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European Journal of Heart Failure 2007 9(1):23-29; doi:10.1016/j.ejheart.2006.04.014
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© 2007 European Society of Cardiology

Changes in connexin 43, metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy in dogs

Jing-quan Zhong, Wei Zhang, Haiqing Gao, Yan Li, Ming Zhong, Duoling Li, Cheng Zhang and Yun Zhang*

Cardiology Department, Qilu Hospital of Shandong University 107 Wen Hua Xi Lu, Jinan 250012, Shandong Province, China
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health China

* Corresponding author. Tel.: +86 531 8216 9339; fax: +86 531 8692 7544. E-mail address: yun-zhang{at}163.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: To study changes in connexin, metalloproteinase and tissue inhibitor of metalloproteinase levels during tachycardia-induced cardiomyopathy (TIC).

Methods: Canine models of TIC were established by rapid right atrial pacing at 350–400 beats per min for 8 weeks in 11 dogs, six dogs acted as a sham operation group. Echocardiography, left ventricular pressure and its first derivation with time (positive and negative maximum, dp/dtmax, –dp/dtmax), and intracardiac electrograms were recorded before and after rapid pacing at 1, 4 and 8 weeks. Data were acquired in sinus rhythm. Ultrastructural changes in left ventricular tissue were observed by transmission electron microscope. Connexin 43 (Cx43) levels in the left ventricular myocardium were measured by confocal laser microscopy. The relative abundance of matrix metalloproteinase (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-2) were studied by immunoblotting.

Result and conclusions: (1) Ventricular dilatation and systolic dysfunction occurred after 1 week of rapid right atrial pacing. (2) There was structural damage to the myofibrils, mitochondria, and the sarcoplasmic reticulum with intercalated disk discontinuity. (3) Levels of Cx43 decreased significantly and gap junction remodelling occurred during TIC. (4) TIC may result from several mechanisms, such as ultrastructural changes or gap junction and matrix remodelling.

Key Words: Tachycardia-induced cardiomyopathy • Connexin 43 • Metalloproteinase • Tissue inhibitor of metalloproteinase

Received January 8, 2006; Revised February 28, 2006; Accepted April 25, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Tachycardia-induced cardiomyopathy (TIC) is characterized by ventricular systolic dysfunction and dilatation, and by clinical manifestations of heart failure that are reversible with normalization of heart rate [1]. Myocyte cell loss and myocyte reactive hypertrophy are the major components of ventricular remodelling in TIC [2]. Spinale et al. [3] found TIC to be associated with extracellular matrix (fibrillar collagen, basement membrane and proteoglycans) remodelling, demonstrated via reduced collagen concentration, diminished myocyte basement membrane adhesion capacity and increased proteoglycans. It has become apparent that gap-junctional coupling of the myocardium, mainly in connexins and irrespective of fibrosis, is central to arrhythmogenic alterations to the myocardial architecture in TIC [4]. Severe end-stage heart failure is associated with reduced expression of the major ventricular gap junction protein, Cx43 [5,6], which is thought to affect conduction anisotropy and alter the spatial and temporal coordination of electrical activation in the heart, leading to induction of ventricular arrhythmias [7]. However, little is known about how connexin remodelling during TIC is established. Fibrillar collagen is an important determinant of the passive material properties of myocardium, affecting diastolic dimensions and compliance of the intact heart. Damage to the myocardial interstitial matrix has the potential to alter both diastolic and systolic cardiac function [3]. MMP-2 and TIMP-2 are the main proteinases of fibrillar collagen, however, little is known about MMP-2 and TIMP-2 during TIC.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animal preparation
Seventeen mongrel dogs of either sex, weighing 11.517 kg (mean 14.09±1.85 kg), were divided randomly into two groups: A TIC group of 11 dogs and another six dogs as a control group (sham group). The randomisation was generated by computer. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the Animal Care Committee of Qi Lu Hospital. We used a dog TIC model of rapid atrial pacing, as previously described [8,9].

Dogs were anaesthetized with sodium pentobarbital (30 mg/kg i.v.) in a supine position with legs fixed during the operation. ECG was established using intra-muscular electrodes. The operation was performed using sterile surgical techniques.

2.2. TIC model
Stimulation and recording were performed as previously described [8,9]. Briefly, under sterile conditions, a unipolar screw-in Medtronic J pacing lead was inserted via the right external jugular vein and fixed in the right atrial appendage under fluoroscopic guidance. The lead was then connected to a Medtronic pacemaker unit (model 8084) in a subcutaneous pocket of the neck. The pacemaker was programmed to capture the atrium at 350400/min, at twice threshold current. ECGs were recorded immediately after atrial pacing at 1, 4 and 8 weeks. Dogs in the sham group were operated on the same as the atrial pacing group, except the lead and pacemaker were not used. A variable atrial pacing rate of 350-400 beats per minute was used because the atria of some dogs could not be paced at 400 beats per minute.

2.3. Echocardiography and cardiac catheterization studies
Serial transthoracic echocardiographic studies were performed at baseline and after 1, 4 and 8 weeks of pacing. Each examination was performed with the pacemaker off and in sinus rhythm, 5 min after the pacemaker was stopped. Acoustic quantification (AQ) technology (a real-time automated endocardial border detection and evaluation of left ventricular function method) [10] was used to record left ventricular volume changes with time in real time. The apical 4- and 2-chamber views were obtained and recorded on videotape for off-line measurements. Special care was taken to obtain similar imaging planes on serial examinations. Maximum mitral valvular blood flow spectrum was measured. Fifteen continuous consecutive cardiac cycles were used for each measurement. Left ventricular (LV) end-diastolic and end-systolic volumes were measured using the biplane Simpson's method of discs. The LV ejection fraction was calculated as the difference between both volumes divided by the LV end-diastolic volume.

Cardiac catheterization studies were performed using sterile surgical techniques before pacemaker implantation and two hours after the last echocardiography study at 8 weeks. A pigtail catheter was inserted into left ventricle through the right femoral artery with the Seldinger method. Left ventricular systolic pressure (LVSP), LVEDP, dp/dtmax and –dp/dtmax of the left ventricle were obtained [11]. To prevent obstruction, a sodium heparin 100 U/kg bolus was injected from the artery. {tau} was calculated from the Weiss formula [12]: {tau}=P0/|–dp/dtmax|.

2.4. Tissue acquisition and processing for electron microscopy
After week 8, the hearts in the TIC and control groups were rapidly excised after cardiac catheterization, rinsed in a beaker with 4 °C saline to wash out residual blood and trimmed of major vessels. Each heart was cut into three samples of approximately 1 mm3 transversely from the left ventricular free wall. One 1-mm3 section was fixed in 3% glutaraldehyde, dehydrated in ethanol and embedded in Spurr's low-viscosity epoxy resin. After the resin had been polymerized, ultrathin (50100 nm) sections were cut for electron microscopy. The other two tissue samples were stored at –70 °C for subsequent immunoprecipitation assays.

2.5. Immunohistochemistry and quantitative confocal microscopy of Cx43
The SABC method was used for immunohistochemistry [13-15]. Briefly, frozen tissues were thawed and refrozen in OCT freezing medium before sectioning. Frozen 4-µm sections were fixed in acetone, followed by immunostaining. After cooling to room temperature, tissue sections were simultaneously permeabilized and blocked by incubating them in PBS containing SABCFITC and 3% normal goat serum. The sections were then incubated with the primary antibody (diluted 1:200 in PBS) overnight at 4 °C, brought to room temperature, washed three times in PBS and incubated with goat anti-rabbit IgG (diluted 1:200) for 2 h at 25 °C before being examined by laser scanning confocal microscopy (Zeiss LSM510). Immunostaining controls used PBS solution instead of primary antibody. FITC was triggered by 450 nm blue light and produced by 519 nm green light. Multiple fields from each ventricular sample were digitized and the proportion of total myocardial tissue area occupied by specific Cx43 immunofluorescent signals quantified using Sigma Scan Pro 5.0 [13-16].

2.6. Immunoblotting to determine the relative abundance of MMP-2 and TIMP-2
MMP-2 and TIMP-2 analyses were performed on each sample following previously published methods [17-19].

2.7. Statistical analysis
Differences between groups of various indexes were analyzed using unpaired ANOVA. Differences within the group of indexes were analysed by t-test and repeated measure ANOVA. A value of P<0.05 was considered statistically significant. All data are expressed as mean±S.D.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Three dogs were excluded from analysis in the TIC group: one dog died suddenly after 24 h of pacing, another suffered severe heart failure after the 4th week of pacing, while the third stopped pacing by itself in the 8th week. Therefore, data from eight dogs in the TIC group and the six dogs, which all underwent successful procedures in the control group, were analyzed.

3.1. Echocardiography results
The E wave deceleration time (EDT) of the mitral valve decreased after pacing for 4 and 8 weeks compared with the control group. E/A ratio (peak E velocity/peak A wave velocity of the mitral valve blood-flow spectrum) only decreased after 8 weeks of pacing (Table 1). Left atrial filling volume (AF, 1.01±0.29 ml vs. 1.85±0.46 ml; p<0.01), left atrial rapid filling fraction (0.11±0.003 vs. 0.35±0.12; p<0.001) and left atrial peak rapid filling rate (PAFR, 15.45±16.86 vs. 40.64±14.82 ml/s, p<0.01) decreased significantly. Left ventricular rapid filling volume (RF, 8.14±1.48 vs. 3.72±2.13 ml; p<0.001), rapid filling fraction (0.89±0.003 vs. 0.62±0.12; p<0.001), peak rapid filling rate (PRFR, 116.93±26.86 vs. 62.85±17.71 ml/s; p<0.01) increased significantly after 8 weeks of pacing, with no differences after pacing in the 1st or 4th week compared with the control group (Table 1).


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  		Table 1 Echocardiographic indices (mean±S.D.)

 
Compared with the control group, LVEF decreased significantly after 1-week pacing (0.46±0.20 vs. 0.58±0.01; p<0.05), 4-week (0.43±0.18 vs. 0.58±0.01; p<0.05) and 8-week (0.4±0.17 vs. 0.58±0.01; p<0.05).

3.2. Cardiac catheterization results
Compared with the control group, dp/dtmax (2950±886 vs. 4466.7±1769.4 mm Hg/s; p<0.05); –dp/dtmax (–2462.5±699 vs. –3933.3±301.1 mm Hg/s; p<0.001) decreased, LVEDP increased (14.88±2.78 vs. 10±3.95 mm Hg; p<0.05) and {tau} (36.47±9.81 s vs. 24.54±4.69 s; p<0.05) was prolonged significantly after 8 weeks pacing (Table 2).


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  		Table 2 Cardiac catheterization indices after 8 weeks pacing compared with control

 
3.3. Electron microscopy results
Severe changes in the architecture of the left ventricular myocardium were documented by electron microscopy after 8 weeks of rapid atrial pacing. Changes in intracellular membranous ultrastructures, including the mitochondria and sarcoplasmic reticulum, were observed (Figs. 1 and 2). Large stores of glycogen were visible and myocardial fibers were in disarray, with the fibers running in various directions. Mitochondria clustered with waveform and sarcoplasmic reticulum network density decreased. Intercalated disk discontinuity was also displayed.


Figure 01
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  		Fig. 1 Representative transmission electron micrograph of the left ventricle in the control group (x12,000). Mitochondria (blue arrow), sarcoplasmic reticulum and nuclear chromatin are shown and intercalated disk (black arrow) are arrayed regularly. Glycogen (green arrow) and collagen fiber (yellow arrow) are also seen. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

 


Figure 02
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  		Fig. 2 Representative transmission electron micrograph of the left ventricle in the 8-week TIC group (x20,000). Enlarged and disarrayed fibers (yellow arrow), and mitochondria with disintegrated crystal and an anarchic pattern (blue arrow), are seen. Moderate dilation of the rough endoplasmic reticulum and intercalated disk discontinuity (green arrow) are also shown. Large stores of glycogen (red arrow) are visible. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

 
3.4. Quantitative confocal microscopy results
Compared to the control group (Fig. 3), the mean Cx43 immunofluorescent staining value was significantly lower in the 8-week TIC group (2.31±0.40 vs. 4.35±0.83; p<0.001). The distribution of Cx43 was irregular compared with the control group (Fig. 4).


Figure 03
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  		Fig. 3 Example of immunofluorescent staining for Cx43 and laser confocal micrographs in a specimen from the left ventricle of a dog from the control group. High-intensity specific immunoreactive signal of Cx43 is clearly identified at points of intercellular apposition. Little or no signal is observed intracellularly.

 


Figure 04
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  		Fig. 4 Example of immunofluorescent staining and quantitative laser confocal micrograph in a specimen from the left ventricle of an 8-week TIC dog. From inspection of sections stained with anti-Cx43 antibodies, it was obvious that the number of signals was reduced.

 
3.5. MMP and TIMP results
Compared with the control group, MMP-2 in the 8-week TIC group was significantly higher (0.669±2.44E-02 vs. 1.114±5.883E-02 separately, P<0.001). TIMP-2 decreased significantly compared with the control group (0.578±8.244E-02 vs. 0.221±9.776E-03 separately, P<0.001).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The first TIC case was reported in 1913 in a young man with atrial fibrillation (AF) [20], and many cases of TIC have been reported since [21-28]. The incidence of TIC is unknown; most reports have been small retrospective series or case studies involving patients with AF. In patients with AF, approximately 25-50% of those with left ventricular dysfunction have some degree of TIC [1]. The present study describes the characteristics of a canine TIC model induced by sustained, paced AF. This model may be the experimental counterpart of clinically observed cardiomyopathy induced by tachycardia. Our model is reproducible, with TIC induced ideally after 8-weeks pacing in 11 dogs (success rate 72.7%).

Alterations observed at the cellular level, such as the increase in mitochondrial size and disruption of the sarcoplasmic reticulum, may create ionic alterations that increase atrial vulnerability, thereby, triggering AF [9,29]. Cellular changes include disarrayed myofibrils, decreased sarcoplasmic reticulum network density and discontinuous intercalated disks, which may be due to derangements of the extracellular collagen matrix [1].

The development of dilated cardiomyopathy in patients and animals has been shown to result in accumulation of glycogen [29] and discontinuity of the fibrillar collagen network [3,2,30,]. Our results are consistent with these findings. These previous light and electron microscopic studies have demonstrated that changes in fibrillar collagen structure occur with development and recovery from TIC. The collagen matrix is a three-dimensional latticework, essential for coordinated transmission and maintenance of myocyte geometry and alignment within the ventricle wall. Reduction in the collagen struts results in disruption of adjacent myocytes [30]. Active MMP-2 can degrade fragments of fibrillar collagen, which occurs only after initial degradation by collagenase [31].

Active MMP-2 plays an important role in physiological and pathological connective tissue remodelling, including wound healing, tumour invasion and chronic inflammatory disorders. MMP-2 is increased in chronic ischaemic and idiopathic dilated cardiomyopathy [32,33], and after myocardial infarction [34], suggesting a role in the pathogenesis of ventricular enlargement in these conditions. This is further supported by the finding that LV dilatation after infarction is attenuated in transgenic mice with targeted deletion of the MMP-2 gene, compared with sibling wild-type mice [34]. TIMP-2 has an inhibitory effect on MMP-2; therefore, a reduction in TIMP-2 may lead to activation of MMP-2. Our study demonstrated that MMP-2 increased significantly and TIMP-2 decreased, with the same significance, during TIC.

It has been proposed that changes in fibrillar collagen within the extracellular matrix may significantly influence myocardial remodelling and, in turn, significantly affect left ventricular function, particularly diastole. Furthermore, our previously reported study, using an angiotensin-converting enzyme inhibitor, which is known to influence fibroblast activity and collagen production directly, showed beneficial effects on ventricular function and structure [35], in agreement with the results of Reinhardt et al. [36]. Synthetic MMP inhibitors have been shown to attenuate ventricular enlargement and contractile dysfunction following experimental myocardial infarction [37] and heart failure [38]. Therefore, MMP inhibitors may be evaluated for the treatment of TIC in future studies [3].

The number, size and arrangement of gap junctions are important determinants of conduction properties in different parts of the heart under both physiological and pathophysiological conditions [39-42]. Cx43 is the predominant ventricular gap junction channel protein. Slow ventricular conduction in Cx43 +/– mice is related directly to diminished Cx43 in gap junctions (i.e. fewer intercellular channels resulting in increased resistance to current transfer) rather than differences in other determinants of conduction velocity, such as active membrane properties or the anatomy of the conduction pathway [15]. A novel genetic murine model of primary sudden cardiac death defined gap function abnormalities as a key molecular feature of the arrhythmogenic substrate [43,44]. Another study showed Cx43 expression patterns can potentially contribute to an arrhythmic substrate in the failing myocardium [45]. Our quantitative confocal microscopy results in the present study showed that Cx43 decreased significantly in the TIC group compared with the control group.

A peptide, ZP123, has been shown to increase gap junction conductance and, so, prevent reentrant ventricular tachycardia in a myocardial ischaemia dog model [46] and to decrease defibrillation threshold in a ventricular fibrillation rabbit model [47]. No doubt ZP123 will be a novel addition to TIC and other heart failure studies.

Cx43 not only induces arrhythmias, but also affects myocardial structure and function. Reduced expression of gap functional channel protein is commonly observed in chronic heart disease [48]. Impaired intercellular coupling between myocytes under pathologic conditions, such as hypoxia or acidosis, may result in contractile dysfunction secondary to abnormal regional wall motion and generation of ventricular arrhythmias. However, whether the heterogeneous distribution of gap functional channel protein directly decreases heart function needs further study, although Gustein et al. [49] showed that heterogeneous Cx43 expression, by disturbing the normal pattern of coordinated myocardial excitation, may directly depress cardiac performance. Therefore, whether heart failure, including both left ventricular systolic and diastolic function, in the present model, was induced by a decrease in Cx43 or conversely the decrease in Cx43 induced heart failure, needs further study.

There are several limitations in our study. Our TIC model did not include a recovery period; however, several other studies have used the same procedure [8,9]. Also, we did not investigate other MMPs, such as MMP-1, MMP-8 or MMP-9, and we only studied TIMP-2, and did not investigate the other TIMPs, such as TIMP-1 or TIMP-3. We did not investigate aggregate gap junction length or the number of gap junctions further using electron microscopy [15]; however, quantitative confocal analysis showed a reduction in the number, rather than size, of gap junctions in the TIC group.


   Acknowledgements
 
This study was supported by a grant-in-aid from Shandong Superexcellence Youth Foundation of China (No 03BS057 and 2005GG4402033). And we thank Asian Science Editing for refining the English writing of the manuscript.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Umana E., Solares C.A., Alpert M.A. Tachycardia-induced cardiomyopathy. Am J Med (2003) 114:51–55.[CrossRef][Web of Science][Medline]
  2. Kajstura J., Zhang X., Liu Y., et al. The cellular basis of pacing-induced dilated cardiomyopathy myocyte cell loss and myocyte cellular reactive hypertrophy. Circulation (1995) 92:2306–2317.[Abstract/Free Full Text]
  3. Spinale F.G., Zellner J.L., Johnson W.S., Eble D.M., Munver P.D. Cellar and extracellular remodeling with the development and recovery from tachycardia-induced cardiomyopathy: changes in fibrillar collagen, myocyte adhesion capacity and proteoglycans. J Mol Cell Cardiol (1996) 28:1591–1608.[CrossRef][Web of Science][Medline]
  4. Peters N.S., Wit A.L. Myocardial architecture and ventricular arrhythmogenesis. Circulation (1998) 97:1746–1754.[Free Full Text]
  5. Kaprielian R.R., Gunning M., Dupont E., et al. Downregulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation (1998) 97:651–660.[Abstract/Free Full Text]
  6. Wang X., Gerdes A.M. Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: III. Intercalated disc remodeling. J Mol Cell Cardiol (1999) 31:333–343.[CrossRef][Web of Science][Medline]
  7. Poelzing S., Akar F.G., Baron E., Rosenbaum D.S. Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall. Am J Physiol (2004) 286:H2001–H2009.[Web of Science]
  8. Fareh S., Villemaire C., Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation (1998) 98:2202–2209.[Abstract/Free Full Text]
  9. 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]
  10. Bednarz J.E., Marcus R.H., Lang R.M. Technical guidelines for performing automated border detection studies. J Am Soc Echocardiogr (1995) 8:293–305.[CrossRef][Medline]
  11. Mathew R., Wang J., Gewitz M.H., Hintze T.H., Wolin M.S. Congestive heart failure alters receptor-dependent cAMP-mediated relaxation of canine pulmonary arteries. Circulation (1993) 87:1722–1728.[Abstract/Free Full Text]
  12. Weiss J.L., Frederiksen J.W., Weisfeldt M.L. Hemodynamic determinants of the time course of fall in canine left ventricular pressure. J Clin Invest (1976) 58:751–760.[Web of Science][Medline]
  13. Yamamoto T., Ochalski A., Hertzberg E.L., Nagy J.I. LM and EM immunolocalization of the gap functional protein connexin 43 in rat brain. Brain Res (1990) 508:313–319.[CrossRef][Web of Science][Medline]
  14. Dolber P.C., Beyer E.C., Junker J.L., Spach M.S. Distribution of gap junctions in dog and rat ventricle studied with a double-label technique. J Mol Cell Cardiol (1992) 24:1443–1457.[CrossRef][Web of Science][Medline]
  15. Saffitz J.E., Green K.G., Kraft W.J., Schechtman K., Yamada K.A. Effects of diminished expression of connexin43 on gap junction number and size in ventricular myocardium. Am J Physiol (2000) 278:H1662–H1670.[Web of Science]
  16. Luke R.A., Beyer E.C., Hoyt R.H., Saffitz J.E. Quantitative analysis of intercellular connections by immunohistochemistry of the cardiac gap junction protein connexin43. Circ Res (1989) 65:1450–1457.[Abstract/Free Full Text]
  17. Nagatomo Y., Carabello B.A., Coker M.L., et al. Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control. Am J Physiol (2000) 278:H151–H161.[Web of Science]
  18. Spinale F.G., Coker M.L., Heung L.J., et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation (2000) 102:1944–1949.[Abstract/Free Full Text]
  19. Thomas C.V., Coker M.L., Zellner J.L., Handy J.R., Crumbley A.J. III, Spinale F.G. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation (1998) 97:1708–1715.[Abstract/Free Full Text]
  20. Gossage A.M., Braxton Hicks J.A. On auricular fibrillation. Q J Med (1913) 6:435–440.[Web of Science]
  21. Grogan M., Smith H.C., Gersh B.J., Wood D.L. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol (1992) 69:1570–1573.[CrossRef][Web of Science][Medline]
  22. Van Gelder I.C., Crijns H.J., Blanksma P.K., et al. Time course of hemodynamic changes and improvement of exercise tolerance after cardioversion of chronic atrial fibrillation unassociated with cardiac valve disease. Am J Cardiol (1993) 72:560–566.[CrossRef][Web of Science][Medline]
  23. Rodriguez L.M., Smeets J.L., Xie B., et al. Improvement in left ventricular function by ablation of atrioventricular nodal conduction in selected patients with lone atrial fibrillation. Am J Cardiol (1993) 72:1137–1141.[CrossRef][Web of Science][Medline]
  24. Edner M., Caidahl K., Bergfeldt L., Darpo B., Edvardsson N., Rosenqvist M. Prospective study of left ventricular function after radiofrequency ablation of atrioventricular junction in patients with atrial fibrillation. Br Heart J (1995) 74:261–267.[Abstract/Free Full Text]
  25. Twidale N., McDonald T., Nave K., Seal A. Comparison of the effects of AV nodal ablation versus AV nodal modification in patients with congestive heart failure and uncontrolled atrial fibrillation. Pacing Clin Electrophysiol (1998) 21:641–651.[CrossRef][Medline]
  26. Morady F., Hasse C., Strickberger S.A., et al. Long term follow up after radiofrequency modification of the atrioventricular node in patients with atrial fibrillation. J Am Coll Cardiol (1997) 29:113–121.[Abstract]
  27. Geelen P., Goethals M., de Bruyne B., Brugada P. A prospective hemodynamic evaluation of patients with chronic atrial fibrillation undergoing radiofrequency catheter ablation of the atrioventricular junction. Am J Cardiol (1997) 80:1606–1609.[CrossRef][Web of Science][Medline]
  28. Brown C.S., Mills R.M., Conti J.B., Curtis A.B. Clinical improvement after atrioventricular nodal ablation for atrial fibrillation does not correlate with improved ejection fraction. Am J Cardiol (1997) 80:1090–1091.[CrossRef][Web of Science][Medline]
  29. Schaper J., Froede R., Hein S., et al. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation (1991) 83:504–514.[Abstract/Free Full Text]
  30. Weber K.T., Pick R., Silver M.A., et al. Fibrillar collagen and remodeling of dilated canine left ventricle. Circulation (1990) 82:1387–1401.[Abstract/Free Full Text]
  31. Tyagi S.C., Kumar S.G., Haas S.J., et al. Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol (1996) 28:1415–1428.[CrossRef][Web of Science][Medline]
  32. Spinale F.G., Tomita M., Zellner J.L., Cook J.C., Crawford F.A. Collagen remodeling and changes in LV function during development and recovery from supraventricular tachycardia. Am J Physiol (1991) 261:H308–H318.[Web of Science][Medline]
  33. Lu L., Gunja-Smoth Z., Woessner J.F., et al. Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo. Am J Physiol (2000) 279:H601–H609.[Web of Science]
  34. Hayashidani S., Tsutsui H., Ikeuchi M., et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. Am J Physiol (2003) 285:H1229–H1235.[Web of Science]
  35. Ming Z., Wei Z., Yun Z., et al. Ultrastructural changes of right ventricular myocardium due to sustained atrial fibrillation in the canine. J Shandong Univ Healthy Sci (2005) 43:208–210.
  36. Reinhardt D., Sigusch H.H., Henβe J., Tyagi S.C., Körfer R., Figulla H.R. Cardiac remodelling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart (2002) 88:525–530.[Abstract/Free Full Text]
  37. Rohde L.E., Ducharme A., Arroyo L.H., et al. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation (1999) 99:3063–3070.[Abstract/Free Full Text]
  38. Spinale F.G., Coker M.L., Thomas C.V., Walker J.D., Mukherjee, Hebbar L. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function. Circ Res (1998) 82:482–495.[Abstract/Free Full Text]
  39. Saffitz J.E., Schuessler R.B., Yamada K. Mechanisms of remodeling of gap junction distributions and the development of anatomic substrates of arrhythmias. Cardiovasc Res (1999) 42:309–317.[Free Full Text]
  40. Yeager M. Structure of cardiac gap junction intercellular channels. J Struct Biol (1998) 121:231–245.[CrossRef][Web of Science][Medline]
  41. Peters N.S., Coromilas J., Severs N.J., Wit A. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation (1997) 95:988–996.[Abstract/Free Full Text]
  42. Darrow B.J., Fast V.G., Kléber A.G., Beyer E.C., Saffitz J.E. Functional and structural assessment of intercellular communication: increased conduction velocity and enhanced connexin expression in dibutyryl cAMP-treated cultured cardiac myocytes. Circ Res (1996) 79:174–183.[Abstract/Free Full Text]
  43. Van Rijen H., Eckardt D., Degen J., et al. Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation (2004) 109:1048–1055.[Abstract/Free Full Text]
  44. Poelzing S., Rosenbaum D.S. Altered connexin43 expression produces arrhythmia substrate in heart failure. Am J Physiol (2004) 287:H1762–H1770.[Web of Science]
  45. Gutstein D.E., Morley G.E., Tamaddon H., et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res (2001) 88:333–339.[Abstract/Free Full Text]
  46. Xing D.Z., Kj{phi}lbye A.L., Nielsen M.S., et al. ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs. J Cardiovasc Electrophysiol (2003) 14:510–520.[CrossRef][Web of Science][Medline]
  47. Dorian P., Zhong J.Q., Hu X., So P.P., Debicki D. Increasing gap junction conductance with ZP123 improves defibrillation success in experiment cardiac arrest. Circulation (2005) 112(17 Suppl):637.
  48. Kitamura H., Ohnishi Y., Yoshida A., Okajima K., Azumi H. Heterogeneous loss of connexin43 protein in nonischemic dilated cardiomyopathy with ventricular tachycardia. J Cardiovasc Electrophysiol (2002) 13:865–870.[CrossRef][Web of Science][Medline]
  49. Gustein D.E., Morley G.E., Vaidya D., et al. Heterogeneous expression of gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation (2001) 104:1194–1199.[Abstract/Free Full Text]

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