Integrative Physiology |
From the Section of Myocardial Biology, Cardiovascular Institute, Departments of Medicine (D.E.G., G.I.F.), Biochemistry and Molecular Biology (H.S., G.I.F.), and Physiology and Biophysics (G.I.F.), Mount Sinai School of Medicine, New York, NY; Department of Pharmacology (G.E.M., H.T., D.V.), SUNY Upstate Medical University, Syracuse, NY; Center for Cardiovascular Development (M.D.S.), Baylor College of Medicine, Houston, Tex; and UCSD-Salk NHLBI Program in Molecular Medicine (J.C., K.R.C.), Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, Calif. Present address for H.S. is Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif.
Correspondence to Dr Glenn I. Fishman, Mount Sinai School of Medicine, One Gustave L. Levy Pl, Box 1269, New York, NY 10029. E-mail fishmg01{at}doc.mssm.edu
| Abstract |
|---|
|
|
|---|
Key Words: gap junction connexin43 arrhythmia conduction
| Introduction |
|---|
|
|
|---|
Efforts to genetically define the role of gap junction channels in cardiac conduction and arrhythmogenesis in vivo have been limited by the perinatal lethal developmental phenotype observed in Cx43 knockout (KO) mice.15 Data on conduction properties in Cx43 heterozygous KO mice, which develop normally and have normal lifespans, have been contradictory, likely reflecting differing methodologies. Some investigators have reported conduction slowing,16 whereas others find no statistically significant electrophysiological differences compared with wild-type hearts.17 Regardless, hearts from Cx43 heterozygous mice seem to be abnormally susceptible to the development of ventricular tachycardia in response to acute ischemia, providing evidence, at least in isolated heart preparations, that altered gap junction expression may be proarrhythmic.11
To test whether Cx43 is essential for cardiac electrical stability and whether altered gap junction expression is arrhythmogenic in vivo, we conditionally inactivated the Cx43 gene exclusively in cardiomyocytes. Cardiac morphogenesis in conditional KO (CKO) mice is normal, demonstrating no intrinsic cardiomyocyte cellautonomous requirement for Cx43 during heart development. Despite normal cardiac structure and contractile performance, Cx43 CKO mice show profound conduction defects and uniformly develop spontaneous ventricular arrhythmias and sudden cardiac death by 2 months of age. Thus, in contrast to all existing murine models of altered cardiac electrophysiology, primary derangements in Cx43 expression lead to formation of a highly arrhythmogenic substrate culminating in uniform sudden cardiac death.
| Materials and Methods |
|---|
|
|
|---|
Southern Blot Analysis and Polymerase Chain
Reaction
Southern blotting and polymerase chain reaction (PCR)
were performed according to established techniques. Southern blots were
probed with a 700-bp 3' flanking probe from a region outside of the
targeting vector.
Western Blot Analysis
Western blot analyses were performed with polyclonal
antibodies to Cx4319 and
Cx40 (Alpha Diagnostic). Blotting for Cx45 was performed with a
monoclonal antibody (directed against amino acids 354367; Chemicon)
and embryonic mouse-heart lysate from embryonic day (E) 13.5 was used
as a positive control. For normalization of signals, blotting was also
performed with antiß-tubulin (Zymed Laboratories) or antisarcomeric
myosin heavy chain (MHC) (Developmental Studies Hybridoma Bank)
monoclonal antibodies, followed by blotting with horseradish
peroxidaseconjugated secondary antibody, chemiluminescent processing
(ECL, Amersham Pharmacia Biotech), and
autoradiography.
Histology, Immunofluorescence, and Confocal
Analysis
Hearts were removed from experimental mice at
predetermined times and flash-frozen in liquid nitrogen. Hearts were
later thawed and refrozen in O.C.T. freezing medium before sectioning.
Embryos at E12.5 were frozen directly in O.C.T. medium before
sectioning. Frozen sections were fixed in acetone followed by
immunostaining. Double staining of myocardial tissue with anti-Cx43
antisera and wheat germ agglutinin to visualize myocyte borders was
performed as previously
described.20 Cx43 was
detected using a polyclonal antibody (custom manufactured by Research
Genetics) directed against the same epitope used by Yamamoto et
al.19 Sections stained by
immunofluorescence were visualized by confocal microscopy. For the
evaluation of myocardial fibrosis, tissue was fixed in 4%
paraformaldehyde and embedded in paraffin, followed by staining with
modified Masons trichrome stain.
Telemetry Monitoring
For ambulatory electrocardiographic monitoring,
miniature telemetry transmitter devices (Data Sciences International)
were implanted as previously
described.21 The animals
were allowed 48 hours to recover from the surgery before telemetry
recordings were acquired. Recordings from CKO mice were continuous
beginning 48 hours after implantation until the time of
death.
Echocardiography
Echocardiography was performed under light anesthesia
with avertin using an Acuson Sequoia echocardiography machine and a
15-MHz linear probe. Measurements were performed online in a blinded
fashion. Fractional shortening (FS), left ventricular volumes, and
ejection fraction (EF) were calculated according to a standard formula,
as applied previously in
rodents.22 23
Optical Mapping of Ventricular
Activation
Mice were heparinized (heparin sodium 0.5 U/g
intraperitoneally) and killed by cervical dislocation, and hearts were
removed and perfused as previously
described.17 24
After 15 minutes of equilibration, the hearts were stained with a
voltage-sensitive dye (di-4-ANEPPS, Molecular Probes). Epicardial
pacing was performed with a unipolar electrode (stimuli at 1.5x
diastolic threshold) at a cycle length of 120 ms (control and MHC-CKO).
High-resolution optical mapping of voltage-dependent fluorescence was
performed on an upright Olympus microscope (BX50WI) with a reflected
light fluorescence attachment (BX-FLA). Excitation light from a
100-watt mercury arc lamp (Olympus) was filtered (480 to 550; dichroic
mirror 570 nm), and the emitted fluorescent light (>590 nm) was
projected onto a CCD camera (Dalsa). Images were acquired at 912
frames per second with 12-bit resolution from a 64x64-pixel array,
which provided a spatial resolution of 40 µm (4x objective, NA
0.28).
To obtain a representative sequence of activation during epicardial pacing, 10 to 15 beats were averaged. No pharmacological or mechanical manipulations were used to limit motion. Because contraction begins during repolarization, it is possible to identify action potential upstrokes using dF/dtmax. Local fluorescence maxima and minima were determined within an 8-ms window centered on the dF/dtmax. A pixel was considered activated when its fluorescent signal exceeded 50% of this local fluorescence range.
Conduction Velocity
Conduction velocities were calculated as described
previously.17 Briefly, local
conduction velocities were calculated from the gradient of activation
times. Vectors near the stimulating electrode and at a distance from
the electrode were excluded to remove stimulus artifacts and the
effects of 3-dimensional propagation. In addition, vectors that
deviated >60 degrees from their neighboring sites were excluded from
analysis to remove the effect of wavefront collisions.
Statistics
Western blot densitometry, echocardiographic and
conduction velocity (CV) data are expressed as mean±SEM. Comparisons
between groups were performed with a 2-tailed
t test using Microsoft Excel
software. For analysis of CVmax,
CVmin, and anisotropic ratio, because only 2 of
these parameters can be considered independent, we chose to test
significance for CVmin and anisotropic ratio.
Kaplan-Meier survival curves for the CKO mice were constructed and
compared (with the logrank test) using StatView software.
P<0.05 was considered
statistically significant.
| Results |
|---|
|
|
|---|
|
Cx43 CKO Mice Develop Normally
Homozygous Cx43flox/flox
mice were crossed with strains of mice expressing Cre recombinase (Cre)
exclusively in cardiomyocytes. These included a transgenic strain in
which Cre was driven by regulatory elements from the
-MHC
gene27 and a second strain
in which Cre has been knocked in to the myosin light chain 2v (MLC2v)
locus.28 Both the
-MHCCre:Cx43flox/flox CKO (MHC-CKO) and
the MLC2v-Cre:Cx43flox/flox CKO (MLC-CKO)
mice were born with the expected mendelian frequency and were grossly
indistinguishable from their non-KO littermates.
Efficient inactivation of Cx43 expression in the hearts of
CKO mice was examined by immunofluorescence. At both E12.5
(Figures 2A
through 2C) and at 4 weeks postpartum
(Figures 2D
through 2F), a marked reduction of Cx43 expression
was observed in CKO hearts, with extensive areas that were completely
devoid of Cx43 immunoreactivity.
|
To quantify the reduction in Cx43 expression, Western blot
analysis was performed. At 4 weeks of age, compared with control
littermates, Cx43 expression was reduced by 95% in the MHC-CKO mice
(P=0.027; n=3 MHC-CKO mice and
4 controls) and by 86% in MLC-CKO mice
(P<0.01; n=4 MLC-CKO and 4
controls), consistent with the immunofluorescence data
(Figure 3A
). There was no apparent compensatory increase in
the expression of other connexins known to be expressed in myocytes. By
Western blot analysis, Cx40 levels in both the MHC-CKO and MLC-CKO
strains were unchanged compared with littermate controls
(Figure 3B
). Cx45 expression was below the limits of
detection in both CKO and control hearts, in agreement with previous
studies of normal murine
heart.29 In addition, no
expression of Cx40 or Cx45 was detected by immunofluorescence in
working ventricular myocardium (not shown).
|
Histological examination of CKO hearts at several time points revealed no evidence of the right ventricular outflow tract (RVOT) obstruction phenotype associated with germline ablation of Cx43. Both at 1 week after birth (n=2 CKO and 3 Cre- littermate hearts) and in older mice at 8 weeks of age (n=3 CKO and 3 Cre- littermate hearts), the ventricular muscle appeared entirely normal, without fibrosis, hypertrophy, or myofibrillar disarray (not shown).
Contractile performance, left ventricular chamber sizes, and
wall thicknesses, as assessed by echocardiography in 1-month-old
MHC-CKO mice, were no different
than in non-KO littermates
(Table
).
Thus, Cre recombinase, driven by regulatory elements from either the
-MHC or MLC2v genes, efficiently and specifically inactivated Cx43
expression in the myocyte compartment of the heart, with no discernible
compensatory effect on the abundance of other cardiac connexins.
Moreover, there appeared to be no intrinsic cardiomyocyte
cellautonomous requirement for Cx43 during heart development. This
conclusion is consistent with evidence suggesting a primary neural
crest origin of the Cx43 KO
phenotype.30
|
Sudden Cardiac Death in Cx43 CKO Mice
Although the Cx43 CKO mice appeared morphologically and
functionally normal, they began to die suddenly at 2 to 3 weeks of age
(Figure 4
). Within the first 2 months of life, 13 of 13
MLC-CKO mice and 15 of 15 MHC-CKO mice died suddenly, all without
previous signs of illness. In contrast, there was no mortality among
the
Cre-:Cx43flox/flox
littermates (n=25) during the first 6 months of life.
|
We implanted miniaturized telemetry transmitter devices in
four 5-week-old MHC-CKO mice to record the cardiac rhythm during
episodes of sudden death.21
During the continuous recording period, all 4 MHC-CKO mice were in
normal sinus rhythm, with no evidence of ventricular ectopy. In 3 of
the mice, we successfully captured the abrupt onset of spontaneous
ventricular tachyarrhythmias, confirming that the deaths were
arrhythmic in nature
(Figure 5
). In the fourth mouse, the recording device was
inadvertently inactive at the time of death.
|
Abnormal Conduction Properties and Arrhythmias
in MHC-CKO Hearts
To directly examine the consequences of loss of Cx43 on
ventricular conduction, we optically mapped electrical activity in the
hearts of MHC-CKO mice and littermate controls using a
voltage-sensitive dye. In hearts from 5- to 8-week-old control mice
(n=6;
Figure 6B
), the normal anisotropic pattern of electrical
activation was
observed,17 21
without evidence of conduction abnormalities or spontaneous
arrhythmias. In contrast, hearts from 5- to 8-week-old MHC-CKO mice
demonstrated markedly abnormal conduction parameters
(Figure 6C
). Six of the 10 MHC-CKO mouse hearts tested
developed spontaneous polymorphic ventricular tachyarrhythmias that
could not be terminated by high-frequency pacing. The remaining MHC-CKO
hearts initially were in normal sinus rhythm and could be paced.
However, conduction parameters in these hearts were markedly abnormal.
Compared with control hearts, CV in these 4 MHC-CKO hearts was
substantially reduced in all directions, as visualized by optical
mapping. CV was reduced most drastically in the transverse
(CVmin) direction (control
CVmin=0.38±0.02 m/s; MHC-CKO
CVmin=0.17±0.02 m/s;
P<0.001;
Figure 6D
), presumably reflecting the lessening of
rotational anisotropy attributable to extreme uncoupling between
epicardial and deeper cell
layers.31 32
CVmax decreased from 0.62±0.02 m/s in controls
to 0.36±0.05 m/s in MHC-CKO mice (significance was not tested). As a
result, the anisotropic ratio
(CVmax/CVmin) was
significantly increased in the CKO hearts (1.66±0.06 in control hearts
versus 2.1±0.13 in MHC-CKO hearts;
P<0.01;
Figure 6D
).
|
The MHC-CKO hearts were highly susceptible to spontaneous
ventricular arrhythmias, which occurred before or during the standard
pacing protocol
(Figure 6E
). Interestingly, within the group of MHC-CKO
hearts, spontaneous arrhythmias at explantation that prevented pacing
were more common in mice older than 7 weeks of age (3 of 3 MHC-CKO
hearts) than in those younger than 7 weeks (3 of 7 MHC-CKO hearts).
There were no age-dependent differences in conduction parameters in the
control group. In total, 8 of 10 MHC-CKO mice studied had spontaneous
ventricular arrhythmias, compared with 0 of 6
controls.
| Discussion |
|---|
|
|
|---|
The first novel finding in this study is the demonstration
that there is no intrinsic cardiomyocyte cellautonomous requirement
for Cx43 during heart development. A similar conclusion was made for
the RXR gene when inactivated by crossing with the same MLC2v-Cre mouse
used in this study.28
Whether recombination was catalyzed in the Cx43 floxed mice with Cre
recombinase expressed under the transcriptional control of the MLC2v or
MHC regulatory elements, where Cx43 expression is inactivated no
later than E12.5, heart development proceeded normally, without the
RVOT phenotype observed with germline knockout of
Cx43.15 Thus, the lethal
developmental defect resulting from global inactivation of Cx43 seems
to result from a nonmyocyte lineage, consistent with previous
experimental evidence suggesting a primary neural-crest origin of this
phenotype.30 33
Lineage-restricted inactivation of Cx43 using strains of mice
expressing Cre recombinase preferentially in the cardiac neural crest,
such as Wnt-134 or
Pax3,35 may unequivocally
answer this question. In addition, targeted ablation of Cx43 in
additional lineages will likely provide additional insight into the
tissue-specific functions of this widely expressed gap junction channel
protein.
By circumventing the lethal RVOT phenotype caused by germline deletion of Cx43 with the conditional strategy, we were able to examine the consequences of loss of Cx43 exclusively in the myocardium. Despite normal heart structure and contractile performance, Cx43 CKO mice uniformly developed sudden cardiac death, apparently from spontaneous ventricular tachycardia. These data support the critical role of the gap junction channel in maintaining cardiac electrical stability. Indeed, it seems that loss of Cx43 function, even in the absence of other identifiable structural cardiac abnormalities, can lead to a substrate in which spontaneous, lethal cardiac arrhythmias are inevitable.
Although CV is markedly slowed in the Cx43 CKO mice, successful impulse propagation is maintained, at least until the abrupt onset of lethal ventricular tachyarrhythmias. This observation is consistent with modeling suggesting that the safety factor for conduction is paradoxically increased with reduced gap junctional coupling.5 Because only scattered myocytes express Cx43 in the CKO mice, our data suggest that the myocardium must be coupled by low-level expression of gap junction channels formed from other connexin isoforms.
The electrophysiological mechanisms leading to the lethal
ventricular arrhythmias and the factors accounting for the timing of
sudden cardiac death in the CKO mice are uncertain. Cellular uncoupling
resulting from loss of Cx43 gap junction channels might unmask ectopic
foci or trigger arrhythmias by enhancing the generation of early
afterdepolarizations
(EADs).36 Computer modeling
studies indicate that moderate decreases in junctional coupling
predispose to the generation of EADs, whereas higher levels of
junctional resistance limit their
propagation.37 Thus, the
residual level of junctional coupling in the CKOs may allow for the
generation and propagation of EADs. Indeed, a pause-dependent EAD may
account for the initiation of the arrhythmia shown in
Figure 5
, top.
By enhancing dispersion of action potential duration (APD) and repolarization, reduced cell coupling also predisposes to the formation of unidirectional block and reentry.36 38 Modeling of a multicellular theoretical fiber suggests that decreased gap junction coupling, although causing a paradoxical increase in the safety factor as CV decreases, also may facilitate microreentry.5 Furthermore, on the basis of in vitro studies of dissociated myocytes,39 it has been theorized that extreme conduction slowing in combination with geometrical factors may permit reentrant excitation to occur in extremely small areas of cardiac tissue. These factors in combination with the progressive growth of individual myocytes after birth, which is predicted to increase the discontinuous nature of propagation, may also play a role in the time course of the arrhythmic phenotype.3
In recent years, increasing attention has focused on the complex interactions between passive and active membrane properties. The Cx43 CKO mice provide a novel experimental system to examine these relationships in a multicellular preparation, particularly with respect to formation of a substrate that clearly enhances the propensity for spontaneous arrhythmias. For example, theoretical simulations by Rudy and colleagues5 36 38 predict that reduced cellular coupling markedly increases APD dispersion and also renders action potential propagation increasingly dependent on the L-type calcium current. Moreover, Laurita et al40 have presented evidence that APD restitution is influenced by cell-to-cell coupling. While recognizing the significant differences in the shape and ionic components of the action potential in various species, additional analyses of impulse propagation in intact hearts or multicellular fibers from wild-type and homozygous Cx43 CKO mice may yield experimental data that can be directly compared with predictions based on theoretical modeling. In addition, with the availability of the Cx43 CKO mice, one can envision increasingly complex genetic strategies in which both the extent of cellular coupling and the magnitude of specific sarcolemmal currents are simultaneously modified, thereby modeling the complex electrophysiological derangements typically observed in diseased myocardium.
In summary, the results of the present study provide strong evidence that loss of Cx43 expression may serve as a critical event in the formation of the arrhythmogenic substrate. Indeed, altered gap junction channel expression in the heart seems sufficient to induce spontaneous ventricular tachycardia with complete penetrance. Moreover, in contrast to other murine models associated with premature cardiovascular mortality, Cx43 CKO mice develop uniform sudden cardiac death in the absence of cardiac dysfunction and morphological abnormalities. Because gap junction remodeling has been described in many forms of human cardiac disease, restoration of normal intercellular coupling in the myopathic heart may well serve as a novel target in the treatment of patients at risk for lethal ventricular arrhythmias.
| Acknowledgments |
|---|
| Footnotes |
|---|
| References |
|---|
|
|
|---|
2. Goodenough DA, Goliger JA, Paul DL. Connexins, connexons, and intercellular communication. Annu Rev Biochem. 1996;65:475502.[Medline] [Order article via Infotrieve]
3.
Spach M, Heidlage
J, Dolber P, Barr R. Electrophysiological effects of remodeling cardiac
gap junctions and cell size: experimental and model studies of normal
cardiac growth. Circ Res. 2000;86:302311.
4.
Quan W, Rudy Y.
Unidirectional block and reentry of cardiac excitation: a model study.
Circ Res. 1990;66:367382.
5.
Shaw RM, Rudy Y.
Ionic mechanisms of propagation in cardiac tissue: roles of the sodium
and L-type calcium currents during reduced excitability and decreased
gap junction coupling. Circ
Res. 1997;81:727741.
6. Luke RA, Saffitz JE. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J Clin Invest. 1991;87:15941602.
7.
Peters NS, Green
CR, Poole-Wilson PA, Severs NJ. Reduced content of connexin43 gap
junctions in ventricular myocardium from hypertrophied and ischemic
human hearts. Circulation. 1993;88:864875.
8. Smith JH, Green CR, Peters NS, Rothery S, Severs NJ. Altered patterns of gap junction distribution in ischemic heart disease: an immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol. 1991;139:801821.[Abstract]
9.
Peters NS,
Coromilas J, Severs NJ, Wit AL. 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;95:988996.
10.
Kaprielian RR,
Gunning M, Dupont E, Sheppard MN, Rothery SM, Underwood R, Pennell DJ,
Fox K, Pepper J, Poole-Wilson PA, Severs NJ. Downregulation of
immunodetectable connexin43 and decreased gap junction size in the
pathogenesis of chronic hibernation in the human left ventricle.
Circulation. 1998;97:651660.
11.
Lerner DL, Yamada
KA, Schuessler RB, Saffitz JE. Accelerated onset and increased
incidence of ventricular arrhythmias induced by ischemia in
Cx43-deficient mice.
Circulation. 2000;101:547552.
12.
Matsushita T,
Oyamada M, Fujimoto K, Yasuda Y, Masuda S, Wada Y, Oka T, Takamatsu T.
Remodeling of cell-cell and cell-extracellular matrix interactions at
the border zone of rat myocardial infarcts.
Circ Res. 1999;85:10461055.
13.
Peters NS, Wit
AL. Myocardial architecture and ventricular arrhythmogenesis.
Circulation. 1998;97:17461754.
14.
Costeas C, Peters
NS, Waldecker B, Ciaccio EJ, Wit AL, Coromilas J. Mechanisms causing
sustained ventricular tachycardia with multiple QRS morphologies:
results of mapping studies in the infarcted canine heart.
Circulation. 1997;96:37213731.
15.
Reaume AG, de
Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC, Juneja SC, Kidder
GM, Rossant J. Cardiac malformation in neonatal mice lacking
connexin43. Science. 1995;267:18311834.
16. Guerrero PA, Schuessler RB, Davis LM, Beyer EC, Johnson CM, Yamada KA, Saffitz JE. Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J Clin Invest. 1997;99:19911998.[Medline] [Order article via Infotrieve]
17. Morley GE, Vaidya D, Samie FH, 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;10:13611375.[Medline] [Order article via Infotrieve]
18. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69:915926.[Medline] [Order article via Infotrieve]
19. Yamamoto T, Ochalski A, Hertzberg EL, Nagy JI. LM and EM immunolocalization of the gap junctional protein connexin 43 in rat brain. Brain Res. 1990;508:313319.[Medline] [Order article via Infotrieve]
20. Dolber PC, Beyer EC, Junker JL, Spach MS. Distribution of gap junctions in dog and rat ventricle studied with a double-label technique. J Mol Cell Cardiol. 1992;24:14431457.[Medline] [Order article via Infotrieve]
21. Lee P, Morley G, Huang Q, Fischer A, Seiler S, Horner JW, Factor S, Vaidya D, Jalife J, Fishman GI. Conditional lineage ablation to model human diseases. Proc Natl Acad Sci U S A. 1998;15:1137111376.
22. Vazquez de Prada JA, Jiang L, Handschumacher MD, Xie SW, Rivera JM, Schwammenthal E, Guerrero JL, Weyman AE, Levine RA, Picard MH. Quantification of pericardial effusions by three-dimensional echocardiography. J Am Coll Cardiol. 1994;24:254259.[Abstract]
23.
Cittadini A,
Stromer H, Katz SE, Clark R, Moses AC, Morgan JP, Douglas PS.
Differential cardiac effects of growth hormone and insulin-like growth
factor-1 in the rat: a combined in vivo and in vitro evaluation.
Circulation. 1996;93:800809.
24.
Vaidya D, Morley
GE, Samie FH, Jalife J. Reentry and fibrillation in the mouse heart: a
challenge to the critical mass hypothesis.
Circ Res. 1999;85:174181.
25.
Baubonis W, Sauer
B. Genomic targeting with purified Cre recombinase.
Nucleic Acids Res. 1993;21:20252029.
26. Pereira L, Andrikopoulos K, Tian J, Lee SY, Keene DR, Ono R, Reinhardt DP, Sakai LY, Biery NJ, Bunton T, Dietz HC, Ramirez F. Targeting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet. 1997;17:218222.[Medline] [Order article via Infotrieve]
27. Agah R, Frenkel PA, French BA, Michael LH, Overbeek PA, Schneider MD. Gene recombination in postmitotic cells: targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J Clin Invest. 1997;100:169179.[Medline] [Order article via Infotrieve]
28.
Chen J, Kubalak
SW, Chien KR. Ventricular muscle-restricted targeting of the RXR
gene reveals a non-cell-autonomous requirement in cardiac chamber
morphogenesis. Development. 1998;125:19431949.[Abstract]
29.
Coppen SR, Dupont
E, Rothery S, Severs NJ. Connexin45 expression is preferentially
associated with the ventricular conduction system in mouse and rat
heart. Circ Res. 1998;82:232243.
30. Ewart JL, Cohen MF, Meyer RA, Huang GY, Wessels A, Gourdie RG, Chin AJ, Park SMJ, Lazatin BO, Villabon S, Lo CW. Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene. Development. 1997;124:12811292.[Abstract]
31. Muzikant AL, Henriquez CS. Paced activation mapping reveals organization of myocardial fibers: a simulation study. J Cardiovasc Electrophysiol. 1997;8:281294.[Medline] [Order article via Infotrieve]
32. Berenfeld O, Pertsov AM. Dynamics of intramural scroll waves in three-dimensional continuous myocardium with rotational anisotropy. J Theor Biol. 1999;199:383394.[Medline] [Order article via Infotrieve]
33. Lo CW, Cohen MF, Huang GY, Lazatin BO, Patel N, Sullivan R, Pauken C, Park SM. Cx43 gap junction gene expression and gap junctional communication in mouse neural crest cells. Dev Genet. 1997;20:119132.[Medline] [Order article via Infotrieve]
34. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM. Fate of the mammalian cardiac neural crest. Development. 2000;127:16071616.[Abstract]
35. Li J, Liu KC, Jin F, Lu MM, Epstein JA. Transgenic rescue of congenital heart disease and spina bifida in Splotch mice. Development. 1999;126:24952503.[Abstract]
36.
Viswanathan PC,
Shaw RM, Rudy Y. Effects of IKr and IKs heterogeneity on action
potential duration and its rate dependence: a simulation study.
Circulation. 1999;99:24662474.
37. Saiz J, Ferrero JMJ, Monserrat M, Ferrero JM, Thakor NV. Influence of electrical coupling on early afterdepolarizations in ventricular myocytes. IEEE Trans Biomed Eng. 1999;46:138147.[Medline] [Order article via Infotrieve]
38.
Viswanathan PC,
Rudy Y. Cellular arrhythmogenic effects of congenital and acquired
long-QT syndrome in the heterogeneous myocardium.
Circulation. 2000;101:11921198.
39.
Rohr S, Kucera
JP, Kleber AG. Slow conduction in cardiac tissue, I: effects of a
reduction of excitability versus a reduction of electrical coupling on
microconduction. Circ Res. 1998;83:781794.
40.
Laurita KR,
Girouard SD, Rudy Y, Rosenbaum DS. Role of passive electrical
properties during action potential restitution in intact heart.
Am J Physiol. 1997;273:H1205H1214.
This article has been cited by other articles:
![]() |
K. Maass, S. E. Chase, X. Lin, and M. Delmar Cx43 CT domain influences infarct size and susceptibility to ventricular tachyarrhythmias in acute myocardial infarction Cardiovasc Res, August 21, 2009; (2009) cvp250v2. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Menasche Stem Cell Therapy for Heart Failure: Are Arrhythmias a Real Safety Concern? Circulation, May 26, 2009; 119(20): 2735 - 2740. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Qu, F. M. Volpicelli, L. I. Garcia, N. Sandeep, J. Zhang, L. Marquez-Rosado, P. D. Lampe, and G. I. Fishman Gap Junction Remodeling and Spironolactone-Dependent Reverse Remodeling in the Hypertrophied Heart Circ. Res., February 13, 2009; 104(3): 365 - 371. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. L. Manias, I. Plante, X.-Q. Gong, Q. Shao, J. Churko, D. Bai, and D. W. Laird Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant Cardiovasc Res, December 1, 2008; 80(3): 385 - 395. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. E. Leaf, J. E. Feig, C. Vasquez, P. L. Riva, C. Yu, J. M. Lader, A. Kontogeorgis, E. L. Baron, N. S. Peters, E. A. Fisher, et al. Connexin40 Imparts Conduction Heterogeneity to Atrial Tissue Circ. Res., October 24, 2008; 103(9): 1001 - 1008. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. J. Severs, A. F. Bruce, E. Dupont, and S. Rothery Remodelling of gap junctions and connexin expression in diseased myocardium Cardiovasc Res, October 1, 2008; 80(1): 9 - 19. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Nakagami, H. Tanaka, P. Dai, S.-F. Lin, T. Tanabe, H. Mani, K. Fujiwara, H. Matsubara, and T. Takamatsu Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers Cardiovasc Res, July 1, 2008; 79(1): 70 - 79. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. S. Penn and A. A. Mangi Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy Circ. Res., June 20, 2008; 102(12): 1471 - 1482. [Abstract] [Full Text] [PDF] |
||||
![]() |
K.-J. Boogerd, L.Y. E. Wong, V. M. Christoffels, M. Klarenbeek, J. M. Ruijter, A. F.M. Moorman, and P. Barnett Msx1 and Msx2 are functional interacting partners of T-box factors in the regulation of Connexin43 Cardiovasc Res, June 1, 2008; 78(3): 485 - 493. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. Munoz, K. Campbell, and J. Shibayama Fibroblasts: modulating the rhythm of the heart J. Physiol., May 15, 2008; 586(10): 2423 - 2424. [Full Text] [PDF] |
||||
![]() |
Y. Mori, G. I. Fishman, and C. S. Peskin Ephaptic conduction in a cardiac strand model with 3D electrodiffusion PNAS, April 29, 2008; 105(17): 6463 - 6468. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. B. Danik, G. Rosner, J. Lader, D. E. Gutstein, G. I. Fishman, and G. E. Morley Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts FASEB J, April 1, 2008; 22(4): 1204 - 1212. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Sato, T. Ohkusa, H. Honjo, S. Suzuki, M.-a. Yoshida, Y. S. Ishiguro, H. Nakagawa, M. Yamazaki, M. Yano, I. Kodama, et al. Altered expression of connexin43 contributes to the arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1164 - H1173. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. F. Bruce, S. Rothery, E. Dupont, and N. J. Severs Gap junction remodelling in human heart failure is associated with increased interaction of connexin43 with ZO-1 Cardiovasc Res, March 1, 2008; 77(4): 757 - 765. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. M. Wolf, M. Arad, F. Ahmad, A. Sanbe, S. A. Bernstein, O. Toka, T. Konno, G. Morley, J. Robbins, J.G. Seidman, et al. Reversibility of PRKAG2 Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations Circulation, January 15, 2008; 117(2): 144 - 154. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Kalcheva, J. Qu, N. Sandeep, L. Garcia, J. Zhang, Z. Wang, P. D. Lampe, S. O. Suadicani, D. C. Spray, and G. I. Fishman Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia PNAS, December 18, 2007; 104(51): 20512 - 20516. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Maass, J. Shibayama, S. E. Chase, K. Willecke, and M. Delmar C-Terminal Truncation of Connexin43 Changes Number, Size, and Localization of Cardiac Gap Junction Plaques Circ. Res., December 7, 2007; 101(12): 1283 - 1291. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. E. Zemljic-Harpf, J. C. Miller, S. A. Henderson, A. T. Wright, A. M. Manso, L. Elsherif, N. D. Dalton, A. K. Thor, G. A. Perkins, A. D. McCulloch, et al. Cardiac-Myocyte-Specific Excision of the Vinculin Gene Disrupts Cellular Junctions, Causing Sudden Death or Dilated Cardiomyopathy Mol. Cell. Biol., November 1, 2007; 27(21): 7522 - 7537. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. A. Palatinus and R. G. Gourdie Xin and the art of intercalated disk maintenance Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2626 - H2628. [Full Text] [PDF] |
||||
![]() |
S. Baba, T. Heike, M. Yoshimoto, K. Umeda, H. Doi, T. Iwasa, X. Lin, S. Matsuoka, M. Komeda, and T. Nakahata Flk1+ cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model Cardiovasc Res, October 1, 2007; 76(1): 119 - 131. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. E. Bondarenko and R. L. Rasmusson Simulations of propagated mouse ventricular action potentials: effects of molecular heterogeneity Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1816 - H1832. [Abstract] [Full Text] [PDF] |
||||
![]() |
V. S. Kasi, H. D. Xiao, L. L. Shang, S. Iravanian, J. Langberg, E. A. Witham, Z. Jiao, C. J. Gallego, K. E. Bernstein, and S. C. Dudley Jr. Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H182 - H192. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Sridharan, L. Simon, D. D. Meling, D. G. Cyr, D. E. Gutstein, G. I. Fishman, F. Guillou, and P. S. Cooke Proliferation of Adult Sertoli Cells Following Conditional Knockout of the Gap Junctional Protein GJA1 (Connexin 43) in Mice Biol Reprod, May 1, 2007; 76(5): 804 - 812. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. P. Collis, M. B. Meyers, J. Zhang, C. K. L. Phoon, E. A. Sobie, W. A. Coetzee, and G. I. Fishman Expression of a sorcin missense mutation in the heart modulates excitation-contraction coupling FASEB J, February 1, 2007; 21(2): 475 - 487. [Abstract] [Full Text] [PDF] |
||||
![]() |
J.-q. Zhong, W. Zhang, H. Gao, Y. Li, M. Zhong, D. Li, C. Zhang, and Y. Zhang Changes in connexin 43, metalloproteinase and tissue inhibitor of metalloproteinase during tachycardia-induced cardiomyopathy in dogs Eur J Heart Fail, January 1, 2007; 9(1): 23 - 29. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. London, L. C. Baker, P. Petkova-Kirova, J. M. Nerbonne, B.-R. Choi, and G. Salama Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT J. Physiol., January 1, 2007; 578(1): 115 - 129. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. A. Pijnappels, M. J. Schalij, J. van Tuyn, D. L. Ypey, A. A.F. de Vries, E. E. van der Wall, A. van der Laarse, and D. E. Atsma Progressive increase in conduction velocity across human mesenchymal stem cells is mediated by enhanced electrical coupling Cardiovasc Res, November 1, 2006; 72(2): 282 - 291. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Kojodjojo, P. Kanagaratnam, O. R. Segal, W. Hussain, and N. S. Peters The Effects of Carbenoxolone on Human Myocardial Conduction: A Tool to Investigate the Role of Gap Junctional Uncoupling in Human Arrhythmogenesis J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1242 - 1249. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. L. Lindsey, G. P. Escobar, R. Mukherjee, D. K. Goshorn, N. J. Sheats, J. A. Bruce, I. M. Mains, J. K. Hendrick, K. W. Hewett, R. G. Gourdie, et al. Matrix Metalloproteinase-7 Affects Connexin-43 Levels, Electrical Conduction, and Survival After Myocardial Infarction Circulation, June 27, 2006; 113(25): 2919 - 2928. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Y. Kresh Cell replacement therapy: The functional importance of myocardial architecture and intercellular gap-junction distribution J. Thorac. Cardiovasc. Surg., June 1, 2006; 131(6): 1310 - 1313. [Full Text] [PDF] |
||||
![]() |
S. Liu, F. Liu, A. E. Schneider, T. St. Amand, J. A. Epstein, and D. E. Gutstein Distinct cardiac malformations caused by absence of connexin 43 in the neural crest and in the non-crest neural tube Development, May 15, 2006; 133(10): 2063 - 2073. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Matsushita, H. Kurihara, M. Watanabe, T. Okada, T. Sakai, and A. Amano Alterations of Phosphorylation State of Connexin 43 during Hypoxia and Reoxygenation Are Associated with Cardiac Function J. Histochem. Cytochem., March 1, 2006; 54(3): 343 - 353. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Li, V. V. Patel, and G. L. Radice Dysregulation of cell adhesion proteins and cardiac arrhythmogenesis. Clin. Med. Res., March 1, 2006; 4(1): 42 - 52. [Abstract] [Full Text] [PDF] |
||||
![]() |
Q. Zheng-Fischhofer, A. Ghanem, J.-S. Kim, M. Kibschull, G. Schwarz, J. O. Schwab, J. Nagy, E. Winterhager, K. Tiemann, and K. Willecke Connexin31 cannot functionally replace connexin43 during cardiac morphogenesis in mice J. Cell Sci., February 15, 2006; 119(4): 693 - 701. [Abstract] [Full Text] [PDF] |
||||
![]() |
I. R. Efimov and C. M. Ripplinger Tornado in a dish: Revealing the mechanisms of ventricular arrhythmias in engineered cardiac tissues Cardiovasc Res, February 1, 2006; 69(2): 307 - 308. [Full Text] [PDF] |
||||
![]() |
T. Betsuyaku, N. S. Nnebe, R. Sundset, S. Patibandla, C. M. Krueger, and K. A. Yamada Overexpression of cardiac connexin45 increases susceptibility to ventricular tachyarrhythmias in vivo Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H163 - H171. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. M. Flenniken, L. R. Osborne, N. Anderson, N. Ciliberti, C. Fleming, J. E. I. Gittens, X.-Q. Gong, L. B. Kelsey, C. Lounsbury, L. Moreno, et al. A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia Development, October 1, 2005; 132(19): 4375 - 4386. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. A.B. van Veen, M. Stein, A. Royer, K. Le Quang, F. Charpentier, W. H. Colledge, C. L.-H. Huang, R. Wilders, A. A. Grace, D. Escande, et al. Impaired Impulse Propagation in Scn5a-Knockout Mice: Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging Circulation, September 27, 2005; 112(13): 1927 - 1935. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Li, V. V. Patel, I. Kostetskii, Y. Xiong, A. F. Chu, J. T. Jacobson, C. Yu, G. E. Morley, J. D. Molkentin, and G. L. Radice Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis Circ. Res., September 2, 2005; 97(5): 474 - 481. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. E. Gutstein, S. B. Danik, S. Lewitton, D. France, F. Liu, F. L. Chen, J. Zhang, N. Ghodsi, G. E. Morley, and G. I. Fishman Focal gap junction uncoupling and spontaneous ventricular ectopy Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1091 - H1098. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. J. Gard, K. Yamada, K. G. Green, B. C. Eloff, D. S. Rosenbaum, X. Wang, J. Robbins, R. B. Schuessler, K. A. Yamada, and J. E. Saffitz Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy Cardiovasc Res, August 15, 2005; 67(3): 539 - 547. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. C. Mounkes, S. V. Kozlov, J. N. Rottman, and C. L. Stewart Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice Hum. Mol. Genet., August 1, 2005; 14(15): 2167 - 2180. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Ando, R. G. Katare, Y. Kakinuma, D. Zhang, F. Yamasaki, K. Muramoto, and T. Sato Efferent Vagal Nerve Stimulation Protects Heart Against Ischemia-Induced Arrhythmias by Preserving Connexin43 Protein Circulation, July 12, 2005; 112(2): 164 - 170. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Ouvrard-Pascaud, Y. Sainte-Marie, J.-P. Benitah, R. Perrier, C. Soukaseum, A. N. D. Cat, A. Royer, K. Le Quang, F. Charpentier, S. Demolombe, et al. Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias Circulation, June 14, 2005; 111(23): 3025 - 3033. [Abstract] [Full Text] [PDF] |
||||
![]() |
X. Liang, Q. Zhou, X. Li, Y. Sun, M. Lu, N. Dalton, J. Ross Jr., and J. Chen PINCH1 Plays an Essential Role in Early Murine Embryonic Development but Is Dispensable in Ventricular Cardiomyocytes Mol. Cell. Biol., April 15, 2005; 25(8): 3056 - 3062. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. V.M. van Rijen, J. M.T. de Bakker, and T. A.B. van Veen Hypoxia, electrical uncoupling, and conduction slowing: Role of conduction reserve Cardiovasc Res, April 1, 2005; 66(1): 9 - 11. [Full Text] [PDF] |
||||
![]() |
N. Zeevi-Levin, Y. D. Barac, Y. Reisner, I. Reiter, G. Yaniv, G. Meiry, Z. Abassi, S. Kostin, J. Schaper, M. R. Rosen, et al. Gap junctional remodeling by hypoxia in cultured neonatal rat ventricular myocytes Cardiovasc Res, April 1, 2005; 66(1): 64 - 73. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. E. Morley, S. B. Danik, S. Bernstein, Y. Sun, G. Rosner, D. E. Gutstein, and G. I. Fishman Reduced intercellular coupling leads to paradoxical propagation across the Purkinje-ventricular junction and aberrant myocardial activation PNAS, March 15, 2005; 102(11): 4126 - 4129. [Abstract] [Full Text] [PDF] |
||||
![]() |
I. Kostetskii, J. Li, Y. Xiong, R. Zhou, V. A. Ferrari, V. V. Patel, J. D. Molkentin, and G. L. Radice Induced Deletion of the N-Cadherin Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure Circ. Res., February 18, 2005; 96(3): 346 - 354. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. A. Iacobas, S. Iacobas, W. E. I. Li, G. Zoidl, R. Dermietzel, and D. C. Spray Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart Physiol Genomics, February 10, 2005; 20(3): 211 - 223. [Abstract] [Full Text] [PDF] |
||||
![]() |
X. Ai and S. M. Pogwizd Connexin 43 Downregulation and Dephosphorylation in Nonischemic Heart Failure Is Associated With Enhanced Colocalized Protein Phosphatase Type 2A Circ. Res., January 7, 2005; 96(1): 54 - 63. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. B. Danik, F. Liu, J. Zhang, H. J. Suk, G. E. Morley, G. I. Fishman, and D. E. Gutstein Modulation of Cardiac Gap Junction Expression and Arrhythmic Susceptibility Circ. Res., November 12, 2004; 95(10): 1035 - 1041. [Abstract] [Full Text] [PDF] |
||||
![]() |
H.-H. Chen, C. J. Baty, T. Maeda, S. Brooks, L. C. Baker, T. Ueyama, E. Gursoy, S. Saba, G. Salama, B. London, et al. Transcription Enhancer Factor-1-Related Factor-Transgenic Mice Develop Cardiac Conduction Defects Associated With Altered Connexin Phosphorylation Circulation, November 9, 2004; 110(19): 2980 - 2987. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. E.J. Teunissen, H. J. Jongsma, and M. F.A. Bierhuizen Regulation of myocardial connexins during hypertrophic remodelling Eur. Heart J., November 2, 2004; 25(22): 1979 - 1989. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Ito, N. Morita, D. Miura, Y.-i. Koma, T. R. Kataoka, H. Yamasaki, Y. Kitamura, Y. Kita, and H. Nojima A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells Carcinogenesis, October 1, 2004; 25(10): 2015 - 2022. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. S. Turner, G. A. Haywood, P. Andreka, L. You, P. E. Martin, W. H. Evans, K. A. Webster, and N. H. Bishopric Reversible Connexin 43 Dephosphorylation During Hypoxia and Reoxygenation Is Linked to Cellular ATP Levels Circ. Res., October 1, 2004; 95(7): 726 - 733. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. London Staying Connected Without Connexin43: Can You Hear Me Now? Circ. Res., July 23, 2004; 95(2): 120 - 121. [Full Text] [PDF] |
||||
![]() |
P. Beauchamp, C. Choby, T. Desplantez, K. de Peyer, K. Green, K. A. Yamada, R. Weingart, J. E. Saffitz, and A. G. Kleber Electrical Propagation in Synthetic Ventricular Myocyte Strands From Germline Connexin43 Knockout Mice Circ. Res., July 23, 2004; 95(2): 170 - 178. [Abstract] [Full Text] [PDF] |
||||
![]() |
K.-G. Shyu, B.-W. Wang, Y.-H. Yang, S.-C. Tsai, S. Lin, and C.-C. Lee Amphetamine activates connexin43 gene expression in cultured neonatal rat cardiomyocytes through JNK and AP-1 pathway Cardiovasc Res, July 1, 2004; 63(1): 98 - 108. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. L. Christie, R. Mui, T. W. White, and G. Valdimarsson Molecular cloning, functional analysis, and RNA expression analysis of connexin45.6: a zebrafish cardiovascular connexin Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1623 - H1632. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Sohl and K. Willecke Gap junctions and the connexin protein family Cardiovasc Res, May 1, 2004; 62(2): 228 - 232. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. E.J Teunissen and M. F.A Bierhuizen Transcriptional control of myocardial connexins Cardiovasc Res, May 1, 2004; 62(2): 246 - 255. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Delmar, W. Coombs, P. Sorgen, H. S Duffy, and S. M Taffet Structural bases for the chemical regulation of Connexin43 channels Cardiovasc Res, May 1, 2004; 62(2): 268 - 275. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Gros, L. Dupays, S. Alcolea, S. Meysen, L. Miquerol, and M. Theveniau-Ruissy Genetically modified mice: tools to decode the functions of connexins in the heart--new models for cardiovascular research Cardiovasc Res, May 1, 2004; 62(2): 299 - 308. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. R de Groot and R. Coronel Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis Cardiovasc Res, May 1, 2004; 62(2): 323 - 334. [Abstract] [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] |
||||
![]() |
M. J Vink, S. O Suadicani, D. M Vieira, M. Urban-Maldonado, Y. Gao, G. I Fishman, and D. C Spray Alterations of intercellular communication in neonatal cardiac myocytes from connexin43 null mice Cardiovasc Res, May 1, 2004; 62(2): 397 - 406. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. G. Petrich, B. C. Eloff, D. L. Lerner, A. Kovacs, J. E. Saffitz, D. S. Rosenbaum, and Y. Wang Targeted Activation of c-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects J. Biol. Chem., April 9, 2004; 279(15): 15330 - 15338. [Abstract] [Full Text] [PDF] |
||||
![]() |
H. V.M. van Rijen, D. Eckardt, J. Degen, M. Theis, T. Ott, K. Willecke, H. J. Jongsma, T. Opthof, and J. M.T. de Bakker Slow Conduction and Enhanced Anisotropy Increase the Propensity for Ventricular Tachyarrhythmias in Adult Mice With Induced Deletion of Connexin43 Circulation, March 2, 2004; 109(8): 1048 - 1055. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Alcolea, T. Jarry-Guichard, J. de Bakker, D. Gonzalez, W. Lamers, S. Coppen, L. Barrio, H. Jongsma, D. Gros, and H. van Rijen Replacement of Connexin40 by Connexin45 in the Mouse: Impact on Cardiac Electrical Conduction Circ. Res., January 9, 2004; 94(1): 100 - 109. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. R. de Groot, T. Veenstra, A. O. Verkerk, R. Wilders, J. P.P. Smits, F. J.G. Wilms-Schopman, R. F. Wiegerinck, J. Bourier, C. N.W. Belterman, R. Coronel, et al. Conduction slowing by the gap junctional uncoupler carbenoxolone Cardiovasc Res, November 1, 2003; 60(2): 288 - 297. [Abstract] [Full Text] [PDF] |
||||
![]() |
J.-A. Yao, D. E. Gutstein, F. Liu, G. I. Fishman, and A. L. Wit Cell Coupling Between Ventricular Myocyte Pairs From Connexin43-Deficient Murine Hearts Circ. Res., October 17, 2003; 93(8): 736 - 743. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. C. SAEZ, V. M. BERTHOUD, M. C. BRANES, A. D. MARTINEZ, and E. C. BEYER Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions Physiol Rev, October 1, 2003; 83(4): 1359 - 1400. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. N. Tulenko Regulating Cross-Talk Between Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1707 - 1709. [Full Text] [PDF] |
||||
![]() |
X. Lin, M. Crye, and R. D. Veenstra Regulation of Connexin43 Gap Junctional Conductance by Ventricular Action Potentials Circ. Res., September 19, 2003; 93 (6): e63 - e73. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. D. Spragg, C. Leclercq, M. Loghmani, O. P. Faris, R. S. Tunin, D. DiSilvestre, E. R. McVeigh, G. F. Tomaselli, and D. A. Kass Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart Circulation, August 26, 2003; 108(8): 929 - 932. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. E. Gutstein, S. B. Danik, J. B. Sereysky, G. E. Morley, and G. I. Fishman Subdiaphragmatic murine electrophysiological studies: sequential determination of ventricular refractoriness and arrhythmia induction Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1091 - H1096. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. P. Thomas, J. P. Kucera, L. Bircher-Lehmann, Y. Rudy, J. E. Saffitz, and A. G. Kleber Impulse Propagation in Synthetic Strands of Neonatal Cardiac Myocytes With Genetically Reduced Levels of Connexin43 Circ. Res., June 13, 2003; 92(11): 1209 - 1216. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Menasche Cell transplantation in myocardium Ann. Thorac. Surg., June 1, 2003; 75(90060): S20 - 28. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Menasche Skeletal muscle satellite cell transplantation Cardiovasc Res, May 1, 2003; 58(2): 351 - 357. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Reffelmann and R. A. Kloner Cellular cardiomyoplasty--cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure? Cardiovasc Res, May 1, 2003; 58(2): 358 - 368. [Full Text] [PDF] |
||||
![]() |
P. Menasche, A. A. Hagege, J.-T. Vilquin, M. Desnos, E. Abergel, B. Pouzet, A. Bel, S. Sarateanu, M. Scorsin, K. Schwartz, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1078 - 1083. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Al Attar, C. Carrion, S. Ghostine, I. Garcin, J.-T. Vilquin, A. A. Hagege, and P. Menasche Long-term (1 year) functional and histological results of autologous skeletal muscle cells transplantation in rat Cardiovasc Res, April 1, 2003; 58(1): 142 - 148. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. E. Gutstein, F.-y. Liu, M. B. Meyers, A. Choo, and G. I. Fishman The organization of adherens junctions and desmosomes at the cardiac intercalated disc is independent of gap junctions J. Cell Sci., March 1, 2003; 116(5): 875 - 885. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. R. Kwak, N. Veillard, G. Pelli, F. Mulhaupt, R. W. James, M. Chanson, and F. Mach Reduced Connexin43 Expression Inhibits Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, February 25, 2003; 107(7): 1033 - 1039. [Abstract] [Full Text] [PDF] |
||||
![]() |
H.-I. Yeh, Y.-J. Lai, Y.-N. Lee, Y.-J. Chen, Y.-C. Chen, C.-C. Chen, S.-A. Chen, C.-I. Lin, and C.-H. Tsai Differential Expression of Connexin43 Gap Junctions in Cardiomyocytes Isolated from Canine Thoracic Veins J. Histochem. Cytochem., February 1, 2003; 51(2): 259 - 266. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. London, L. C. Baker, J. S. Lee, V. Shusterman, B.-R. Choi, T. Kubota, C. F. McTiernan, A. M. Feldman, and G. Salama Calcium-dependent arrhythmias in transgenic mice with heart failure Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H431 - H441. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. A. Detillieux, F. Sheikh, E. Kardami, and P. A. Cattini Biological activities of fibroblast growth factor-2 in the adult myocardium Cardiovasc Res, January 1, 2003; 57(1): 8 - 19. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. P. Kucera, S. Rohr, and Y. Rudy Localization of Sodium Channels in Intercalated Disks Modulates Cardiac Conduction Circ. Res., December 13, 2002; 91(12): 1176 - 1182. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. J. Barker and R. G. Gourdie JNK Bond Regulation: Why Do Mammalian Hearts Invest in Connexin43? Circ. Res., October 4, 2002; 91(7): 556 - 558. [Full Text] [PDF] |
||||
![]() |
B. G. Petrich, X. Gong, D. L. Lerner, X. Wang, J. H. Brown, J. E. Saffitz, and Y. Wang c-Jun N-Terminal Kinase Activation Mediates Downregulation of Connexin43 in Cardiomyocytes Circ. Res., October 4, 2002; 91(7): 640 - 647. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. E. Olgin and S. Verheule Transgenic and knockout mouse models of atrial arrhythmias Cardiovasc Res, May 1, 2002; 54(2): 280 - 286. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Chu, A. N. Carr, K. B. Young, J.W. Lester, A. Yatani, A. Sanbe, M. C. Colbert, S. M. Schwartz, K. F. Frank, P. D. Lampe, et al. Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure Cardiovasc Res, April 1, 2002; 54(1): 105 - 116. [Abstract] [Full Text] [PDF] |
||||
![]() |
S.-Y. Shai, A. E. Harpf, C. J. Babbitt, M. C. Jordan, M. C. Fishbein, J. Chen, M. Omura, T. A. Leil, K. D. Becker, M. Jiang, et al. Cardiac Myocyte-Specific Excision of the {beta}1 Integrin Gene Results in Myocardial Fibrosis and Cardiac Failure Circ. Res., March 8, 2002; 90(4): 458 - 464. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2001 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |