AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 285: H10-H16, 2003. First published March 6, 2003; doi:10.1152/ajpheart.01074.2002
0363-6135/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
285/1/H10    most recent
01074.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sims, J. J.
Right arrow Articles by Wiegert, N. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sims, J. J.
Right arrow Articles by Wiegert, N. A.

TRANSLATIONAL PHYSIOLOGY

Regional gap junction inhibition increases defibrillation thresholds

J. Jason Sims, Kell L. Schoff, Jennifer M. Loeb, and Nicholas A. Wiegert

School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705

Submitted 10 December 2002 ; accepted in final form 26 February 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is clear that ischemia inhibits successful defibrillation by altering regional electro-physiology. However, the exact mechanisms are unclear. This study investigated whether regional gap junction inhibition increases biphasic shock defibrillation thresholds (DFT). Sixteen swine were instrumented with a mid-left anterior descending (LAD) perfusion catheter for regional infusion of 0.5 mM/h heptanol (n = 8) or saline (n = 8). DFT values and effective refractory periods (ERP) at five myocardial sites were determined. Regional conduction velocity (CV) was determined in an LAD drug-perfused and nondrug-perfused region in an additional seven swine. Regional heptanol infusion increased 50% DFT values by 33% (P = 0.01) and slowed CV by 42–59% (P < 0.01) but did not affect ERP. Regional heptanol also increased CV dispersion by ~270% (P < 0.05) but did not change ERP dispersion. Regional placebo did not alter any of these parameters. Furthermore, regional heptanol infusion induced spontaneous ventricular fibrillation in eight of eight animals. Increasing spatial conduction velocity dispersion by impairing regional gap junction conductance increased DFT values. Dispersion in conduction velocity slowing during regional ischemia may be an important determinant of defibrillation efficacy.

conduction velocity; electric countershock; ventricular arrhythmias

DESPITE ADVANCES in implantable cardioverter-defibrillator (ICD) therapy, sudden cardiac arrest due to ventricular fibrillation (VF) remains a significant cause of death (44, 47). This may be due to the fact that up to 70% of ICD patients have ischemic coronary artery disease that impairs the ability of a shock to defibrillate (16, 46). Recent studies indicate that VF associated with regional myocardial ischemia requires higher defibrillation shock energy to successfully defibrillate (2, 3, 28, 35, 40). However, the exact mechanisms by which ischemia impairs electrical defibrillation are unknown.

Electrical and optical mapping studies demonstrate that nonuniform activation patterns occur following a defibrillation shock and are responsible for failed defibrillation (21, 45). Furthermore, previous studies indicate that postshock nonuniform propagation is likely due to spatial myocardial electrical heterogeneity (30, 38, 43). Regional myocardial ischemia can increase myocardial electrical heterogeneity by locally altering a number of factors, including increasing extracelluar potassium concentrations, decreasing pH, increasing adenosine levels, and increasing passive tissue resistance (7, 17). The net effect is increased electrical heterogeneity because of a regional slowing in conduction velocity and/or a regional change in refractoriness. We have previously shown that an increase in spatial conduction velocity dispersion via regional sodium channel blockade impairs defibrillation (38). Thus homogeneity of conduction velocity appears to be an important determinant of defibrillation efficacy. Regional myocardial ischemia may increase conduction velocity heterogeneity by impairing regional gap junction channel activity.

Gap junctions are composed of connexins, predominantly connexin43, in the human ventricle, and provide aqueous conduits between cells for electrical current flow (7, 39). After ~15 min of ischemia, gap junctions "uncouple," which results in impaired cell-to-cell communication, increased passive tissue resistance, and decreased myocardial conduction (4, 22). Thus regional ischemia may uncouple gap junctions, increase conduction velocity heterogeneity, and impair defibrillation. The current study assessed the effects of regional gap junction inhibition on defibrillation efficacy.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal preparation and surgical instrumentation. The University of Wisconsin Research Animal Resource Center and Animal Care Unit approved the following procedures. Domestic farm swine (25–30 kg) were premedicated with ketamine (15 mg/kg), anesthetized with pentobarbital (15 mg · kg-1 · h-1), and mechanically ventilated. With the use of fluoroscopy, monophasic action potential catheters (EP Technologies; Mountain View, CA) were placed into the right ventricular apex and against the left ventricle lateral wall. Defibrillation leads (Sprint, Medtronic; Minneapolis, MN) were placed into the right ventricular apex (anode) and superior vena cavae (cathode). Subcutaneous wire arrays (cathode) were placed within the lateral anterior chest wall. The defibrillation leads were interfaced with an external biphasic defibrillator using a truncated waveform (65% fixed tilt) and pulse duration between 8 and 14 ms. Device output was determined by preset voltage adjustments (Ventak ECD, Guidant; St. Paul, MN).

As previously illustrated, following a sternotomy, a small area (3–5 mm) on the left anterior descending (LAD), just past the second diagonal, was isolated from the surrounding myocardium (30, 38). A 24-gauge plastic catheter was inserted into the LAD and affixed to adjacent epicardium. A 2-mm ultrasonic flow probe (VF-1, Crystal Biotech) was placed distal to the catheter, which demonstrated that coronary flow was unaffected by the catheter. At this point, the perfusion solution only contained normal saline, 100 U/ml heparin, and 0.5 mg/ml nitroglycerin infused at 10 ml/h to prevent clotting and vasospasm. After 30 min, the coronary infusion consisted of saline and heparin. Quadrapolar (5 mm interpole distance) Ag-AgCl electrodes (In Vivo Metrics, Healdsburg, CA) were placed onto the epicardium of the left ventricular apex (LAD catheter-perfused area), left ventricular base, and right ventricular outflow tract. Monophasic action potential probes were placed adjacent to these electrodes. An intramural temperature probe (Yellow Springs) was placed in the perfused area. Myocardial temperature consistently remained 0.5°C above rectal temperature. The chest was draped to retain moisture and heat. Arterial blood gases and sodium and potassium concentrations were measured every 20–30 min and maintained at physiological values (Rapidlab 348, Chiron Diagnostics; Medfield, MA) (31).

Study design. Electrophysiology and defibrillation threshold (DFT) values were measured at baseline. Subsequently, the coronary perfusion (10 ml/h) was changed to the randomly determined treatment group. The control group (n = 8) received heparinized normal saline. The heptanol group (n = 8) received 0.5 mM/h heptanol in heparinized saline. The dose of heptanol was chosen to impair gap junction conductance without significantly altering sodium channel activity. Previous studies indicate that heptanol (0.5 mmol/l) will inhibit gap junction conductance without significantly altering sodium channel activity (1, 25, 33). Thus we chose to infuse heptanol at 0.5 mM/h into the LAD. A 30-min period separated baseline and treatment periods to completely clear the infusion line.

DFT testing. Defibrillation shocks were applied ~8 s after VF induction (21). Defibrillation trials were repeated every 4 min but not until arterial blood pressure was within 10% of preshock value. DFT values were measured using a stepdown, step-up method that incorporates 12 fibrillation-defibrillation trials per study phase (36). This estimates the energy-response curve (20–80% successful response) that achieves 20% (ED20), 50% (ED50), and 80% (ED80) successful responses using an iterative computer program (MERFFIT, Guidant; St. Paul, MN) (36).

Conduction velocity. Regional changes in conduction velocity were evaluated in seven additional animals. The animals were instrumented as described above except that two 16-pole electrode arrays were affixed to the epicardium. One array was located within the LAD-perfused region (left ventricular apex) while the other was affixed to a nonperfused region located at the right ventricular base. As previously illustrated, the electrodes were arranged in bipolar pairs in two perpendicular rows with each row containing four bipolar Ag-AgCl electrodes (2 mm interbipole spacing) (19, 30, 38). Conduction velocity was assessed by local cathode pacing at a 300-ms cycle length for 20 s. The anode was located on the right ventricular outflow tract. Fiber orientation was determined during cathode pacing and rotation of the electrode array until the differences in conduction times between the fourth and D electrode were maximal. The signals were processed with a high-gain amplifier and filtered with a bandwidth of 0.1–1 kHz (Universal amplifier, Gould Instruments; Valley View, OH). Conduction velocity was the time required for the impulse from the first electrode of a row to reach the distal electrodes of the same row divided by distance traveled. Arrival time was the point of maximum change in voltage over change in time (dV/dt) at each bipole. After baseline conduction velocity was recorded, heptanol (0.5 mM/h) was continuously infused into the LAD. Conduction velocity was assessed 45 min after initiation of the heptanol infusion to mimic the time needed to conduct DFT testing.

Electrophysiological parameters. The electrophysiological parameters (paced QRS duration and action potential duration) were measured during right ventricular pacing at a 300-ms cycle length and averaged from five consecutive beats. Ventricular pacing was continued for 15–20 s before these parameters were measured to assure a near steady-state level of channel conductance and channel block. Pacing threshold was measured at each stimulation site using an isolated constant current unit (Bloom Associates, Fisher Imaging; Denver, CO) and delivered current was measured with a digital multimeter (Fluke 867, Fluke Instruments; Everett, WA).

Myocardial repolarization was assessed from the monophasic action potential duration at 90% complete repolarization. Local effective refractory period (ERP) was determined at a 300-ms cycle length using a premature stimulus method as previously described (29). Each ventricular recording site was tested in random order. VF cycle length (VFCL) was measured before the defibrillation shock. VFCL was measured from monophasic action potentials recorded from five ventricular sites as previously described (37). Spatial heterogeneity (dispersion) between recording sites was evaluated for the following electrophysiological parameters: action potential duration, ventricular refractoriness, pacing threshold, VFCL, and ventricular conduction velocity. Dispersion was calculated as the difference between the maximum and minimum value of the five recording sites (two sites for conduction velocity). All electrophysiological measurements were obtained at the start and end of the DFT protocol at baseline and drug treatment phases. These values were averaged for each study phase. Electrophysiological and hemodynamic signals were processed with Gould Universal Amplifiers, digitally acquired at 3,000 Hz, and stored for off-line analysis (Datawave; Boulder, CO). Monophasic action potentials were DC coupled, filtered at 300 Hz, amplified, and stored.

Data analysis. Paired t-test or two-way analysis of variance evaluated differences between parameters at baseline and treatment within group (animal as its own control). One-way analysis of variance tested differences between groups. Fisher's exact test compared frequency of VF induction during electrical pacing between treatment groups. All data and statistical analysis were performed with a personal computer using SigmaStat 2.0 (SPSS Science; Chicago, IL). Statistical significance was a P value < 0.05 using a two-tail test. Data are presented as means ± SE.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Defibrillation thresholds. Mean baseline DFT values between the two groups were not different (Fig. 1). DFT values for the control group during saline treatment did not differ from baseline. However, regional heptanol greatly increased baseline DFT20,DFT50, and DFT80 values (Fig. 1: DFT50 = 16.2 ± 1.6 to 21.5 ± 2.8 joules, P = 0.01). The DFT values increased in a relatively linear manner such that 20% (DFT20), 50% (DFT50), and 80% (DFT80) values increased by 22%, 31%, and 46%, respectively. Lead impedance did not differ between the two groups. However, in both groups there was a slight drop in impedance over time, a common finding in this model (41). Thus the above findings cannot be attributed to changes in lead impedance.



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 1. Defibrillation energy requirements achieving 20% defibrillation thresholds (DFT) (DFT 20%), 50% (DFT 50%), and 80% (DFT 80%) success at baseline and treatment study phases for placebo (A) and regional heptanol (B). *P < 0.05, baseline vs. treatment phase.

 

Conduction velocity. Regional heptanol significantly slowed longitudinal and transverse conduction velocity within the perfused region by 59% and 40%, respectively (Fig. 2). However, regional heptanol did not affect conduction velocity at the nonperfused right ventricular site. Hence, regional heptanol increased dispersion in conduction velocity between the left ventricular apex and right ventricular base (Fig. 3) and, likely, other non-LAD-perfused regions. Moreover, regional heptanol inhibited the anisotropic conduction properties of the myocardium at the left ventricular apex such that the ratio of longitudinal to transverse conduction velocity was significantly decreased (2.6:1, baseline vs. 1.8:1, heptanol). Also, QRS duration, a marker of global ventricular conduction velocity, was unaffected by regional heptanol (baseline = 76 ± 3.2 ms vs. heptanol = 77 ± 4.5 ms), demonstrating the local effect of regional heptanol on conduction.



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 2. Line graphs depicting conduction velocity in longitudinal and transverse directions at the left ventricular (LV) epicardial apex site (A) and right ventricular (RV) epicardial base (B). *P < 0.05, baseline vs. regional heptanol for both longitudinal and transverse directions.

 


View larger version (24K):
[in this window]
[in a new window]
  		Fig. 3. Bar graph depicting conduction velocity dispersion values of baseline measurements and measurements made during regional heptanol.

 

Refractoriness and excitability. Similar to regional placebo, regional heptanol did not affect ERP at any site and thus did not increase dispersion in refractoriness (Table 1). However, regional heptanol significantly increased the pacing threshold (decreased excitability) at the left ventricular apex from 0.16 ± 0.03 to 0.32 ± 0.05 mA (P < 0.05). Regional heptanol did not affect pacing thresholds at the four nonperfused pacing sites, indicating this effect was local. Thus regional heptanol increased dispersion in pacing thresholds by 38% (0.21 ± 0.04 to 0.29 ± 0.06 mA, P = 0.06) but did not reach statistical significance. Pacing thresholds in the placebo group remained similar to baseline during the treatment phase at all pacing sites.


View this table:
[in this window]
[in a new window]
  		Table 1. Electrophysiological parameters

 

Ventricular fibrillation. Neither continuous rapid pacing nor a single premature stimulus could induce VF at baseline or during regional saline. However, regional heptanol induced VF in eight of eight animals (P < 0.01 vs. control) with either continuous rapid pacing or a single premature stimulus. Regional heptanol infusion increased VFCL by 28% (P = 0.02) in the heptanol-perfused region, whereas VFCL was not altered in the nonperfused regions (Table 1). Thus spatial VFCL dispersion was increased by 153% (P < 0.05). Furthermore, during VF regional heptanol significantly altered epicardial action potential morphology (Fig. 4) at the left ventricular apex. Specifically, fibrillation action potentials in the control group (regional saline) were fractionated, had double potentials, and rarely reached diastolic potentials. In comparison, regional heptanol decreased the number of action potentials at the perfused recording site, widened the action potential duration, and qualitatively changed the action potential appearance such that fewer double and fractionated potentials were observed. However, no such changes were observed at other recording sites. This suggests that the myocardium in the heptanolperfused region was less likely to be excited by colliding wavefronts and/or there was less block of wavefront propagation in this region (12).



View larger version (18K):
[in this window]
[in a new window]
  		Fig. 4. Monophasic action potentials from LV apex epicardium (LV Apex), LV base epicardium (LV Base), and RV base epicardium (RV Base) recorded during VF and treatment at baseline with placebo (left) and during regional heptanol (right) in a representative animal.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Ventricular arrhythmias and sudden cardiac death are common complications in patients with coronary artery disease. Rapid defibrillation by an ICD is a major advancement in preventing mortality associated with these sequelae (23). Unfortunately, these patients frequently have periods of myocardial ischemia, which may alter the efficacy of these devices by increasing spatial electrical heterogeneity (2, 3, 28, 35, 40). The current study assessed the effects of regional gap junction uncoupling, which occurs during prolonged ischemia, on defibrillation efficacy. We found that regional gap junction inhibition created by a local infusion of heptanol markedly increased biphasic DFT values. The increase in DFT values occurred in tandem with increased myocardial electrical heterogeneity, evidenced by regional conduction velocity slowing, increased conduction velocity dispersion, a regional increase in pacing threshold, and increased dispersion in VFCL. The finding that regional gap junction inhibition increases DFT values, whereas global gap junction inhibition decreases DFT values (27), strongly indicates the importance of regional changes in electrical activity on defibrillation efficacy.

Significant increases in passive tissue resistance begin to occur after 15 min of ischemia and reach peak at around 30 min (4). This increase in passive tissue resistance has been linked with the Ib phase of ventricular arrhythmias (11, 26, 32). Moreover, specific regional gap junction uncoupling without ischemia produces similar ventricular arrhythmias (5). Thus it is clear that cell-to-cell communication, passive tissue resistance, and gap junction conductance play an important role in the induction of ventricular arrhythmias. In the current study, regional gap junction inhibition was shown to significantly increase the energy needed to successfully defibrillate. Therefore, it appears that gap junction conductance also plays an important role in ischemia-induced changes in defibrillation efficacy.

There are several proposed mechanisms of ventricular defibrillation, such as VF organization (12, 13, 34, 37), critical mass (42, 45), virtual electrode polarization (14), and the upper limit of vulnerability (8, 9). It is unlikely that the first two hypotheses account for the findings of the current study. The VF organization hypothesis states that the more organized fibrillation is, the fewer number of wavefronts there are propagating in the myocardium, thus making it easier to defibrillate (13). This hypothesis explains how interventions decrease DFT values and is the proposed mechanism by which global gap junction inhibition lowers DFT values (27). Although regional heptanol made VF less organized as measured by VFCL dispersion, recent data indicate that the VFCL dispersion may not accurately predict changes in DFT values (38). Therefore, we believe that regional heptanol increased DFT values by another mechanism.

The second mechanism, critical mass, relates to cellular excitability and depolarization, such that when a critical mass of myocardium is depolarized VF is extinguished. On the basis of on our measurements of pacing threshold, regional heptanol decreased cellular excitability in the drug-perfused region. Although not reported (27), it is likely that global gap junction inhibition increases pacing thresholds but is associated with decreasing DFT values. Moreover, we have previously shown that very high doses of lidocaine drastically decreased excitability but decreased DFT values (37). Thus we do not believe that altering the critical mass was responsible for the results seen in the current study.

Although separate hypotheses, the virtual electrode polarization and the upper limit of vulnerability hypotheses relate to how defibrillation fails and importantly share a common theme (8–10, 14). Both hypotheses suppose that failed defibrillation results from the shock itself, inducing an electrophysiological state immediately after the shock that promotes reentry and fibrillation, even if a critical mass of myocardium is depolarized. We believe that this may be the mechanism by which regional gap junction inhibition impeded defibrillation. Specifically, regional gap junction inhibition likely increased electrical heterogeneity via conduction velocity dispersion immediately after the shock. Subsequently, this increase in conduction velocity dispersion promoted the propagation of early postshock activations, leading to fibrillation and inhibited successful defibrillation.

Conduction velocity is normally homogeneous across the myocardium, albeit anisotropic, resulting in uniform propagation of an activation front. However, regional ischemia slows regional conduction velocity increasing spatial conduction velocity dispersion, which is highly proarrhythmic, thus increasing the probability of ventricular arrhythmias (5, 11, 26, 32). Consistent with these reports, the present study demonstrated that regional conduction velocity slowing by local heptanol was highly arrhythmogenic to point stimulation, similar to what we have previously reported with regional lidocaine (38). Thus it appears that the conduction velocity dispersion created by regional heptanol increased myocardial vulnerability to VF. In fact, previous computational and mapping studies have shown that VF induction is closely associated with regions of slow conduction velocity and that spatial conduction velocity dispersion can be highly proarrhythmic by causing conduction block, wavefront instability, and wave break (6, 10, 15, 19).

Regional changes in conduction velocity may produce a situation where the propagation of an impulse is fast in one myocardial region while slow in another resulting in conduction block and wave break. This will cause the action potentials in the slow conduction region to be out of phase with action potentials in other myocardial regions. Because the slowly conducting tissue activates later in time compared with tissue in fast conduction region, repolarization and refractoriness will be out of phase even if the action potential duration is similar across the myocardium (15). The resultant dispersion of activation and repolarization between the slow and the normal conduction regions may disrupt uniform propagation (20), creating postshock arrhythmias. However, because of the complexity of defibrillation, it is not likely that postshock conduction velocity dispersion is the sole mechanism.

Limitations. Gap junction inhibition occurred in a single myocardial region. We cannot speculate whether numerous regions of electrical heterogeneity would affect defibrillation in a different manner, or if increasing dispersion by altering gap junction conductance in a myocardial region other than the middistal LAD would behave differently. Second, although all precautions were taken to ensure that heptanol only altered gap junction conductance, we cannot be absolutely sure regional sodium channel blockade did not contribute to effects on DFT values. However, regional heptanol in the current study produced significantly different effects on conduction velocity than previous results with regional lidocaine, indicating a different affect on conduction velocity than sodium channel blockade (38). Nonetheless, it is not wise to make assumptions that the gap junction uncoupling produced in this model provide a direct mechanism for ischemia-induced increases in DFT values. Finally, we did not document that regional heptanol increased conduction velocity dispersion postshock. However, drug-induced electrophysiological changes that occur during pacing and fibrillation are similar to changes that occur immediately after a biphasic shock (18, 24, 29).

Clinical implications. Mortality from sudden cardiac death can be prevented by rapid defibrillation. However, high DFT values limit these devices. Previous studies indicate that myocardial ischemia, similar to what occurs in patients with coronary artery disease, causes transient increases in DFT values (3, 28, 40). The current study found that regional gap junction inhibition, such as what occurs during prolonged ischemia, increases DFT values. This suggests that regional gap junction uncoupling may be a mechanism by which myocardial ischemia impairs defibrillation. If future studies that assess other components of myocardial ischemia continue to indicate that regional gap junction uncoupling is the predominate mechanism of ischemia-induced elevation in DFT values, then gap junctions may become a therapeutic target so that device or drug therapies can be developed that limit gap junction uncoupling and postshock conduction heterogeneity.


   ACKNOWLEDGMENTS
 
The authors thank Dr. Michael R. Ujhelyi for consulting on this project.

This work was supported by a Scientist Development Grant from the American Heart Association, Northland Affiliate, and the Astra-Zeneca Clinical Pharmacy Research Award.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. J. Sims, School of Pharmacy, Univ. of Wisconsin, 777 Highland Ave., Madison, WI 53705 (E-mail: jjsims{at}pharmacy.wisc.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Akar FG, Roth BJ, and Rosenbaum DS. Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation. Am J Physiol Heart Circ Physiol 281: H533-H542, 2001.[Abstract/Free Full Text]
  2. Babbs CF, Paris RL, Tacker WA, and Bourland JD. Effects of myocardial infarction on catheter defibrillation threshold. Med Instrum 17: 18-20, 1983.[Web of Science][Medline]
  3. Bailin SJ, Merkely DF, and Schubert HH. Impact of transient ischemia on transveous defibrillation thresholds: implications for clincal safety margins (Abstract). Pacing Clin Electrophysiol 21: 790, 1998.
  4. Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kleber AG, Schuessler RB, and Saffitz JE. Dephosphorylation and intracellular redistribution of ventricular connexin 43 during electrical uncoupling induced by ischemia. Circ Res 87: 656-662, 2000.[Abstract/Free Full Text]
  5. Callans DJ, Kieval RS, Hook BG, Moore EN, and Spear JF. Effect of coronary perfusion of heptanol or potassium on conduction and ventricular arrhythmias. Am J Physiol Heart Circ Physiol 263: H1382-H1389, 1992.[Abstract/Free Full Text]
  6. Cao JM, Qu Z, Kim YH, Wu TJ, Garfinkel A, Weiss JN, Karagueuzian HS, and Chen PS. Spatiotemporal heterogeneity in the induction of ventricular fibrillation by rapid pacing: importance of cardiac restitution properties. Circ Res 84: 1318-1331, 1999.[Abstract/Free Full Text]
  7. Cascio WE. Myocardial ischemia: what factors determine arrhythmogenesis? J Cardiovasc Electrophysiol 12: 726-729, 2001.[Web of Science][Medline]
  8. Chen PS, Shibata N, Dixon EG, Martin RO, and Ideker RE. Comparison of the defibrillation threshold and the upper limit of ventricular vulnerability. Circulation 73: 1022-1028, 1986.[Abstract/Free Full Text]
  9. Chen PS, Swerdlow CD, Hwang C, and Karagueuzian HS. Current concepts of ventricular defibrillation. J Cardiovasc Electrophysiol 9: 553-562, 1998.[Web of Science][Medline]
  10. Cheng Y, Mowrey KA, Nikolski V, Tchou PJ, and Efimov IR. Mechanisms of shock-induced arrhythmogenesis during acute global ischemia. Am J Physiol Heart Circ Physiol 282: H2141-H2151, 2002.[Abstract/Free Full Text]
  11. de Groot JR, Wilms-Schopman FJ, Opthof T, Remme CA, and Coronel R. Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart: role of electrical cellular coupling. Cardiovasc Res 50: 362-372, 2001.[Abstract/Free Full Text]
  12. Dorian P and Newman D. Tedisamil increases coherence during ventricular fibrillation and decreases defibrillation energy requirements. Cardiovasc Res 33: 485-494, 1997.[Abstract/Free Full Text]
  13. Dorian P, Penkoske PA, and Witkowski FX. Order in disorder: effect of barium on ventricular fibrillation. Can J Cardiol 12: 399-406, 1996.[Web of Science][Medline]
  14. Efimov IR, Gray RA, and Roth BJ. Virtual electrodes and deexcitation: new insights into fibrillation induction and defibrillation. J Cardiovasc Electrophysiol 11: 339-353, 2000.[Web of Science][Medline]
  15. Fishler MG and Thakor NV. A computer model study of the ventricular fibrillation vulnerable window: sensitivity to regional conduction depressions. Ann Biomed Eng 22: 610-621, 1994.[Web of Science][Medline]
  16. Gold MR, Peters RW, Johnson JW, and Shorofsky SR. Complications associated with pectoral cardioverter-defibrillator implantation: comparison of subcutaneous and submuscular approaches. J Am Coll Cardiol 28: 1278-1282, 1996.[Abstract]
  17. Janse MJ and Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 69: 1049-1169, 1989.[Free Full Text]
  18. Kirchhof PF, Fabritz CL, Zabel M, and Franz MR. The vulnerable period for low and high energy T-wave shocks: role of dispersion of repolarisation and effect of d-sotalol. Cardiovasc Res 31: 953-962, 1996.[Web of Science][Medline]
  19. Kondo T, Yamaki M, Kubota I, Tachibana H, and Tomoike H. Electrophysiologic effects of sodium channel blockade on anisotropic conduction and conduction block in canine myocardium: preferential slowing of longitudinal conduction by flecainide versus disopyramide or lidocaine. J Am Coll Cardiol 29: 1639-1644, 1997.[Abstract]
  20. Kozhevnikov D and Restivo M. Mechanism of enhanced arrhythmogenicity of acute ischemia in the hypertrophied heart (Abstract). Circulation 106: II-128, 2002.
  21. Kwaku KF and Dillon SM. Shock-induced depolarization of refractory myocardium prevents wave-front propagation in defibrillation. Circ Res 79: 957-973, 1996.[Abstract/Free Full Text]
  22. Lerner DL, Beardslee MA, and Saffitz JE. The role of altered intercellular coupling in arrhythmias induced by acute myocardial ischemia. Cardiovasc Res 50: 263-269, 2001.[Free Full Text]
  23. Multicenter Automatic Defibrillator Implantation Trial Investigators. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 335: 1933-1940, 1996.[Abstract/Free Full Text]
  24. Murakawa Y, Yamashita T, Ajiki K, Sezaki K, and Omata M. Effects of a class III antiarrhythmic drug and biphasic shocks on the post defibrillation refractory period of relatively refractory myocardium. J Cardiovasc Electrophysiol 7: 603-611, 1996.[Web of Science][Medline]
  25. Nelson WL and Makielski JC. Block of sodium current by heptanol in voltage-clamped canine cardiac purkinje cells. Circ Res 68: 977-983, 1991.[Abstract/Free Full Text]
  26. Pollard AE, Cascio WE, Fast VG, and Knisley SB. Modulation of triggered activity by uncoupling in the ischemic border: a model study with phase 1b-like conditions. Cardiovasc Res 56: 381-392, 2002.[Abstract/Free Full Text]
  27. Qi X, Varma P, Newman D, and Dorian P. Gap junction blockers decrease defibrillation thresholds without changes in ventricular refractoriness in isolated rabbit hearts. Circulation 104: 1544-1549, 2001.[Abstract/Free Full Text]
  28. Qin H, Walcott GP, Killingsworth CR, Rollins DL, Smith WM, and Ideker RE. Impact of myocardial ischemia and reperfusion on ventricular defibrillation patterns, energy requirements, and detection of recovery. Circulation 105: 2537-2542, 2002.[Abstract/Free Full Text]
  29. Sims JJ, Miller AW, and Ujhelyi MR. Disparate effects of biphasic and monophasic shocks on postshock refractory period dispersion. Am J Physiol Heart Circ Physiol 274: H1943-H1949, 1998.[Abstract/Free Full Text]
  30. Sims JJ, Miller AW, and Ujhelyi MR. Regional hyperkalemia increases ventricular defibrillation energy requirements: role of electrical heterogeneity in defibrillation. J Cardiovasc Electrophysiol 11: 634-641, 2000.[Web of Science][Medline]
  31. Sims JJ, Winecoff AP, and Ujhelyi MR. Lidocaine does not affect myocardial electrical heterogeneity: implications for low proarrhythmic actions. Pharmacotherapy 17: 1267-1273, 1997.[Web of Science][Medline]
  32. Smith WT, Fleet WF, Johnson TA, Engle CL, and Cascio WE. The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Circulation 92: 3051-3060, 1995.[Abstract/Free Full Text]
  33. Spear JF, Balke CW, Lesh MD, Kadish AH, Levine JL, and Moore EN. Effect of cellular uncoupling by heptanol on conduction in infarcted myocardium. Circ Res 66: 202-217, 1990.[Abstract/Free Full Text]
  34. Sweeney RJ, Gill RM, and Reid PR. Refractory interval after transcardiac shocks during ventricular fibrillation. Circulation 94: 2947-2952, 1996.[Abstract/Free Full Text]
  35. Tacker WA, Geddes LA, Cabler PS, and Moore AG. Electrical threshold for defibrillation of canine ventricles following myocardial infarction. Am Heart J 88: 476-481, 1974.[Web of Science][Medline]
  36. Ujhelyi MR, Schur M, Frede T, Gabel M, and Markel ML. Differential effects of lidocaine on defibrillation threshold with monophasic versus biphasic shock waveforms. Circulation 92: 1644-1650, 1995.[Abstract/Free Full Text]
  37. Ujhelyi MR, Sims JJ, and Miller AW. High-dose lidocaine does not affect defibrillation efficacy: implications for defibrillation mechanisms. Am J Physiol Heart Circ Physiol 274: H1113-H1120, 1998.[Abstract/Free Full Text]
  38. Ujhelyi MR, Sims JJ, and Miller AW. Induction of electrical heterogeneity impairs ventricular defibrillation: an effect specific to regional conduction velocity slowing. Circulation 100: 2534-2540, 1999.[Abstract/Free Full Text]
  39. van Kempen MJ, Fromaget C, Gros D, Moorman AF, and Lamers WH. Spatial distribution of connexin 43, the major cardiac gap junction protein, in the developing and adult rat heart. Circ Res 68: 1638-1651, 1991.[Abstract/Free Full Text]
  40. Walcott GP, Killingsworth CR, Smith WM, and Ideker RE. Biphasic waveform external defibrillation thresholds for spontaneous ventricular fibrillation secondary to acute ischemia. J Am Coll Cardiol 39: 359-365, 2002.[Abstract/Free Full Text]
  41. Winecoff Miller AP, Sims JJ, McSwain R, and Ujhelyi MR. Lidocaine's effect on defibrillation threshold are dependent on the defibrillation electrode system: epicardial versus endocardial. J Cardiovasc Electrophysiol 9: 312-320, 1998.[Web of Science][Medline]
  42. Witkowski FX, Penkoske PA, and Plonsey R. Mechanism of cardiac defibrillation in open-chest dogs with unipolar DC-coupled simultaneous activation and shock potential recordings. Circulation 82: 244-260, 1990.[Abstract/Free Full Text]
  43. Yabe S, Smith WM, Daubert JP, Wolf PD, Rollins DL, and Ideker RE. Conduction disturbances caused by high current density electric fields. Circ Res 66: 1190-1203, 1990.[Abstract/Free Full Text]
  44. Zheng ZJ, Croft JB, Giles WH, and Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 104: 2158-2163, 2001.[Abstract/Free Full Text]
  45. Zhou X, Daubert JP, Wolf PD, Smith WM, and Ideker RE. Epicardial mapping of ventricular defibrillation with monophasic and biphasic shocks in dogs. Circ Res 72: 145-160, 1993.[Abstract/Free Full Text]
  46. Zipes DP and Roberts D. Results of the international study of the implantable pacemaker cardioverter-defibrillator: a comparison of epicardial and endocardial lead systems. Circulation 92: 59-65, 1995.[Abstract/Free Full Text]
  47. Zipes DP and Wellens HJJ. Sudden cardiac death. Circulation 98: 2334-2351, 1998.[Free Full Text]



This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
J. P. Daubert and S.-S. Sheu
Mystery of Biphasic Defibrillation Waveform Efficacy: Is it Calcium?
J. Am. Coll. Cardiol., September 2, 2008; 52(10): 836 - 838.
[Full Text] [PDF]

Home page
 J CARDIOVASC PHARMACOL THERHome page
J.-q. Zhong, G. Laurent, P. P.-S. So, Xudong Hu, J. K. Hennan, and P. Dorian
Effects of Rotigaptide, a Gap Junction Modifier, on Defibrillation Energy and Resuscitation From Cardiac Arrest in Rabbits
Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 69 - 77.
[Abstract] [PDF]

Home page
 CirculationHome page
B. C. Eloff, E. Gilat, X. Wan, and D. S. Rosenbaum
Pharmacological Modulation of Cardiac Gap Junctions to Enhance Cardiac Conduction: Evidence Supporting a Novel Target for Antiarrhythmic Therapy
Circulation, December 23, 2003; 108(25): 3157 - 3163.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
285/1/H10    most recent
01074.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sims, J. J.
Right arrow Articles by Wiegert, N. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sims, J. J.
Right arrow Articles by Wiegert, N. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.