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Cardiovascular Research 2002 54(2):280-286; doi:10.1016/S0008-6363(02)00225-0
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Copyright © 2002, European Society of Cardiology

Transgenic and knockout mouse models of atrial arrhythmias

Jeffrey E. Olgin* and Sander Verheule

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

* Corresponding author. Indiana University School of Medicine, Noyes Pavilion, Room E410, Methodist Hospital, 1800 North Capital, Indianapolis, IN 46202, USA. Tel.: +1-317-962-0101; fax: +1-317-962-0100 jolgin{at}iupui.edu

Received 19 September 2001; accepted 18 December 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Types of genetic...
 3 Techniques for study...
 4 Other mouse models...
 5 Conclusion
 References
 
While much has been learned about atrial fibrillation from large animal models, many of these studies are correlative. Genetically-altered mouse models have provided much information about such genetic diseases as the long QT syndrome, but have to date not been utilized much to study atrial fibrillation. The ability to study the importance of a single gene product in pathophysiology make this a potentially powerful tool to understand the causal relationship of several proteins and the substrate for atrial fibrillation. In this manuscript we review the techniques available to study atrial electrophysiology and some of the genetically-altered mouse models that have implications for atrial fibrillation.

KEYWORDS Arrhythmia (mechanisms); Atrial function; Gene expression


   1 Introduction
Top
 Abstract
 1 Introduction
2 Types of genetic...
 3 Techniques for study...
 4 Other mouse models...
 5 Conclusion
 References
 
Atrial fibrillation (AF) is a heterogeneous disease. It can be idiopathic (or lone) or can be associated with a variety of underlying conditions including hypertension, heart failure, mitral valve disease and aging. It also appears to be a progressive disease, despite the underlying heart disease — the longer the AF persists, the more difficult it is to restore sinus rhythm. In addition, paroxysmal AF often becomes persistent with time.

Several canine models of AF have given some insight into the substrate for maintenance of AF. The elegant work by Morrillo et al. and Wijffels et al. have demonstrated that prolonged rapid rates in the atrium produce electrophysiologic changes (decrease in atrial refractoriness and loss of rate adaptivity of refractoriness) that promote sustained atrial fibrillation [1,2]. Li et al. have developed a second model of electrophysiologic remodeling due to chronic congestive heart failure in dogs (produced by rapid ventricular pacing) [3,4]. This model develops the substrate for sustained AF; however, the electrophysiologic abnormalities are different than the rapid atrial pacing model. In the heart failure model, atrial refractoriness is not changed at longer cycle lengths, lengthened at shorter cycle lengths, and conduction shows regional slowing, but is not slow overall. We have reported a third model of sustained AF, produced by chronic atrial dilation from mitral regurgitation [5]. In this model, atrial refractoriness is prolonged at all cycle lengths and conduction is more heterogeneous. Despite these three models having different electrophysiology, they all have the substrate for sustained AF.

Numerous physiologic abnormalities have been reported with the models (predominantly in the rapid atrial pacing model) and in some studies of human atria (many of these are described in detail elsewhere in this issue). These include alterations in Ca channels, potassium channels, gap junctions, autonomic innervation, fibrosis, ultrastructural changes, cytokines and paracrine factors [6,7]. Despite the large body of literature, precise mechanisms remain unknown and causal links between some of these abnormalities and atrial fibrillation are still lacking. This is largely due to the limitations of the models being used. While these models are vitally important to our understanding of atrial fibrillation because they have clear correlates to human disease states, they produce myriad alterations in physiology.

In the past 20 years genetically-altered mice have been used to unravel the pathophysiology of some ventricular arrhythmias including the long QT syndrome and Brugada's syndrome. Applicability to atrial fibrillation has been more limited for several reasons: no clear genetic component to atrial fibrillation, the critical mass hypothesis, and difficulty in studying the phenotype (i.e. atrial electrophysiology). More recently, however, many of the limitations of studying the phenotype has been overcome (see below) and the critical mass hypothesis has been challenged since ventricular fibrillation and atrial fibrillation have been produced in mouse models [8,9]. Genetically altered mice are a potentially powerful tool to try to dissect out the importance of and causal relationship between the observed abnormalities described above and atrial fibrillation. The purpose of this manuscript is to review the existing techniques and data that employ transgenic models to specifically study potential mechanisms of atrial fibrillation.


   2 Types of genetic alterations
Top
 Abstract
 1 Introduction
 2 Types of genetic...
3 Techniques for study...
 4 Other mouse models...
 5 Conclusion
 References
 
Current molecular biology techniques to create genetically altered animals does more than simply determine the importance of a particular gene in producing a genetic disease; it is a powerful tool to determine the effects of a particular protein or part of a protein. Because of their relative inexpensiveness, short gestation and established techniques, mice are frequently used, although rat and rabbit can also be used in some instances. Several types of genetic manipulations can be performed. A transgenic mouse is one in which a DNA sequence is inserted into the native genetic code of the animal. In most instances, the inserted genetic sequence codes for a particular protein. This protein can either be functionally active or inactive. In addition, it can act as either an activator or an inhibitor of another endogenous protein. The latter is often a genetically altered sequence (resulting in the substitution of amino acid pairs into the protein sequence, rendering it inactive, but still able to bind to its respective receptor). Additionally, an alteration of a protein rendering that protein inactive can result in inhibition or can ‘knock down’ the expression of the endogenous, functional protein when this altered protein is overexpressed. This is referred to as dominant negative construct. Transgenic models are useful to determine the effects of overexpression (increased levels) of a particular protein or to produce a non-pharmacologic inhibitor of a particular protein. A knockout is a model in which a specific DNA sequence is removed from the genetic code of the animal. Again, the sequence removed often codes for a specific protein. Knockout models are useful to study the effects of eliminating (homozygous) or reducing (heterozygous) a particular protein.

After in utero development, cardiac myocytes no longer divide, making transfection (insertion of DNA into the host DNA) of genetic material difficult in the postnatal animal. For this reason, the majority of genetic alterations must be made early in in utero development. Therefore, in many transgenic and knockout models, cardiac development itself is often affected by the genetic alteration. In addition, to restrict the expression of the transgene to cardiac tissue, a cardiac specific promoter (a genetic sequence which turns on the transcription of a particular protein from the genetic code) is used. This is for a protein specific to the heart and known to be produced throughout adult life in large quantities. Most often a myosin heavy chain promoter is used since this is produced in large quantities throughout life. It is expressed in both the atrium and the ventricle. Expression can be further restricted by choosing a more restrictive promoter. For example, an ANF promoter largely restricts the expression of the protein from the transgene to the atrium.


   3 Techniques for study of electrophysiologic phenotype
Top
 Abstract
 1 Introduction
 2 Types of genetic...
 3 Techniques for study...
4 Other mouse models...
 5 Conclusion
 References
 
Because of the small size of the mouse heart, functional electrophysiology of transgenic mice can be challenging. Mouse electrophysiology can be affected by the type of anesthesia used. For example, barbiturates slow the heart rate down and can effect the surface ECG with a resultant increase in sinus cycle length of about 200 ms [10]. Tribromoethanol and urethane seem to have the least effects [11]. Moreover, there appear to be differences in different strains of mice; therefore, littermate controls are necessary for comparative data. Continuous ambulatory monitoring of mouse ECGs have also been described using an implanted telemetry system or specially-designed cages [12]. However, the ability to resolve P waves and diagnose atrial arrhythmias have not yet been demonstrated.

Several techniques have been described to study the intact, in vivo mouse heart. These include transesophageal pacing and recording which allows the recording of atrial electrograms and pacing of the atrium to perform programmed stimulation (Fig. 1) [9,13]. Berul et al. [10] and Verheule et al. [14] have described a technique of direct impalement of fine wire electrodes into the myocardium in an open-chest, ventilated mouse. This technique allows programmed stimulation in the atrium and ventricle (Fig. 2). Gehrmann et al. [15] have developed a technique and a specially-designed catheter to perform transvenous, endocardial electrophysiology studies in mice. The catheter is 1.7 Fr octapolar catheter with 0.5 mm inter-electrode distance which is placed via the jugular vein into the right atrium and right ventricle (Fig. 3). The catheter can be used as a single pass catheter for pacing and recording and can also record His potentials in mice [15]. In addition, it has a lumen through which drugs can be infused.


Figure 1
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  		Fig. 1 Transesophageal pacing to pace the atrium to assess sinus node and AV node function. In (A) the atrium is paced to determine the sinus node recovery time. The last few seconds of pacing and spontaneous recovery of sinus rhythm is shown. In (B) the atrium is decrementally paced to determine the AV node Wenckebach cycle length. The longest pacing cycle length at which Wenckebach conduction occurs is shown.

 

Figure 2
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  		Fig. 2 Epicardial pacing and recording of the atrium in a Cx40+/– knockout mouse. The top tracing reveals the epicardial recording during paced induction of atrial fibrillation with a short burst. The pacing is following by atrial fibrillation and spontaneous reversion to sinus rhythm.

 

Figure 3
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  		Fig. 3 Octapolar endocardial catheter (A) for pacing and recording in mice (CiberMouse, Inc.) Recordings from such a catheter placed endovascularly into the right atrium and ventricle. Tracings (B) from top to bottom are from distal bipoles (IC 1–2) progressively to proximal bipoles (IC 7–8). These same electrodes can be used to pace the atrium or ventricle.

 
Although these techniques are useful to determine arrhythmia vulnerability and refractoriness at a few select sites, they are limited by being unable to measure conduction abnormalities and multisite refractoriness, which are important determinants of AF substrate. Higher resolution epicardial mapping has been described by van Rijen et al. using a multi-electrode array in the ventricle [16]. However, its utility in the atrium is unclear. Optical mapping has also been used to obtain high resolution mapping of murine hearts. Morley et al. has used optical mapping to obtain high-resolution activation mapping in heterozygous connexin 43 knockout mice [17]. Others have used optical mapping in other mouse models as well [18–20]. Not only does optical mapping allow measurement of conduction with high spatial and temporal resolution, it also offers the ability to obtain optically-derived action potentials (Fig. 4) [18].


Figure 4
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  		Fig. 4 High-resolution optical voltage map of mouse ventricle. Each pixel is an optically-derived action potential from a photodiode array. The mouse is perfused through the aorta and the voltage sensate fluorescent dye Di-4-ANEPS is used to detect membrane voltage. Activation and repolarization can be obtained at varying spatial resolutions, depending on the optics. Singles are normalized for display purposes only.

 
3.1 Connexin models of AF
Atria express connexin 40, 43 and 45, which are thought to be important determinants of conduction. Although connexin 40 and 43 have clearly been demonstrated in the atrium, the presence of connexin 45 is somewhat more controversial, but likely does exist in the atrium, albeit at lower levels [21,22]. To date knockout models of connexin 45 has not been studied, since they are embryonic-lethal due to abnormal vascular development [23,24]. Homozygous knockout (Cx43–/–; null expression) of connexin 43 is also lethal [25]; however, heterozygous (Cx43+/–) mice survive and have normal cardiac development. Controversy exists as to whether conduction abnormalities occur in the ventricle of these mice [17,26]. There is little data concerning the vulnerability to atrial arrhythmias or alterations in atrial electrophysiology in these mice. One study found no change in atrial conduction velocities in these mice, but did find slowing of conduction in the ventricle [26]. Homozygous null connexin 40 mice do survive without cardiac abnormalities. Two groups have studied these mice and have found no significant electrophysiologic abnormalities in the ventricle, but did find prolonged sinus node recovery times, slowed atrial conduction and increased vulnerability to atrial arrhythmias [13,14]. Both groups found a significantly longer P wave duration on surface ECG in the homozygous null connexin 40 mice (22.4–26.0 ms) compared to littermate wild-type controls (16.7–17.9 ms) or in heterozygous littermates (16.8–18.5 ms) [13,14]. Direct atrial conduction velocity was measured with a multiple electrode array placed on the epicardial surface of the atria in the study by Verheule et al. [14]. Atrial conduction velocity was 30% slower in the homozygous mice compared to the controls and heterozygous mice (which showed no significant slowing). Interestingly, heterozygous mice, which have less than half the amount of Cx40 than wild-type controls [27], did not have significant conduction abnormalities [13,14]. Moreover, there were no conduction abnormalities in the ventricle. Atrial arrhythmias were also inducible in five of eight homozygous mice in one study [13] and five of 10 mice in the other study [14]. In neither study were atrial arrhythmias inducible in wild-type, littermate controls. Fig. 2 shows an example of induced atrial fibrillation in one such mouse. Since the distribution of connexin 40 is similar in mice and humans, this may be a relevant model to test the relationship between alterations in connexins and atrial fibrillation. However, the studies in animal models of AF (i.e. rapid pacing in goats) reveal a heterogeneous decrease in Cx40 with no change in Cx43 [28,29] and an increase in Cx40 in patients susceptible to post-operative atrial fibrillation [30]. Moreover, the abnormalities in gap junctions are likely more complex than simply a decrease or increase in a specific connexin. Changes in ratios of connexin expression, gating of gap junctions or heteromeric gap junctions may play a more significant role. As genetic models to investigate these alterations become available, more complex alterations can be better assessed.


   4 Other mouse models of AF
Top
 Abstract
 1 Introduction
 2 Types of genetic...
 3 Techniques for study...
 4 Other mouse models...
5 Conclusion
 References
 
Fibrosis has been associated with atrial fibrillation in both human pathologic studies and in some animal models of atrial fibrillation [3,31,32]. However, atrial fibrillation itself may also causes fibrosis [33]. Therefore, it is unclear whether fibrosis alone is sufficient to cause atrial fibrillation. Nakajima et al. have described a unique transgenic mouse model which overexpresses a constitutively active form of TGF-β1 [34]. In this model, heart development appears to be normal and the atria become progressively fibrotic while the ventricle remains normal throughout life [34]. We have studied the electrophysiologic properties of the heart in these mice [9]. Surface ECG reveals normal intervals and QRS, however, there is a progressive diminution of the P wave voltage with age. AV and sinus node properties (AV conduction and SNRT) appears to be normal. However, episodes of atrial fibrillation were induced in the transgenic mice (8/14) (Fig. 5) but infrequently in littermate controls (1/11) [9]. This model suggest that fibrosis does play a causative role in producing the substrate for AF and not simply a by-product of the rapid rates. Further study into the mechanisms of this fibrosis is currently underway.


Figure 5
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  		Fig. 5 An episode of atrial fibrillation in a transgenic mouse overexpressing a constitutively active form of TGF-β1. The conversion of atrial fibrillation to sinus rhythm is shown at the end. A magnified view of this transition is shown below.

 

   5 Conclusion
Top
 Abstract
 1 Introduction
 2 Types of genetic...
 3 Techniques for study...
 4 Other mouse models...
 5 Conclusion
References
 
There are currently few genetic models of AF. However, multiple abnormalities have been described in patients and animal models of AF, which are detailed elsewhere in this special issue. The importance of many of these abnormalities are potentially able to be tested with genetic models. We and others have described an increase in sympathetic innervation with remodeling that may play a role in the substrate for sustained AF [35–37]. Mouse models that overexpress β-receptors and inhibitors of the β-adrenoreceptor kinases have been described and extensively studied in ventricular tissue [38]. Similar models with expression restricted to the atrium may provide useful information about the role of the sympathetic nervous system in AF.

While familial AF has been described and the gene locus identified in some cases [39], there is currently no animal model. The precise genetic abnormality or affected gene product has not yet been identified. The gene locus is near that which codes for β and alpha receptors [39]. Perhaps investigation of these receptors may prove useful in understanding mechanisms of AF.

As genetic abnormalities or abnormalities in expression of particular proteins are identified in various human and animal models of AF, genetically-altered mice may prove very useful to confirm causality.

Time for primary review 30 days.


   References
Top
 Abstract
 1 Introduction
 2 Types of genetic...
 3 Techniques for study...
 4 Other mouse models...
 5 Conclusion
 References
 

  1. Wijffels M.C., Kirchhof C.J., Dorland R., Allessie M.A. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation (1995) 92:1954–1968.[Abstract/Free Full Text]
  2. Morillo C.A., Klein G.J., Jones D.L., Guiraudon C.M. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation (1995) 91:1588–1595.[Abstract/Free Full Text]
  3. Li D., Fareh S., Leung T.K., Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation (1999) 100:87–95.[Abstract/Free Full Text]
  4. Nattel S., Li D., Yue L. Basic mechanisms of atrial fibrillation—very new insights into very old ideas. Annu Rev Physiol. (2000) 62:51–77.[CrossRef][Web of Science][Medline]
  5. Verheule S., Wilson E., Banthia S., Golden K., Sih H.J., Olgin J.E. Electrophysiologic effects of chronic left atrial dilatation in a canine model of mitral regurgitation (abstract). PACE (2001) 24:624.
  6. Allessie M.A. Atrial electrophysiologic remodeling: another vicious circle? J Cardiovasc Electrophysiol (1998) 9:1378–1393.[Web of Science][Medline]
  7. Olgin J.E., Rubart M. Cardiac electrophysiology: from cell to bedside. Zipes D., Jalife J., eds. (1999) 3rd ed. Philadelphia: WB Saunders. 364–378.
  8. Vaidya D., Morley G.E., Samie F.H., Jalife J. Reentry and fibrillation in the mouse heart. A challenge to the critical mass hypothesis. Circ Res (1999) 85:174–181.[Abstract/Free Full Text]
  9. Raiesdana A., Verheule S., Nakajima H., Nakajima H., Field L., Olgin J.E. Inducibility of atrial arrhythmias in transgenic mice with selective atrial fibrosis due to overexpression of TGF-β1 (abstract). PACE (2001) 24:549.
  10. Berul C.I., Aronovitz M.J., Wang P.J., Mendelsohn M.E. In vivo cardiac electrophysiology studies in the mouse. Circulation (1996) 94:2641–2648.[Abstract/Free Full Text]
  11. Kass D.A., Hare J.M., Georgakopoulos D. Murine cardiac function: a cautionary tail. Circ Res (1998) 82:519–522.[Free Full Text]
  12. Kramer K., van Acker S.A., Voss H.P., Grimbergen J.A., van der Vijgh W.J., Bast A. Use of telemetry to record electrocardiogram and heart rate in freely moving mice. J Pharmacol Toxicol Methods (1993) 30:209–215.[CrossRef][Web of Science][Medline]
  13. Hagendorff A., Schumacher B., Kirchhoff S., Luderitz B., Willecke K. Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation. Circulation (1999) 99:1508–1515.[Abstract/Free Full Text]
  14. Verheule S., van Batenburg C.A., Coenjaerts F.E., Kirchhoff S., Willecke K., Jongsma H.J. Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol (1999) 10:1380–1389.[Web of Science][Medline]
  15. Gehrmann J., Berul C.I. Cardiac electrophysiology in genetically engineered mice. J Cardiovasc Electrophysiol (2000) 11:354–368.[Web of Science][Medline]
  16. van Rijen H.V., van Veen T.A., van Kempen M.J., Wilms-Schopman F.J., Potse M., Krueger O., Willecke K., Opthof T., Jongsma H.J., de Bakker J.M. Impaired conduction in the bundle branches of mouse hearts lacking the gap junction protein connexin40. Circulation (2001) 103:1591–1598.[Abstract/Free Full Text]
  17. Morley G.E., Vaidya D., Samie F.H., Lo C., Delmar M., Jalife J. Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J Cardiovasc Electrophysiol (1999) 10:1361–1375.[Web of Science][Medline]
  18. Baker L.C., London B., Choi B.R., Koren G., Salama G. Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia. Circ Res (2000) 86:396–407.[Abstract/Free Full Text]
  19. Gutstein D.E., Morley G.E., Tamaddon H., Vaidya D., Schneider M.D., Chen J., Chien K.R., Stuhlmann H., Fishman G.I. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res (2001) 88:333–339.[Abstract/Free Full Text]
  20. Tamaddon H.S., Vaidya D., Simon A.M., Paul D.L., Jalife J., Morley G.E. High-resolution optical mapping of the right bundle branch in connexin40 knockout mice reveals slow conduction in the specialized conduction system. Circ Res (2000) 87:929–936.[Abstract/Free Full Text]
  21. Coppen S.R., Severs N.J., Gourdie R.G. Connexin45 (alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genet (1999) 24:82–90.[CrossRef][Web of Science][Medline]
  22. Coppen S.R., Dupont E., Rothery S., Severs N.J. Connexin45 expression is preferentially associated with the ventricular conduction system in mouse and rat heart. Circ Res (1998) 82:232–243.[Abstract/Free Full Text]
  23. Kumai M., Nishii K., Nakamura K., Takeda N., Suzuki M., Shibata Y. Loss of connexin45 causes a cushion defect in early cardiogenesis. Development (2000) 127:3501–3512.[Abstract]
  24. Kruger O., Plum A., Kim J.S., Winterhager E., Maxeiner S., Hallas G., Kirchhoff S., Traub O., Lamers W.H., Willecke K. Defective vascular development in connexin 45-deficient mice. Development (2000) 127:4179–4193.[Abstract]
  25. Reaume A.G., de Sousa P.A., Kulkarni S., Langille B.L., Zhu D., Davies T.C., Juneja S.C., Kidder G.M., Rossant J. Cardiac malformation in neonatal mice lacking connexin43. Science (1995) 267:1831–1834.[Abstract/Free Full Text]
  26. Thomas S.A., Schuessler R.B., Berul C.I., Beardslee M.A., Beyer E.C., Mendelsohn M.E., Saffitz J.E. Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction: evidence for chamber-specific molecular determinants of conduction. Circulation (1998) 97:686–691.[Abstract/Free Full Text]
  27. Kirchhoff S., Nelles E., Hagendorff A., Kruger O., Traub O., Willecke K. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice. Curr Biol (1998) 8:299–302.[CrossRef][Web of Science][Medline]
  28. van der Velden H.M., Ausma J., Rook M.B., Hellemons A.J., van Veen T.A., Allessie M.A., Jongsma H.J. Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res (2000) 46:476–486.[Abstract/Free Full Text]
  29. van der Velden H.M., van Kempen M.J., Wijffels M.C., van Zijverden M., Groenewegen W.A., Allessie M.A., Jongsma H.J. Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol (1998) 9:596–607.[Web of Science][Medline]
  30. Dupont E., Ko Y., Rothery S., Coppen S.R., Baghai M., Haw M., Severs N.J. The gap-junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation (2001) 103:842–849.[Abstract/Free Full Text]
  31. Connelly J.H., Clubb F.J., Vaughn W., Duncan M. Morphological changes in atrial appendages removed during the maze procedure: a comparison with autopsy controls. Cardiovasc Pathol (2001) 10:39–42.[CrossRef][Web of Science][Medline]
  32. Frustaci A., Chimenti C., Bellocci F., Morgante E., Russo M.A., Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation (1997) 96:1180–1184.[Abstract/Free Full Text]
  33. Ausma J., van der Velden H.M., Lenders M.H., Duimal H., Borgers M., Allessie M.A. Partial recovery from structural remodelling after prolonged atrial fibrillation (abstract). Circulation (2001) 104:II77.
  34. Nakajima H., Nakajima H.O., Salcher O., Dittie A.S., Dembowsky K., Jing S., Field L.J. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res (2000) 86:571–579.[Abstract/Free Full Text]
  35. Olgin J.E., Sih H.J., Hanish S., Jayachandran J.V., Wu J., Zheng Q.H., Winkle W., Mulholland G.K., Zipes D.P., Hutchins G. Heterogeneous atrial denervation creates substrate for sustained atrial fibrillation. Circulation (1998) 98:2608–2614.[Abstract/Free Full Text]
  36. Jayachandran J.V., Sih H.J., Winkle W., Zipes D.P., Hutchins G.D., Olgin J.E. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation (2000) 101:1185–1191.[Abstract/Free Full Text]
  37. Chang C.M., Wu T.J., Zhou S., Doshi R.N., Lee M.H., Ohara T., Fishbein M.C., Karagueuzian H.S., Chen P.S., Chen L.S. Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation (2001) 103:22–25.[Abstract/Free Full Text]
  38. Koch W.J., Rockman H.A., Samama P., Hamilton R.A., Bond R.A., Milano C.A., Lefkowitz R.J. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science (1995) 268:1350–1353.[Abstract/Free Full Text]
  39. Brugada R., Tapscott T., Czernuszewicz G.Z., Marian A.J., Iglesias A., Mont L., Brugada J., Girona J., Domingo A., Bachinski L.L., Roberts R. Identification of a genetic locus for familial atrial fibrillation. New Engl J Med (1997) 336:905–911.[Abstract/Free Full Text]

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