillation.

Shortening of ERP has long been regarded as an important substrate for atrial fibrillation (24). On the other hand, the refractory heterogeneity has also become a subject of attention, which may be associated with fractionation of wave fronts and fibrillatory conduction (17, 19). The present study identified a marked ERP shortening in the pulmonary vein antrum (104.0 ± 2.1 ms before acetylcholine application vs. 52.0 ± 1.6 ms after acetylcholine application) and a distinct refractory heterogeneity between the pulmonary vein antrum (ERP in the pulmonary vein antrum: 52.0 ± 1.6 ms) and its vicinity (ERP in the LAPW, roof, LAFW, LAA, and RAFW: 75.1 ± 2.0, 77.2 ± 1.7, 85.6 ± 1.7, 64.3 ± 2.1, and 90.5 ± 1.3 ms, respectively) as induced by acetylcholine. Thus the pulmonary vein antrum may be a site with high response to acetylcholine. Remarkable ERP shortening induced by acetylcholine (from 104.0 ± 2.1 to 52.0 ± 1.6 ms), which is consistent with the clinical findings (28), together with the ERP heterogeneity, may be inclined to promote reentry and ultimately atrial fibrillation. The therapeutic effect of the pulmonary vein antrum isolation is most likely attributed to the isolation of the atrial fibrillation substrates within the pulmonary vein antrum (cholinergic stimulation-induced ERP shortening) and the abolition of the electrophysiological basis for fractionation of wave fronts and fibrillatory conduction (cholinergic stimulation-induced refractory heterogeneity).

In summary, the pulmonary vein antrum is a region of unique electrophysiological importance with high sensitivity to acetylcholine stimulation. The dense M2R distribution in the pulmonary vein antrum is most likely to be responsible for such high sensitivity to acetylcholine. Cholinergic stimulation induced dramatic ERP heterogeneity in the atrium, which may be a possible substrate for atrial fibrillation. Our work also presents the potential value of cholinergic antagonists in the treatment of certain types of atrial fibrillation.

Limitations

The relationship between ERP and atrial fibrillation has been identified previously, and our study suggested that cholinergic stimulation induced dramatic ERP heterogeneity in the atrium. However, the direct relationship between muscarinic receptor distribution heterogeneity and atrial fibrillation was not established in the present study.

Arora et al. (2) showed that M2R is predominantly located in the LAPW, whereas Huang et al. and Zhao et al. demonstrate that M2R is more abundant in atrial appendage than in other sites (11, 32). However, the present study showed that M2R density in the pulmonary vein antrum was the highest. It is possible that this discrepancy is attributed to species differences.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by the National Science Fund for Distinguished Young Scholars (30425016), the National Science Fund of China (30330290, 30528011, 30670872, and 30470961), the "973" (2007CB512100) and "863" Programmes (2007AA02Z438) of China, the Programme Fund for Outstanding Medical Academic Leader of Shanghai, China, the Programme Fund for Shanghai Subject Chief Scientist, China, the Yangze Scholars Programme Fund by the Ministry of Education, China, and the Programme Fund for Innovative Research Team by the Ministry of Education, China (all grants were to Y.-H. Chen).


   FOOTNOTES
 

Address for reprint requests and other correspondence: Y.-H. Chen, Dept. of Cardiology, Tongji Hospital, and Heart Rhythm Research Center, Tongji Univ., 389 Xin Cun Rd., Shanghai 200065, China (e-mail: yihanchen{at}mail.tongji.edu.cn)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* L. Liang, Q. Pan, Y. Liu, and H. Chen contributed equally to this work. Back


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Aquila-Pastir LA, DiPaola NR, Matteo RG, Smedira NG, McCarthy PM, Moravec CS. Quantitation and distribution of β-tubulin in human cardiac myocytes. J Mol Cell Cardiol 34: 1513–1523, 2002.[CrossRef][Web of Science][Medline]
  2. Arora R, Ulphani JS, Villuendas R, Ng J, Harvey LA, Thordson S, Inderyas F, Lu Y, Gordon D, Denes P, Greene R, Crawford S, Decker RS, Morris A, Goldberger JJ, Kadish AH. Neural substrate for atrial fibrillation: implication for targeted parasympathetic blockade in the posterior left atrium. Am J Physiol Heart Circ Physiol 294: H134–H144, 2008.[Abstract/Free Full Text]
  3. Calkins H. Is pulmonary vein antrum isolation safe and effective in valvular heart disease and open heart surgery? Nat Clin Pract Cardiovasc Med 1: 12–13, 2004.[Web of Science][Medline]
  4. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, Kim YH, Klein G, Packer D, Skanes A. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 111: 1100–1105, 2005.
  5. Chevalier P, Tabib A, Meyronnet D, Chalabreysse L, Restier L, Ludman V, Alies A, Adeleine P, Thivolet F, Burri H, Loire R, Francois L, Fanton L. Quantitative study of nerves of the human left atrium. Heart Rhythm 2: 518–522, 2005.[CrossRef][Web of Science][Medline]
  6. Dmochowski IJ, Dmochowski JE, Oliveri P, Davidson EH, Fraser SE. Quantitative imaging of cis-regulatory reporters in living embryos. Proc Natl Acad Sci USA 99: 12895–12900, 2002.[Abstract/Free Full Text]
  7. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114: e257–e354, 2006.[Free Full Text]
  8. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 339: 659–666, 1998.[Abstract/Free Full Text]
  9. Hirose M, Ohkubo Y, Takano M, Hamazaki M, Sekido T, Yamada M. Mechanisms of the preventive effect of pilsicainide on atrial fibrillation originating from the pulmonary vein. Circ J 71: 1805–1814, 2007.[CrossRef][Web of Science][Medline]
  10. Horikawa-Tanami T, Hirao K, Furukawa T, Isobe M. Mechanism of the conversion of a pulmonary vein tachycardia to atrial fibrillation in normal canine hearts: role of autonomic nerve stimulation. J Cardiovasc Electrophysiol 18: 534–541, 2007.[CrossRef][Web of Science][Medline]
  11. Huang CX, Zhao QY, Liang JJ, Chen H, Yang B, Jiang H, Li GS. Differential densities of muscarinic acetylcholine receptor and I(K,ACh) in canine supraventricular tissues and the effect of amiodarone on cholinergic atrial fibrillation and I(K,ACh). Cardiology 106: 36–43, 2006.[CrossRef][Web of Science][Medline]
  12. Huang JL, Tai CT, Lin YJ, Ting CT, Chen YT, Chang MS, Lin FY, Lai WT, Chen SA. The mechanisms of an increased dominant frequency in the left atrial posterior wall during atrial fibrillation in acute atrial dilatation. J Cardiovasc Electrophysiol 17: 178–188, 2006.[CrossRef][Web of Science][Medline]
  13. Inomata N, Ohno T, Ishihara T, Akaike N. Antiarrhythmic agents act differently on the activation phase of the ACh-response in guinea-pig atrial myocytes. Br J Pharmacol 108: 111–115, 1993.[Web of Science][Medline]
  14. Jalife J, Berenfeld O. Molecular mechanisms and global dynamics of fibrillation: an integrative approach to the underlying basis of vortex-like reentry. J Theor Biol 230: 475–487, 2004.[CrossRef][Web of Science][Medline]
  15. Jalife J, Berenfeld O, Mansour M. Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovasc Res 54: 204–216, 2002.[Abstract/Free Full Text]
  16. Chen J, Zhu JX, Wilson I, Cameron JS. Cardioprotective effects of KATP channel activation during hypoxia in goldfish Carassius auratus. J Exp Biol 208: 2765–2772, 2005.[Abstract/Free Full Text]
  17. Kalifa J, Tanaka K, Zaitsev AV, Warren M, Vaidyanathan R, Auerbach D, Pandit S, Vikstrom KL, Ploutz-Snyder R, Talkachou A, Atienza F, Guiraudon G, Jalife J, Berenfeld O. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 113: 626–633, 2006.[Abstract/Free Full Text]
  18. Khaykin Y, Marrouche NF, Saliba W, Schweikert R, Bash D, Chen MS, Williams-Andrews M, Saad E, Burkhardt DJ, Bhargava M, Joseph G, Rossillo A, Erciyes D, Martin D, Natale A. Pulmonary vein antrum isolation for treatment of atrial fibrillation in patients with valvular heart disease or prior open heart surgery. Heart Rhythm 1: 33–39, 2004.[CrossRef][Web of Science][Medline]
  19. Kneller J, Zou R, Vigmond EJ, Wang Z, Leon LJ, Nattel S. Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties. Circ Res 90: E73–E87, 2002.[CrossRef][Web of Science][Medline]
  20. Kolossov E, Lu Z, Drobinskaya I, Gassanov N, Duan Y, Sauer H, Manzke O, Bloch W, Bohlen H, Hescheler J, Fleischmann BK. Identification and characterization of embryonic stem cell-derived pacemaker and atrial cardiomyocytes. FASEB J 19: 577–579, 2005.[Abstract/Free Full Text]
  21. Lazar S, Dixit S, Marchlinski FE, Callans DJ, Gerstenfeld EP. Presence of left-to-right atrial frequency gradient in paroxysmal but not persistent atrial fibrillation in humans. Circulation 110: 3181–3186, 2004.
  22. Mansour M, Mandapati R, Berenfeld O, Chen J, Samie FH, Jalife J. Left-to-right gradient of atrial frequencies during acute atrial fibrillation in the isolated sheep heart. Circulation 103: 2631–2636, 2001.[Abstract/Free Full Text]
  23. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, Vasavakul T, Khunnawat C, Ngarmukos T. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 43: 2044–2053, 2004.[Abstract/Free Full Text]
  24. Nattel S. New ideas about atrial fibrillation 50 years on. Nature 415: 219–226, 2002.[CrossRef][Web of Science][Medline]
  25. Oral H, Chugh A, Good E, Sankaran S, Reich SS, Igic P, Elmouchi D, Tschopp D, Crawford T, Dey S, Wimmer A, Lemola K, Jongnarangsin K, Bogun F, Pelosi F Jr, Morady F. A tailored approach to catheter ablation of paroxysmal atrial fibrillation. Circulation 113: 1824–1831, 2006.
  26. Oral H, Pappone C, Chugh A, Good E, Bogun F, Pelosi F Jr, Bates ER, Lehmann MH, Vicedomini G, Augello G, Agricola E, Sala S, Santinelli V, Morady F. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 354: 934–941, 2006.[Abstract/Free Full Text]
  27. Pappone C, Santinelli V, Manguso F, Vicedomini G, Gugliotta F, Augello G, Mazzone P, Tortoriello V, Landoni G, Zangrillo A, Lang C, Tomita T, Mesas C, Mastella E, Alfieri O. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 109: 327–334, 2004.
  28. Soylu M, Demir AD, Ozdemir O, Soylu O, Topaloglu S, Kunt A, Sasmaz A, Korkmaz S, Tasdemir O. Increased dispersion of refractoriness in patients with atrial fibrillation in the early postoperative period after coronary artery bypass grafting. J Cardiovasc Electrophysiol 14: 28–31, 2003.[CrossRef][Web of Science][Medline]
  29. Tan AY, Li H, Wachsmann-Hogiu S, Chen LS, Chen PS, Fishbein MC. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrial-pulmonary vein junction. J Am Coll Cardiol 48: 132–143, 2006.[Abstract/Free Full Text]
  30. Wood MA, Ellenbogen KA. Catheter ablation of chronic atrial fibrillation- the gap between promise and practice. N Engl J Med 354: 967–969, 2006.[Free Full Text]
  31. Yamada T, Murakami Y, Okada T, Okamoto M, Shimizu T, Toyama J, Yoshida Y, Tsuboi N, Ito T, Muto M, Kondo T, Inden Y, Hirai M, Murohara T. Electrophysiological pulmonary vein antrum isolation with a multielectrode basket catheter is feasible and effective for curing paroxysmal atrial fibrillation: efficacy of minimally extensive pulmonary vein isolation. Heart Rhythm 3: 377–384, 2006.[CrossRef][Web of Science][Medline]
  32. Zhao QY, Huang CX, Liang JJ, Chen H, Yang B, Jiang H, Li GS. Effect of vagal stimulation and differential densities of M(2) receptor and I(K,ACh) in canine atria. Int J Cardiol In press.




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
105/1/293    most recent
01270.2007v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Liang, L.
Right arrow Articles by Chen, Y.-H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liang, L.
Right arrow Articles by Chen, Y.-H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.