EXPERIMENTAL STUDY
Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria
Lioudmila Polontchouk, PhD*,
Jacques-Antoine Haefliger, PhD ,
Berit Ebelt*,
Thomas Schaefer, PhD ,
Dominik Stuhlmann, MSc,
Uwe Mehlhorn, MD ,
Ferdinand Kuhn-Regnier, MD,
E. Rainer De Vivie, MD, PhD and
Stefan Dhein, MD, PhD*
* Department of Pharmacology, Martin Luther University of Halle-Wittenberg, Halle/S, Germany
Department of Internal Medicine B, Laboratory of Molecular Biology, Centre Hospitalier Universitaire Vañdias Lausanne, Lausanne, Switzerland
Department of Pharmacology, University of Cologne, Cologne, Germany
Clinic of Cardiothoracic Surgery, University of Cologne, Cologne, Germany
Manuscript received July 25, 2000;
revised manuscript received May 14, 2001,
accepted May 23, 2001.
Reprint requests and correspondence: Prof. Dr. Stefan Dhein, Department of Pharmacology, Martin Luther University of Halle-Wittenberg, Magdeburger Str. 4, D-06097 Halle/S, Germany
stefan.dhein{at}medizin.uni-halle.de
OBJECTIVES
To elucidate the structural basis for the electrophysiologic remodeling induced by chronic atrial fibrillation (AF), we investigated connexin40 and connexin43 (Cx40 and Cx43) expression and distribution in atria of patients with and without chronic AF and in an animal model of AF with additional electrophysiologic investigation of anisotropy (ratio of longitudinal and transverse velocities).
BACKGROUND
Atrial fibrillation is a common arrhythmia that has a tendency to become persistent. Since gap junctions provide the syncytial properties of the atrium, changes in expression and distribution of intercellular connections may accompany the chronification of AF.
METHODS
Atrial tissues isolated from 12 patients in normal sinus rhythm at the time of cardiac surgery and from 12 patients with chronic AF were processed for immunohistology and immunoblotting for the detection of the gap junction proteins. The functional study of the cardiac tissue anisotropy was performed in rat atria in which AF was induced by 24 h of rapid pacing (10 Hz).
RESULTS
Immunoblotting revealed that AF did not induce any significant change in Cx43 content in human atria. In contrast, a 2.7-fold increase in expression of Cx40 was observed in AF. Immunohistologic analysis indicated that AF resulted in an increase in the immunostaining of both connexins at the lateral membrane of human atrial cells. A similar spatial redistribution of the Cx43 signal was seen in isolated rat atria with experimentally-induced AF. In addition, AF in rat atria resulted in decreased anisotropy with slightly enhanced transverse conduction velocity.
CONCLUSIONS
This experimental study showed that AF is accompanied by spatial remodeling of gap junctions that might induce changes in the biophysical properties of the tissue.
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Abbreviations and Acronyms
| | AF | = atrial fibrillation | | anisotropy | = ratio of longitudinal and transverse velocities (VL/VT) | | Cx43 | = connexin43 | | Cx40 | = connexin40 | | d.U. | = densitometric units | | ECL | = enhanced chemiluminescence | | SDS-PAGE | = sodium dodecyl sulfate–polyacrylamide gel electrophoresis | | SR | = sinus rhythm | | VL | = longitudinal velocity | | VT | = transverse velocity |
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|
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|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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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
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August 15, 2006;
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation--Executive Summary: 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,
August 15, 2006;
114(7):
700 - 752.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Authors/Task Force Members, V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J.-Y. Le Heuzey, G. N. Kay, et al.
ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation executive summary: 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
Eur. Heart J.,
August 2, 2006;
27(16):
1979 - 2030.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Guerra, T. H. Everett IV, K. W. Lee, E. Wilson, and J. E. Olgin
Effects of the Gap Junction Modifier Rotigaptide (ZP123) on Atrial Conduction and Vulnerability to Atrial Fibrillation
Circulation,
July 11, 2006;
114(2):
110 - 118.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U Wetzel, A Boldt, J Lauschke, J Weigl, P Schirdewahn, A Dorszewski, N Doll, G Hindricks, S Dhein, and H Kottkamp
Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies
Heart,
February 1, 2005;
91(2):
166 - 170.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Dhein and H. J Jongsma
Forming the network--gap junctions in the cardiovascular system
Cardiovasc Res,
May 1, 2004;
62(2):
225 - 227.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. J. Severs, S. R. Coppen, E. Dupont, H.-I Yeh, Y.-S. Ko, and T. Matsushita
Gap junction alterations in human cardiac disease
Cardiovasc Res,
May 1, 2004;
62(2):
368 - 377.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kostin, S. Dammer, S. Hein, W. P Klovekorn, E. P Bauer, and J. Schaper
Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis
Cardiovasc Res,
May 1, 2004;
62(2):
426 - 436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Wasson, H. K. Reddy, and M. L. Dohrmann
Current Perspectives of Electrical Remodeling and Its Therapeutic Implications
Journal of Cardiovascular Pharmacology and Therapeutics,
April 1, 2004;
9(2):
129 - 144.
[Abstract]
[PDF]
|
|
|
|
|
|
|
I. Savelieva and A. John Camm
Atrial fibrillation and heart failure: natural history and pharmacological treatment
Europace,
January 1, 2003;
5(s1):
S5 - S19.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. T. Cottrell, Y. Wu, and J. M. Burt
Cx40 and Cx43 expression ratio influences heteromeric/ heterotypic gap junction channel properties
Am J Physiol Cell Physiol,
June 1, 2002;
282(6):
C1469 - C1482.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. W. van der Velden, R. Wilders, and H. J. Jongsma
Atrial fibrillation-induced gap junctional remodeling
J. Am. Coll. Cardiol.,
May 15, 2002;
39(10):
1709 - 1709.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Dhein, R. Wilders, H. J. Jongsma, and J.-A. Haefliger
Reply
J. Am. Coll. Cardiol.,
May 15, 2002;
39(10):
1709 - 1710.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Nattel, M. Allessie, and M. Haissaguerre
Spotlight on atrial fibrillation--the 'complete arrhythmia'
Cardiovasc Res,
May 1, 2002;
54(2):
197 - 203.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Shimizu and O. A. Centurion
Electrophysiological properties of the human atrium in atrial fibrillation
Cardiovasc Res,
May 1, 2002;
54(2):
302 - 314.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kostin, G. Klein, Z. Szalay, S. Hein, E. P Bauer, and J. Schaper
Structural correlate of atrial fibrillation in human patients
Cardiovasc Res,
May 1, 2002;
54(2):
361 - 379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
