(Circulation. 2000;101:547.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Accelerated Onset and Increased Incidence of Ventricular Arrhythmias Induced by Ischemia in Cx43-Deficient Mice
From the Departments of Pediatrics, Medicine, Surgery, and Pathology, and The Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Mo.
Correspondence to Jeffrey E. Saffitz, MD, PhD, Department of Pathology, Box 8118, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail saffitz{at}pathology.wustl.edu
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Abstract |
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Background—Myocardial ischemia causes profound changes in both active membrane currents and passive electrical properties. Because these complex changes develop and progress concomitantly, it has not been possible to elucidate the relative contributions of any one component to arrhythmogenesis induced by acute ischemia. Cx43+/- mice express 50% of the normal level of connexin43 (Cx43), the major ventricular electrical coupling protein, but are otherwise identical to wild-type (Cx43+/+) mice. Comparison of arrhythmogenesis in Cx43+/- and +/+ mice can provide insights into the role of changes in electrical coupling as an independent variable in the complex setting of acute ischemia.
Methods and Results—Acute ischemia was induced in isolated perfused mouse hearts by occlusion of the left anterior descending coronary artery. Spontaneous ventricular tachyarrhythmias (VT) occurred in more than twice as many Cx43+/- hearts than Cx43+/+ hearts. VT was induced in nearly 3 times as many Cx43+/- hearts. Multiple runs and prolonged runs of spontaneous VT were more frequent in Cx43+/- hearts. Onset of the first run of VT occurred significantly earlier in Cx43+/- hearts. Premature ventricular beats were also more frequent in Cx43+/- hearts. The size of the hypoperfused region was equivalent in both groups.
Conclusions—Reduced expression of Cx43 accelerates the onset and increases the incidence, frequency, and duration of ventricular tachyarrhythmias after coronary artery occlusion. Thus diminished electrical coupling per se plays a critical role in arrhythmogenesis induced by acute ischemia.
Key Words: arrhythmia • conduction • electrophysiology • ischemia
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Introduction |
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Sudden cardiac death has been described as an "electrical accident" that arises from complex, highly variable interactions between anatomic/functional myocardial substrates, transient initiating events, and cellular/tissue arrhythmia mechanisms.1 For example, malignant ventricular arrhythmias arising in the setting of acute myocardial ischemia are fundamentally related to marked reductions in tissue pH, increases in interstitial potassium and intracellular calcium levels, and neurohumoral changes, all of which interact in a complex, integrative pathophysiological milieu to slow conduction, alter excitability and refractoriness, promote electrical uncoupling, and generate spontaneous electrical activity.1 2 3 Increasingly sophisticated computer models of cardiac myocyte electrophysiology and metabolism have been useful in sorting out the contributions of alterations in specific proteins, channels, currents, or pathophysiological processes in arrhythmogenesis.4 5 However, gaining insights into the specific roles of individual determinants of arrhythmias in experimental systems involving real cardiac cells and tissues has not been possible previously.
Recent development of mouse models in which expression of specific gene products has been manipulated genetically provides an opportunity to define the roles of specific proteins in complex pathophysiological processes such as arrhythmogenesis induced by acute ischemia. We have previously studied mice6 7 in which expression of connexin43 (Cx43), the major ventricular gap junction protein, has been knocked out by homologous recombination.8 In contrast to Cx43-null animals, which die at birth, heterozygotes (Cx43+/-) survive and breed. Active membrane properties appear to be identical in Cx43-deficient (Cx43+/-) and wild-type (Cx43+/+) ventricular myocytes.6 However, Cx43+/- mice exhibit slow ventricular conduction that appears to be attributable solely to diminished coupling caused by expression of only 50% of the wild-type level of Cx43.6 7
We characterized ventricular tachyarrhythmias (VT) in isolated perfused mouse hearts subjected to left anterior descending (LAD) coronary occlusion. Comparison of wild-type and Cx43-deficient mice under identical conditions provided a means to investigate electrical coupling as an independent variable in arrhythmogenesis in the complex setting of acute ischemia. Using this approach, we found that diminished electrical coupling per se accelerates the onset and increases the incidence of tachyarrhythmias induced by acute ischemia.
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Methods |
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Cx43-Deficient and Wild-Type Mice
Hearts were isolated from 12- to 24-week-old mice produced from founders (B6,129-Gja1tm1Kdr) originally purchased from the Jackson Laboratories (Bar Harbor, Me) and maintained in an inbred background. Mice were housed in barrier facilities under strict veterinary supervision. Genotypes were determined by polymerase chain reaction as previously described,8 modified only by changing the sequence of the neoprimer (5'-AGGATCTCGTCGTGACCCAT-GGCGA-3') to minimize primer-dimer formation. Experimental protocols were approved by the Animal Studies Committee of Washington University School of Medicine.
Isolated Perfused Mouse Heart Preparation
An ex vivo model of acute ischemia was studied because
it was more practical to occlude the LAD and record
arrhythmias in isolated hearts. Accordingly, mice were
anesthetized with sodium pentobarbital (150 mg/kg IP), and
their hearts were rapidly excised and placed in oxygenated
Krebs-Henseleit buffer containing (in mmol/L): NaCl 118.3, KCl
2.7, MgSO4 1.0,
KH2PO4 1.4,
NaHCO3 29.0, CaCl2 3.4, and
glucose 10, plus insulin 70 mU/L and BSA 2.8%, at 37°C. Hearts were
perfused by retrograde aortic flow with oxygenated buffer
at 37°C. Flow rates were adjusted to maintain constant perfusion
pressures of 45 to 50 mm Hg. Hearts were
simultaneously superfused in a bath containing
oxygenated buffer at 37°C to maintain constant
temperature.
All hearts were perfused with oxygenated buffer for an initial 20-minute equilibration period. Any heart that demonstrated contractile dysfunction or other evidence of injury was discarded. Two groups of hearts were studied after the 20-minute stabilization interval. One group of 5 Cx43+/- and 5 Cx43+/+ hearts was perfused with oxygenated buffer for an additional 60 minutes and served as controls for the hearts subjected to coronary occlusion. Another group of 16 Cx43+/- and 16 Cx43+/+ hearts was subjected to acute regional ischemia of the apical and anterolateral left ventricle for 60 minutes by ligating the LAD immediately distal to its origin with 8-0 Prolene suture. Perfusion flow rates were adjusted after coronary occlusion to maintain perfusion pressures of 45 to 50 mm Hg. Studies of Cx43+/- and +/+ hearts were randomized and performed with the investigators blinded to the genotypes of the animals.
To assess the size and distribution of the hypoperfused region, hearts were arrested in diastole by perfusion with KCl (40 mEq/L) and then perfused with 0.1 mL of 2% lissamine green dye to stain the perfused regions. Hearts were fixed in 10% formalin for 24 hours and cut in 1-mm-thick transverse (short-axis) slices from the apex to the base. The basal cut surface of each slice was photographed and the areas of the entire left ventricular cut surface (including free walls and interventricular septum) and the hypoperfused (unstained) portion were measured with the use of computer-assisted planimetry. The area of the hypoperfused region was calculated as a percentage of total left ventricular tissue area.
Electrophysiological Recordings and
Programmed Electrical Stimulation
During the initial 20-minute stabilization interval of
oxygenated perfusion, a linear array of 8 bipolar
extracellular electrodes was placed on the epicardial surface of the
right atrium and anterior right ventricle along the maximum
apical-basal dimension in an orientation approximately parallel to the
longitudinal axis of the epicardial fibers. Data were recorded
simultaneously at a gain of 1000 and frequency response of
50 to 1000 Hz. Signals were digitized at 4000 Hz with 12-bit
resolution. A bipolar pacing electrode was placed near the apex of the
heart on the anterior epicardial surface of the right ventricle, a
region outside of the anticipated zone of left ventricular
ischemia created by LAD occlusion. Atrial and
ventricular epicardial electrograms were monitored
continuously during the 60-minute interval of coronary
occlusion or control (normoxic) perfusion.
At the end of the 20-minute stabilization interval in both control and coronary occlusion groups and again at subsequent 30-, 45-, and 60-minute time points, spontaneous cycle length was measured and programmed electrical stimulation was used to measure the effective refractory period and in an attempt to induce VT. Programmed right ventricular stimulation was performed by delivering a train of 8 beats at a basic cycle length of 130 ms (S1s) followed by delivery of a single premature beat (S2). S2 was decremented by 5-ms in multiple runs to determine the effective refractory period. Attempts were made to induce ventricular tachycardia with single extrastimuli down to a coupling interval of 20 ms and with ventricular burst pacing (18 S1s) at intervals of 20 to 80 ms until 1:1 capture was achieved. This protocol was repeated 3 times at each cycle length. Throughout these procedures, hearts were continuously monitored for premature ventricular beats (PVBs) and VT. Induced or spontaneously occurring PVBs and VT were recorded and analyzed. A run of VT was defined as 10 or more beats with a cycle length <100 ms. The number, time of onset, and duration of these events were tabulated for each heart. Both spontaneous and induced arrhythmias were tabulated to maximize opportunities to compare arrhythmogenesis in Cx43+/- and +/+ hearts.
Statistical Analyses
All data are expressed as mean±SD. Comparisons of the
incidence, frequency, and duration of VT in Cx43+/- and +/+ hearts
were made with the Pearson 
2 test. Continuous
data such as cycle length and effective refractory period were compared
with the use of ANOVA. Multiple comparisons between groups were made
with Fisher’s least significant differences method. The time of onset
of the first PVB or the first run of VT was analyzed by the
Kaplan-Meier method, and comparisons between Cx43+/- and +/+ hearts
were made with the Mantel log-rank test. A value of P<0.05
was considered significant.
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Results |
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Electrophysiological Stability of the Isolated Perfused Mouse Heart
All control hearts (not subjected to coronary occlusion) remained in sinus rhythm and contracted vigorously throughout the 60-minute perfusion interval. Spontaneous cycle lengths were equivalent in control hearts of both genotypes and increased by
50 ms
over the 60-minute interval (Table 1
). Effective refractory periods
did not change during perfusion. The effective refractory period was
modestly lower in Cx43+/- compared with Cx43+/+ hearts, but this
difference achieved statistical significance only at the initial
0-minute time point. A single PVB was recorded in only 1 of 5
Cx43+/+ hearts during the entire 60-minute normoxic perfusion period.
Of the 5 Cx43+/- hearts, 1 developed 1 PVB, 1 developed 2 PVBs, and 1
exhibited >20 premature beats during the 60-minute perfusion period.
No runs of spontaneous or pacing-induced VT occurred in any control
Cx43+/- or +/+ hearts. These observations indicate that the isolated
perfused mouse heart preparation is electrically stable during
oxygenated perfusion for 60 minutes.
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Electrophysiological Changes in Cx43+/- and
Cx43+/+ Hearts Induced by Acute Regional Ischemia
The LAD was occluded in 16 Cx43+/- and 16 Cx43+/+ hearts,
producing acute ischemia of the apical and anterolateral left
ventricle. Spontaneous cycle lengths and effective refractory periods
measured immediately before coronary artery occlusion in these
hearts were similar to those shown in Table 1
for control hearts
at the 0-minute time point. During the subsequent 60 minutes of
regional hypoperfusion, spontaneous cycle lengths became prolonged and
the effective refractory periods became shorter, but no significant
differences in these values between Cx43+/- and Cx43+/+ hearts
occurred during the 60-minute interval of ischemia. Cycle
lengths and effective refractory periods could not be determined in
every heart at all time points because some exhibited persistent
arrhythmias.
VT occurred in both Cx43+/- and +/+ ischemic hearts. Figure 1 shows pairs of
simultaneously recorded right atrial and
ventricular electrograms and illustrates examples of the
types of arrhythmias observed after coronary artery
occlusion. Figure 1A demonstrates PVBs and a brief run of VT
that initiated and terminated spontaneously. Figure 1B shows a
polymorphic tachycardia with variable cycle lengths
(53 to 74 ms) and electrogram morphology. Figure 1C shows a
monomorphic tachycardia with uniform cycle lengths (55 to
60 ms) and electrogram morphology. VT cycle lengths were equivalent in
the Cx43+/- and +/+ hearts with arrhythmias (62±12 and 59±7
ms, respectively, P>0.5). The great majority of
tachycardias terminated spontaneously. In a few cases
(<5%), the tachycardia was terminated by the introduction
of an extrastimulus.
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Ventricular Tachyarrhythmias in
Cx43+/- and Cx43+/+ Hearts
Figure 2 shows the incidence of VT
in Cx43+/- and Cx43+/+ hearts after LAD occlusion. Of the 16 hearts in
each group, 12 Cx43+/- and 7 Cx43+/+ hearts had at least 1 run of
either spontaneous or pacing-induced VT (Figure 2A). In
addition, 11 Cx43+/- hearts had multiple (>1) runs of VT compared
with only 5 Cx43+/+ hearts (P<0.05). Four Cx43+/- hearts
exhibited nearly continuous bursts of VT with minimal intervening sinus
rhythm during the final 30 minutes of ischemia compared with
none of the wild-type hearts. Twelve of 16 Cx43+/- hearts had at least
1 run of sustained VT that lasted >3 seconds. The majority of these
runs persisted for >20 seconds. In contrast, only 4 Cx43+/+ hearts had
at least 1 run of sustained VT, and only 1 of these runs lasted >20
seconds.
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P<0.01 by
Significant differences in the incidence, frequency, and duration of
spontaneous and inducible VT occurred in the 2 groups (Figures 2B and C). Spontaneous VT occurred in more than twice as many
Cx43+/- as +/+ hearts (Figure 2B). Nine of 16 Cx43+/- hearts
had multiple runs of spontaneous VT compared with only 1 of 16 Cx43+/+
hearts (P<0.01); 8 Cx43+/- hearts had sustained runs of VT
compared with only 1 Cx43+/+ heart (P<0.01). Pacing-induced
ventricular tachycardias were observed in more
Cx43+/- than +/+ hearts (P<0.01), and a greater number of
Cx43+/- hearts exhibited multiple runs of inducible VT
(P<0.05) (Figure 2C).
The time of onset of the first spontaneous VT after LAD occlusion
occurred significantly earlier in Cx43+/- hearts (P<0.05)
(Figure 3). Of the 9 Cx43+/- hearts that
developed spontaneous tachycardia, 7 exhibited the first
run of VT during the first 12 minutes after coronary artery
occlusion. In contrast, the earliest onset of spontaneous VT in any
Cx43+/+ heart did not occur until after 13 minutes of
ischemia.
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PVBs in Cx43+/- and Cx43+/+ Hearts
At least 1 PVB occurred at some point during the 60-minute
interval of coronary occlusion in nearly all (15 of 16 Cx43+/-
and 14 of 16 +/+) ischemic hearts, but the number of PVBs
differed markedly between the 2 groups. The number of PVBs was counted
for each preparation during each of the four 15-minute intervals of the
entire 60-minute period of coronary occlusion. A maximum of 20
PVBs was tabulated for each 15-minute interval, although the presence
of a greater number was noted. Generally, when the threshold of 20 PVBs
was achieved, many more than 20 PVBs occurred. As shown in Table 2, 2 to 4 times as many Cx43+/- as
Cx43+/+ hearts exceeded the threshold of 
20 PVBs during each
15-minute interval, but because sample sizes were small, only the
difference at the 45-to-60-minute interval achieved statistical
significance. However, 11 of 16 Cx43+/- compared with only 5 of 16 +/+
hearts developed 20 PVBs during any 15-minute interval
(P<0.05). Furthermore, 6 of 16 Cx43+/- hearts exceeded the
threshold in 3 or all 15-minute intervals compared with only 1 of 16
Cx43+/+ hearts (P<0.05).
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Figure 4 shows a Kaplan-Meier plot of the
time of ischemia at which the first PVB occurred. Although PVBs
developed in nearly all hearts over the entire 60-minute interval of
ischemia, analysis of the first 10 minutes of
ischemia revealed significantly earlier onset in Cx43+/-
hearts. During this initial interval, the first PVB occurred in 11
Cx43+/- hearts compared with only 5 Cx43+/+ hearts
(P<0.05). These results suggest that diminished expression
of Cx43 accelerates the onset and increases the frequency of PVBs
during ischemia.
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Size and Distribution of the Hypoperfused Region in Cx43+/- and
Cx43+/+ Hearts
Examination of dye-stained hearts (n=6 for each genotype)
revealed a large, clearly demarcated apical and anterolateral region of
left ventricular hypoperfusion (Figure 5). The size of the hypoperfused
(nonstained) region was equivalent in Cx43+/- and +/+ hearts (53±9%
and 58±15% of the total left ventricular area,
respectively, P>0.5). Thus enhanced arrhythmogenesis in
Cx43+/- hearts was not the result of more extensive ischemic
injury.
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Discussion |
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Altered electrical coupling has been strongly implicated in the development of arrhythmias induced by ischemia,1 2 3 4 9 10 11 12 but because multiple pathobiological responses to ischemia occur concomitantly, it has not been previously possible to elucidate the specific contributions of changes in coupling to arrhythmogenesis in acute myocardial ischemia. Comparison of wild-type and Cx43-deficient hearts allowed us to directly assess the effect of diminished Cx43 expression on arrhythmogenesis induced by ischemia without altering other influential factors at the same time. Our results provide strong, direct evidence that diminished electrical coupling caused by reduced expression of Cx43 accelerates the onset and increases the incidence, frequency, and duration of ventricular arrhythmias after acute regional ischemia. Although we have not formally excluded the possibilities that Cx43+/- hearts have a defect in another ion channel that becomes manifest only during ischemia or that adult Cx43+/- and +/+ myocytes may differ in active membrane properties, comparisons of action potential parameters and quantitative measures of voltage-gated Na+ channel protein expression and activity have revealed no differences in ventricular myocytes from neonatal Cx43+/- and +/+ mice.6 13
Ischemia-Induced VT and Altered Intercellular
Coupling
Defining the role of specific gene products in
arrhythmogenesis in mouse models of human diseases will require
elucidation of arrhythmia mechanisms. Although analysis
of arrhythmia mechanisms in mice will be technically
challenging, Vaidya et al14 have observed stationary
vortexlike reentry on the surface of a mouse heart induced by burst
pacing and manifest in the ECG as sustained monomorphic
tachycardia. Our observations in the present study are
consistent with the hypothesis that reentrant circuits in
Cx43+/- hearts may be more stable and inducible than in Cx43+/+
hearts. Modest conduction slowing under basal conditions in Cx43+/-
hearts probably reduced the wavelength for reentry and further enhanced
development of stable reentrant circuits when progressive regional
uncoupling was induced by coronary occlusion. In a few cases,
prolonged spontaneous tachycardias were easily terminated
by a single extrastimulus, suggesting that the arrhythmias may
have been reentrant. It should be stressed, however, that at least some
of the arrhythmias observed in the present study could have
arisen by nonreentrant mechanisms such as triggered activity, a
mechanism that has been implicated in some monomorphic
ventricular tachyarrhythmias in patients
without organic heart disease.15 16
Accelerated onset of spontaneous VT in Cx43+/- mice supports the concept of a critical threshold of uncoupling in arrhythmogenesis. Cx43+/- hearts probably achieved a pathophysiological level of uncoupling and conduction slowing more rapidly than did Cx43+/+ hearts. Arrhythmias induced by acute ischemia occur in 2 phases, an initial wave (Ia) related in part to altered extracellular K+ levels, and a later wave (Ib) occurring 12 to 30 minutes after the onset of ischemia and related to electrical uncoupling.9 10 11 17 The time course of electrical uncoupling in response to ischemia has not been reported in mice, but the time course of arrhythmias observed in Cx43+/+ hearts is reminiscent of type Ib arrhythmias in pig hearts.11 Future studies will be required to determine whether the time course of uncoupling induced by ischemia differs in Cx43+/- and +/+ hearts.
Ischemia-Induced PVBs and Intercellular Coupling
Significantly more Cx43+/- than +/+ hearts had 20 PVBs in at
least one of the four 15-minute intervals and during 3 or all 15-minute
intervals. Hearts that exceeded the threshold of 20 PVBs generally
exhibited many more premature beats. Thus differences between Cx43+/-
and +/+ hearts in the frequency of PVBs would undoubtedly have been
greater if the actual number of PVBs had been counted. There was also a
clear trend toward earlier onset of PVBs in ischemic Cx43+/-
hearts. Premature ventricular beats may arise by reentry or
be initiated by triggered activity. In the latter mechanism, a focal
depolarization must be propagated to produce the premature beat. We do
not yet know the mechanism responsible for the apparently greater
number and earlier onset of PVBs in Cx43+/- mice after
coronary occlusion, but our observations provide direct
experimental evidence implicating altered coupling in the development
and time of onset of PVBs during ischemia. The observations
also raise intriguing questions about the potential
pathophysiological links between changes in
coupling and the development and propagation of PVBs initiated by
either reentry or triggered activity.
Recent experimental observations and computer modeling studies have begun to delineate the effects of electrical coupling on both the initiation and propagation of triggered events.18 19 20 21 22 For example, Saiz et al22 showed in a modeling study that a moderate amount of uncoupling between normal myocardium and a region conducive to formation of early afterdepolarizations (EADs) (such as an area of acute ischemia) directly enhances both initiation of EADs and spread to neighboring tissue. They found that a specific degree of uncoupling could prolong repolarization and promote the generation of EADs and allow for a critical rise in membrane potential to achieve transfer of the impulse to the surrounding tissue. Our finding of increased PVBs in Cx43-deficient hearts is consistent with these computer models and provides experimental evidence potentially linking alterations in coupling with the generation and propagation of EADs. Future studies will be required to confirm the relation between diminished coupling and the development of PVBs to elucidate the specific mechanisms (reentry and/or triggered activity) responsible for PVBs and to characterize potential pathophysiological links between the development of PVBs and VT in mice with different baseline levels of intercellular coupling.
Clinical Implications
In view of the findings of the present study, it is logical to
suggest that interventions designed to prevent uncoupling could
diminish arrhythmogenesis during ischemia. Although such a
strategy could limit the development of slow conduction and retard
formation of arrhythmia substrates, it also could counteract
potential benefits of uncoupling healthy and ischemic myocytes
from each other. In this setting, uncoupling may be thought of as an
adaptive process that isolates irreversibly injured cells from viable
neighbors. Acute uncoupling may also electrically silence viable but
injured regions and limit their contribution to arrhythmias
dependent on slow conduction and unidirectional conduction block.
Further investigation will be required to elucidate the potential
benefits and risks of modulating cell-to-cell coupling and define the
effects of total versus partial uncoupling in the pathogenesis of
ischemia-induced arrhythmias.
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-32257, HL-33722, and HL-58507 and a Grant-in-Aid from the American Heart Association and the Council on Clinical Cardiology. Dr Lerner was supported by National Institutes of Health Training Grant HL-07275. We thank Joseph M. Smith, MD, PhD, for a critical review of the manuscript and helpful discussions and Kenneth Schechtman, PhD, for assistance with statistical analysis.
Received May 19, 1999; revision received August 9, 1999; accepted August 17, 1999.
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 E. M. Oxford, H. Musa, K. Maass, W. Coombs, S. M. Taffet, and M. Delmar Connexin43 Remodeling Caused by Inhibition of Plakophilin-2 Expression in Cardiac Cells Circ. Res., September 28, 2007; 101(7): 703 - 711. [Abstract] [Full Text] [PDF]
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 K. Boengler, I. Konietzka, A. Buechert, Y. Heinen, D. Garcia-Dorado, G. Heusch, and R. Schulz Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43 Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1764 - H1769. [Abstract] [Full Text] [PDF]
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 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]
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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]
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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]
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 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]
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F. Zhang, J. Cheng, G. Lam, D. K. Jin, L. Vincent, N. R. Hackett, S. Wang, L. M. Young, B. Hempstead, R. G. Crystal, et al. Adenovirus Vector E4 Gene Regulates Connexin 40 and 43 Expression in Endothelial Cells via PKA and PI3K Signal Pathways Circ. Res., May 13, 2005; 96(9): 950 - 957. [Abstract] [Full Text] [PDF]
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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]
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 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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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C. T. Maguire, H. Wakimoto, V. V. Patel, P. E. Hammer, K. Gauvreau, and C. I. Berul Implications of ventricular arrhythmia vulnerability during murine electrophysiology studies Physiol Genomics, September 29, 2003; 15(1): 84 - 91. [Abstract] [Full Text] [PDF]
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 D. J. Mancuso, D. R. Abendschein, C. M. Jenkins, X. Han, J. E. Saffitz, R. B. Schuessler, and R. W. Gross Cardiac Ischemia Activates Calcium-independent Phospholipase A2{beta}, Precipitating Ventricular Tachyarrhythmias in Transgenic Mice: RESCUE OF THE LETHAL ELECTROPHYSIOLOGIC PHENOTYPE BY MECHANISM-BASED INHIBITION J. Biol. Chem., June 13, 2003; 278(25): 22231 - 22236. [Abstract] [Full Text] [PDF]
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S. K. Jain, R. B. Schuessler, and J. E. Saffitz Mechanisms of Delayed Electrical Uncoupling Induced by Ischemic Preconditioning Circ. Res., May 30, 2003; 92(10): 1138 - 1144. [Abstract] [Full Text] [PDF]
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 J. E. I. Gittens, A. A. Mhawi, D. Lidington, Y. Ouellette, and G. M. Kidder Functional analysis of gap junctions in ovarian granulosa cells: distinct role for connexin43 in early stages of folliculogenesis Am J Physiol Cell Physiol, April 1, 2003; 284(4): C880 - C887. [Abstract] [Full Text] [PDF]
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 S. Kanno, A. Kovacs, K. A. Yamada, and J. E. Saffitz Connexin43 as a determinant of myocardial infarct size following coronary occlusion in mice J. Am. Coll. Cardiol., February 19, 2003; 41(4): 681 - 686. [Abstract] [Full Text] [PDF]
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 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]
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 H.-I Yeh, S.-H. Hou, H.-R. Hu, Y.-N. Lee, J.-Y. Li, E. Dupont, S. R. Coppen, Y.-S. Ko, N. J. Severs, and C.-H. Tsai Alteration of gap junctions and connexins in the right atrial appendage during cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., December 1, 2002; 124(6): 1106 - 1112. [Abstract] [Full Text]
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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]
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C. M. Johnson, E. M. Kanter, K. G. Green, J. G. Laing, T. Betsuyaku, E. C. Beyer, T. H. Steinberg, J. E. Saffitz, and K. A. Yamada Redistribution of connexin45 in gap junctions of connexin43-deficient hearts Cardiovasc Res, March 1, 2002; 53(4): 921 - 935. [Abstract] [Full Text] [PDF]
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 B.G. PETRICH, P. LIAO, and Y. WANG Using a Gene-switch Transgenic Approach to Dissect Distinct Roles of MAP Kinases in Heart Failure Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 429 - 438. [Abstract] [PDF]
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H.-I Yeh, Y.-J. Lai, S.-H. Lee, Y.-N. Lee, Y.-S. Ko, S.-A. Chen, N. J. Severs, and C.-H. Tsai Heterogeneity of Myocardial Sleeve Morphology and Gap Junctions in Canine Superior Vena Cava Circulation, December 18, 2001; 104(25): 3152 - 3157. [Abstract] [Full Text] [PDF]
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D. E. Gutstein, G. E. Morley, D. Vaidya, F. Liu, F. L. Chen, H. Stuhlmann, and G. I. Fishman Heterogeneous Expression of Gap Junction Channels in the Heart Leads to Conduction Defects and Ventricular Dysfunction Circulation, September 4, 2001; 104(10): 1194 - 1199. [Abstract] [Full Text] [PDF]
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B. C Eloff, D. L Lerner, K. A Yamada, R. B Schuessler, J. E Saffitz, and D. S Rosenbaum High resolution optical mapping reveals conduction slowing in connexin43 deficient mice Cardiovasc Res, September 1, 2001; 51(4): 681 - 690. [Abstract] [Full Text] [PDF]
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T. A.B. van Veen, H. V.M. van Rijen, and T. Opthof Cardiac gap junction channels: modulation of expression and channel properties Cardiovasc Res, August 1, 2001; 51(2): 217 - 229. [Abstract] [Full Text] [PDF]
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A. O Verkerk, M. W Veldkamp, R. Coronel, R. Wilders, and A. C.G van Ginneken Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias Cardiovasc Res, July 1, 2001; 51(1): 30 - 40. [Abstract] [Full Text] [PDF]
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D. L Lerner, M. A Beardslee, and J. E Saffitz The role of altered intercellular coupling in arrhythmias induced by acute myocardial ischemia Cardiovasc Res, May 1, 2001; 50(2): 263 - 269. [Full Text] [PDF]
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J. R de Groot, F. J.G Wilms-Schopman, T. Opthof, C. A Remme, and R. Coronel Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart Role of electrical cellular coupling Cardiovasc Res, May 1, 2001; 50(2): 362 - 372. [Abstract] [Full Text] [PDF]
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D. E. Gutstein, G. E. Morley, H. Tamaddon, D. Vaidya, M. D. Schneider, J. Chen, K. R. Chien, H. Stuhlmann, and G. I. Fishman Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43 Circ. Res., February 16, 2001; 88(3): 333 - 339. [Abstract] [Full Text] [PDF]
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W. E. Cascio, H. Yang, T. A. Johnson, B. J. Muller-Borer, and J. J. Lemasters Electrical Properties and Conduction in Reperfused Papillary Muscle Circ. Res., October 26, 2001; 89(9): 807 - 814. [Abstract] [Full Text] [PDF]
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