HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 290/2/H607    most recent 00699.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Ueda, N. Articles by Wu, J. Search for Related Content PubMed PubMed Citation Articles by Ueda, N. Articles by Wu, J.

Coronary occlusion and reperfusion promote early afterdepolarizations and ventricular tachycardia in a canine tissue model of type 3 long QT syndrome

Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 27 June 2005 ; accepted in final form 2 September 2005

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Although long QT syndrome (LQTS) and coronary occlusion-reperfusion (O/R) are arrhythmogenic, they affect ventricular action potential duration (APD) differently. In contrast to the prolonged APD in LQTS, ischemia abbreviates APD after a transient prolongation. Thus we hypothesized that the dynamic interactive effects of ischemia and LQTS on APD and its dispersion would affect ventricular arrhythmogenicity. We mapped transmural distribution of action potentials in 6 groups of 10 isolated wedges of canine ventricular walls: LQTS-O/R, LQTS only, and O/R only, with separate groups for pacing cycle lengths (PCL) of 1,000 and 2,000 ms. We created type 3 LQTS with anemone toxin (ATX) II followed >30 min later by arterial occlusion (40 min) and reperfusion (>100 min). Arterial occlusion initially (first 4 min) prolonged and then shortened APD. Early afterdepolarizations (EADs) occurred during the initial 4 min of occlusion in 4 of the 10 LQTS-O/R wedges at PCL of 2,000 ms but not in the other groups. Reperfusion restored APD in the O/R-only groups but caused APD to overshoot its original duration, indicating depressed repolarization reserve, in the LQTS-O/R group. Reperfusion increased the dispersion of APDs and initiated ventricular tachycardia-fibrillation in 7 of 10 and 6 of 10 LQTS-O/R wedges and in 2 of 10 and 1 of 10 O/R-only wedges at PCLs of 1,000 and 2,000 ms, respectively. The LQTS-only wedges exhibited neither EADs nor ventricular tachycardia. We conclude that coronary O/R increased the arrhythmogenicity of LQTS via cumulative prolongation of APD, increase in repolarization dispersion, and suppression of repolarization reserve.

arrhythmias; ischemia; repolarization reserve

Coronary occlusion induces acute ischemia, which rapidly suppresses the transient outward current and induces a slower, but stronger, ATP-sensitive K⁺ current, thus shortening action potential (AP) duration (APD) in the ischemic region after an initial prolongation (8, 15, 28–30). Refractoriness outlasts APD in this situation. Acute ischemia also increases the interstitial concentration of K⁺, which depolarizes the membrane potential, resulting in an initial increase, followed by suppression, of tissue excitability (9). The responses of ventricular tissue to acute ischemia are heterogeneic, occurring faster in the epicardium than in the endocardium because of transmural heterogeneities in membrane ionic currents, especially ATP-sensitive K⁺ and transient outward currents (8, 11). Regional ischemia further expands the dispersion of excitability and refractoriness in the heart (8, 33, 34). During reperfusion, heterogeneic tissue recovery also increases the dispersion of repolarization. The highly dispersed excitability and refractory periods promote arrhythmias during acute coronary O/R (33, 34).

In contrast, LQTS is associated with significantly prolonged APDs and increased dispersion of repolarization. Prolongation of APD increases membrane Ca²⁺ current and promotes the occurrence of early afterdepolarizations (EADs). EADs and high dispersion of repolarization contribute to TdP and ventricular tachycardia (VT) (10, 12, 31, 37). Increasing the activation intervals further prolongs APD and enhances the arrhythmogenicity of LQTS.

The propensity for arrhythmia development during O/R in the setting of LQTS remains unclear, because ischemia and LQTS can have opposite effects on APD. With this in mind, in isolated and arterially perfused wedges of canine ventricular free wall, we tested the hypothesis that the arrhythmogenicity during acute ischemia and reperfusion would be distinctively different between tissues with and without LQTS. We tested the idea that ischemia-induced shortening of APD might mitigate the arrhythmogenic effects of a lengthened Q-T interval, whereas ischemia-reperfusion and LQTS could increase the dispersion of repolarization, which is proarrhythmic.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
The investigation conforms to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and was approved by the Institutional Animal Care and Use Committee of Indiana University School of Medicine. We isolated wedges of canine ventricular free wall as described previously (25–27, 32–34). Briefly, we harvested hearts from 60 mongrel dogs after sufficient anesthesia (pentobarbital sodium at 30 mg/kg body wt) and immediately perfused the hearts through the aorta with a cardioplegic solution [Tyrode solution (see below) with 15 mmol/l KCl at 4°C], which washed out the blood and protected the hearts during the subsequent period of tissue isolation. We isolated from each heart one transmural wedge of left ventricular free wall containing a section of coronary artery (1 mm diameter) along its length (20–30 mm long). The wedges were 4–7 mm wide on the epicardium and 12–20 mm on the transmural surface. Two plastic cannulas, one for perfusion and the other for arterial pressure monitoring, were inserted into the two openings of the artery. Major arterial leaks in the wedges were ligated with silk suture. The isolated tissues were mounted in a warmed chamber with the cut-exposed transmural observation surface up, perfused with 37°C Tyrode solution (in mmol/l: 128.0 NaCl, 4.69 KCl, 22.0 NaHCO₃, 0.65 NaH₂PO₄, 0.50 MgCl₂, 11.1 dextrose, and 2.0 CaCl₂, gassed with 95% O₂-5% CO₂, pH 7.4) at an arterial pressure of 40–50 mmHg (monitored at the no-flow distal cannula), and immersed in the perfusion fluid.

Recovery perfusion of the isolated wedges continued for >60 min to permit healing from the surgery. Each wedge was then stained with 4-{2-[6-(dioctylamino)-2-naphthalenyl)]ethenyl}-1-(3-sulfopropyl)-pyridinium (di-4-ANEPPS, Molecular Probes, Eugene, OR; 4 µmol/l in perfusate), a membrane potential-sensitive fluorescent dye that has no known electrophysiological effects and is used widely in optical mapping studies. All wedges were paced (2-ms duration, 2x diastolic current threshold, with a bipolar electrode) from the endocardium at a pacing cycle length (PCL) of 1,000 ms during recovery. A pair of silver electrodes was placed in the bath next to the epicardium and endocardium to record the transmural ECG.

The recovery perfusion continued until the wedges were fully stabilized (with consistent arterial pressure and contractions, APDs, velocity of conduction, and ECG for >10 min). We evaluated the health of the wedges as described previously (25–27, 32–34). Well-perfused wedges had a vivid reddish color, low-noise optical signals with normal APD, and strong contractions on stimulation, in contrast to the short APD (or inactivation), dull color, weak contraction, and noisy optical signals (poor perfusion and dye staining) of ischemic wedges. Healthy wedges were immobilized with cytochalasin D (Sigma Chemical, St. Louis, MO; 20–30 µmol/l), which has no known effects on canine ventricular AP (7, 32). Tissue immobilization eliminated motion artifacts in optically recorded APs and facilitated the identification of AP domes and EADs. We verified that these procedures produced stable wedges with transmural dispersions of APD and conduction velocity (32) similar to in vivo observations (4, 17).

We studied six groups (10 wedges in each group): LQTS-O/R, LQTS only, and O/R only, with separate groups at PCLs of 1,000 and 2,000 ms (LQTS-O/R-1000, LQTS-O/R-2000, LQTS-only-1000, LQTS-only-2000, O/R-only-1000, and O/R-only-2000). An optical mapping system (32) with a 256-element (16 x 16) photodiode camera (model C4675, Hamamatsu, Hamamatsu City, Japan) collected the fluorescence from a 19.5 x 19.5 mm area on the tissue surface (with minor contributions from subsurface cells) and converted it to 256 channels of electrical signals (fluorescent APs). Each channel of fluorescent AP corresponded to a surface area of 1.1 x 1.1 mm. A custom data acquisition system recorded APs, arterial perfusion pressure, and transmural ECG during PCLs of 1,000 or 2,000 ms (at 1,000 samples·channel^–1·s^–1) after wedges were fully immobilized and stabilized (baseline control recording).

We created type 3 LQTS by adding to the perfusate anemone toxin (ATX) II (20 nmol/l; Calbiochem-Novabiochem, San Diego, CA) (6, 19, 20, 35), an agent that slows the inactivation of Na⁺ channels and prolongs APD, and repeated the baseline recording sequences 30 min later in the LQTS groups. Data were also recorded at the equivalent time in the O/R-only (no ATX II) groups. We then introduced global ischemia by occlusion of the artery for 40 min followed by >100 min of reperfusion in the O/R groups, while perfusion was continued in the LQTS-only groups. Data were recorded at 1-, 5-, and 10-min intervals during the 40 min of arterial occlusion and again with the same sequences during reperfusion in the O/R groups or at 10-min intervals during continuous perfusion over the same period in the LQTS-only groups.

We measured APD from the interval between the maximum rate of depolarization and the peak of the second-order derivative of AP, as we did previously (25–27, 32–34), with visual inspections and manual corrections. Epicardial, endocardial, and midmyocardial APDs were calculated at the recording sites along the first epicardial row, the first endocardial row, and a parallel row with the longest mean APD (APD_L layer). The APD_L layer indicated the statistical transmural position of the longest APD. We defined the presence of M cell behavior as the existence of statistically significant longer APDs in the APD_L layer than in the endocardial and epicardial rows. EADs were identified as a depolarization or hump superimposed on phase 3 or phase 4 of the AP. ANOVA and Fisher's protected least significant difference test were used for intergroup statistical analysis. Differences were considered significant if P < 0.05. Values are means (SD).

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
All wedges were verified healthy and stable with normal distribution of APDs and without any spontaneous VT after recovery perfusion, similar to the wedges we studied previously (25–27, 32–34). There were no motion artifacts in the recorded APs, because the wedges were fully immobilized and stabilized. The APDs in the endocardium were significantly (P < 0.05) longer than those in the epicardium, although not statistically different from those in the APD_L layer, which is in or next to the endocardium during the baseline recordings (control in Fig. 1A), similar to our previous observations (25–27, 32–34). There were no significant intergroup differences in the baseline APDs.

View larger version (33K): [in this window] [in a new window]   Fig. 1. Dependence of midmyocardial (M) cell behavior (A) and position of the longest mean action potential duration (APDL layer; B) on anenome toxin (ATX) II. Data were recorded before (control, 60 wedges) and after ATX II [long QT syndrome (LQTS), 40 wedges] at pacing cycle lengths (PCLs) of 1,000 and 2,000 ms during continued perfusion (before arterial occlusion). Numbers above bars in A are mean APDs. *Statistically confirmed M cell behavior after (in LQTS), but not before, ATX II perfusion (control, A). APDL layers were near the endocardium before (control), but deeper inside the ventricular wall after, the ATX II perfusion (LQTS, B).

Arterial occlusion (40 min) prolonged APD during the initial 4 min but shortened APD during the subsequent period (Fig. 2). Occlusion caused faster and greater APD shortening in the epicardium than in the endocardium and midmyocardium, thus increasing the transmural dispersion of APD (Fig. 3). The epicardium became electrically inactive after >20 min of arterial occlusion (Figs. 2 and 3). The transmural heterogeneity in tissue responses shifted the APD_L layers toward the endocardium during arterial occlusion, especially in the LQTS-O/R groups (Fig. 4).

View larger version (30K): [in this window] [in a new window]   Fig. 2. APDs during occlusion (40 min) and reperfusion (O/R) in the LQTS-O/R (A) and O/R-only (B) groups (10 wedges each) at PCL of 2,000 ms. Corresponding normalized APDs are shown in C (LQTS-O/R) and D (O/R only). Tissue inactivation is indicated as terminated traces during occlusion. APDs were prolonged during the first 4 min of occlusion and then shortened during further occlusion. APDs overshot preocclusion levels during reperfusion, more so in the LQTS-O/R than in the O/R-only group and in the APDL layer than in epicardial and endocardial layers.

View larger version (23K): [in this window] [in a new window]   Fig. 3. Mean dispersions of APD during O/R in LQTS-O/R (A) and O/R-only (B) groups (10 wedges each) at PCL of 2,000 ms. Mean dispersions of APD were derived from averaging all wedges in each group; standard deviations of APD at the epicardial, endocardial, and APDL layers; and differences in mean APDs between APDL and epicardial layers (APDL-Epi). Occlusion increased dispersion of APD along the transmural direction (APDL-Epi) and within each epicardial, endocardial, and APDL layer. Dispersion within each layer recovered after reperfusion. Transmural dispersion persisted after reperfusion in LQTS-O/R wedges.

View larger version (21K): [in this window] [in a new window]   Fig. 4. Transmural shifting of APDL layers during O/R in LQTS-O/R (A) and O/R-only (B) groups (10 wedges each) at PCL of 2,000 ms. Transmural differences in shortening of APD shifted APDL layers toward the endocardium during occlusion. Reperfusion restored transmural positions of APDL layers.

View larger version (25K): [in this window] [in a new window]   Fig. 5. Statistical occurrences of early afterdepolarizations (EADs), torsades de pointes (TdP), and ventricular tachycardia-fibrillation (VT/VF) in LQTS and O/R groups (10 wedges each) at PCLs of 1,000 and 2,000 ms. EADs and TdP were observed only in LQTS-O/R-2000 group. Arterial occlusion induced EADs only during the first 4 min. VT/VF was observed during occlusion (LQTS-O/R-2000 group) and reperfusion (all O/R groups). Continuously perfused LQTS-only groups were stable, without EADs, TdP, or VT/VF.

View larger version (35K): [in this window] [in a new window]   Fig. 6. EADs and VT initiation during initial minutes of arterial occlusion (tissues 1 and 2) and during reperfusion (tissue 3) in wedges pretreated with 20 nmol/l ATX II and paced at 2-s intervals. Action potentials were recorded after arterial occlusion or reperfusion at various times. Examples were selected from dotted sites on cut-exposed transmural surfaces of ventricular preparations. EADs occurred during early occlusion (tissues 1 and 2, traces A and C) and initiated VT (tissue 2). After 1 min of arterial occlusion, the pause following termination of a preceding episode of VT caused additional APD prolongation, which led to EAD and VT (traces B and C) in tissue 2. Significant dispersion of APDs contributed to VT during reperfusion (12 min, traces D–F) in tissue 3.

View larger version (18K): [in this window] [in a new window]   Fig. 7. EADs were observed in all regions except epicardium in 4 and 2 of the 10 LQTS wedges during occlusion, and reperfusion, respectively, at PCL of 2,000 ms.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
New observations. Most information about the electrophysiological changes associated with acute myocardial infarction emphasizes shortening of the APD due to loss of intracellular K⁺. This study demonstrated that transient APD prolongation, initially and in the setting of a type 3 long QT model, causes excessive APD prolongation (by the cumulative effects of ATX II, long PCL, and early ischemia; Fig. 2), resulting in frequent EADs and VT during the initial 4 min of ischemia (Figs. 5 and 6). Similar mechanisms could also contribute to the phase 1A arrhythmias during the first 8 min of coronary occlusion reported previously in intact hearts (14). Further ischemia shortened APD and, thus, reduced the occurrence of spontaneous EADs. The transmural differences in the tissue sensitivity to ischemia caused faster shortening of APD in the epicardium than in the endocardium and, thus, expanded the spatial dispersion of APD (Fig. 3), although local excitability was suppressed after the initial minutes of ischemia. We reported previously that the ischemia-enhanced transmural gradient of refractory periods could block conduction unidirectionally and initiate reentry during rapid endocardial pacing (33). We also showed that the ischemia-produced transmural gradient of excitability provided an asymmetric substrate for reentry during epicardial stimulation (34). Similar transmural heterogeneic tissue responses to ischemia could also contribute to the development of ventricular arrhythmias (Figs. 5 and 6) in the present study.

This study demonstrated for the first time, to our knowledge, the phenomenon of overshoot recovery of APDs during reperfusion (exceeding their preocclusion APD values; Fig. 2) in association with increased arrhythmogenicity (Figs. 5 and 6). There was greater APD overshoot during reperfusion in tissues treated with (LQTS-O/R, Fig. 2C) than without (O/R-only, Fig. 2D) ATX II and in the APD_L layer than in the epicardium and endocardium (Fig. 2, C and D). Transmural heterogeneities in the rate of recovery and in APD overshoot increased the dispersion of repolarization during reperfusion (Fig. 3). The reperfusion overshoot of APD suggests a new mechanism for reperfusion tachyarrhythmias by increasing the dispersion of repolarization and prolonging APD (Fig. 5).

A group of distinctive midmyocardial (M) cells having exceedingly long APD when activated at long PCLs, characteristically different from the epicardial and endocardial myocytes, has been reported in vitro (1, 2). However, M cells were less distinct or even not observed in other in vivo and in vitro studies without or before pharmacological Q-T prolongation (3, 4, 22, 23). We reconciled the previous observations on M cells by demonstrating that the "M cells" were a functional behavior of myocytes in the ventricular wall, rather than a distinctive fixed group of myocytes (26). We statistically confirmed the existence of the M cell behavior after, but not before, ATX II treatment and demonstrated that the locations of the longest APDs depended on the concentration of ATX II in isolated canine ventricular wedges (26). The present study showed for the first time the movement of the APD_L layer (longest mean APD) toward the endocardium during coronary occlusion and return to the original midmyocardial position on reperfusion (Fig. 4), despite APD overshoot (Fig. 2). The ischemia-induced shift in the APD_L layer provided new support for the functional nature of M cell behavior.

This study also provided new support for the repolarization reserve hypothesis (18); i.e., a reduced repolarization reserve promotes the occurrence of EADs. Healthy cardiac myocytes are able to maintain appropriate repolarization and electrophysiological stability during minor electrophysiological perturbations. Reducing repolarization reserve causes cardiac myocytes to exhibit excessive APD responses to disturbances in repolarization ionic currents. The overshoot recovery of APD after reperfusion in the LQTS-O/R groups (Fig. 2, A and C) indicates that the repolarization reserve was insufficient to return APD to its preocclusion level. In contrast, APDs in wedges without ATX II perfusion (O/R-only) recovered to near-preocclusion levels after reperfusion (Fig. 2, B and D), indicating sufficient repolarization reserve.

The present study used a protocol with ATX II perfusion followed by arterial O/R, in the reverse sequence of our previous study (25), and, thus, changed the substrate and triggers of arrhythmia and clinical implications. We found previously (25) that 40 min of ischemia reduced repolarization reserve persistently, even after 60 min of reperfusion, which fully restored the shape and duration of APs. Subsequent exposure to ATX II caused excessive APD prolongation and arrhythmias. In contrast, continuously perfused preparations had significantly less APD prolongation and no arrhythmias in response to ATX II. Therefore, our previous study explored the impact of APD prolongation (as a trigger) on substrates with reduced repolarization reserve. Clinically, similar acute APD prolongation could be provided by pharmacological agents, vagal stimulation (16), or hypothermia, and low repolarization reserve (substrate) could exist in hearts remodeled, for example, by heart failure (24), prior ischemia-infarction, aging, and persistent metabolic stress. In contrast, the present study evaluated the arrhythmogenicity of arterial O/R (as the triggers) in a substrate with LQTS (created with prior perfusion of ATX II). The arrhythmogenicity was caused by the superimposed APD prolongation by ATX II and long PCL during the initial minutes of ischemia and by the increased dispersion of repolarization during reperfusion. Therefore, our previous studies and the present study demonstrated two different mechanisms of arrhythmogenicity by different triggers (APD prolongation vs. ischemia-reperfusion) in different models of diseases (low repolarization reserve vs. LQTS).

In conclusion, this study demonstrated that coronary O/R increased the arrhythmogenicity of LQTS, especially during long PCLs, via cumulative effects on APD prolongation during the initial minutes of ischemia, on increasing the dispersion of APD (Figs. 5 and 6), on overshoot reperfusion recovery of APD, and on suppression of repolarization reserve. Although we used ATX II in an in vitro model, it is likely that the underlying mechanisms and our conclusions would be applicable to any LQTS situations, because the mechanisms we demonstrated and our conclusions do not depend on any specific properties of ATX II or type 3 LQTS. Our previous study (25) and the present study indicate that the combination of ATX II and arterial O/R, whether ATX II was given before ischemia or after apparent complete recovery from a prior episode of ischemia, was highly arrhythmogenic.

Limitations. We immobilized the wedges with 20–30 µmol/l cytochalasin D, which has no measurable effects on the shape of ventricular AP in dogs [verified with microelectrodes at up to 80 µmol/l (7) and with optical recording at up to 40 µmol/l (32)] and rats [5–50 µmol/l (36)]. However, whether effects of cytochalasin D on individual membrane ionic currents (e.g., channels that interact with the cytoskeleton) affect the dynamic electrophysiological behavior of canine and rat ventricular tissue remains unclear. In contrast to canine and rat cardiac AP, mouse cardiac AP is affected by cytochalasin D (5, 13), possibly because of the differences in repolarization currents between species (38). We minimized any possible (unknown) effects of cytochalasin D by using statistical comparisons among the groups, which separated the results of experimental manipulations from the common factors (including cytochalasin D) in all groups. Because of postrepolarization refractoriness, APD in Figs. 2 and 3 does not represent the refractory period during arterial occlusion. The optical recording and statistical representations of the endocardial, epicardial, and midmyocardial APs could cause averaging/filtering effects that increased the APDs and reduced the dispersions of APD. However, these effects should not affect the conclusions.

	GRANTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This research was supported by American Heart Association Midwest Affiliate Grants 0256112Z and 0455517Z, a grant from Alcoholic Beverage Medical Research Foundation, and the Herman C. Krannert Fund (Indianapolis, IN).

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. Wu, Krannert Institute of Cardiology, Indiana Univ. School of Medicine, 1800 North Capitol Ave., Indianapolis, IN 46202 (e-mail: jiaswu{at}iupui.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 GRANTS REFERENCES

 

1. Antzelevitch C and Fish J. Electrical heterogeneity within ventricular wall. Basic Res Cardiol 96: 517–527, 2001.[CrossRef][ISI][Medline]
2. Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, Burashnikov A, Di Diego J, Saffitz J, and Thomas GP. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 10: 1124–1152, 1999.[ISI][Medline]
3. Anyukhovsky EP, Sosunov EA, Gainullin RZ, and Rosen MR. The controversial M cell. J Cardiovasc Electrophysiol 10: 244–260, 1999.[ISI][Medline]
4. Anyukhovsky EP, Sosunov EA, and Rosen MR. Regional differences in electrophysiological properties of epicardium, midmyocardium, and endocardium. In vitro and in vivo correlations. Circulation 94: 1981–1988, 1996.[Abstract/Free Full Text]
5. Baker LC, Wolk R, Choi BR, Watkins S, Plan P, Shah A, and Salama G. Effects of mechanical uncouplers, diacetyl monoxime, and cytochalasin D on the electrophysiology of perfused mouse hearts. Am J Physiol Heart Circ Physiol 287: H1771–H1779, 2004.[Abstract/Free Full Text]
6. Boutjdir M and el-Sherif N. Pharmacological evaluation of early afterdepolarizations induced by sea anemone toxin (ATXII) in dog heart. Cardiovasc Res 25: 815–819, 1991.[ISI][Medline]
7. Biermann M, Rubart M, Moreno A, Wu J, Josiah-Durant A, and Zipes DP. Differential effects of cytochalasin D and 2,3 butanedione monoxime on isometric twitch force and transmembrane action potential in isolated ventricular muscle. J Cardiovasc Electrophysiol 9: 1348–1357, 1998.[ISI][Medline]
8. Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev 79: 917–1017, 1999.[Abstract/Free Full Text]
9. Elharrar V, Foster PR, Jirak TL, Gaum WE, and Zipes DP. Alterations in canine myocardial excitability during ischemia. Circ Res 40: 98–105, 1977.[Abstract/Free Full Text]
10. El-Sherif N, Chinushi M, Caref EB, and Restivo M. Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long QT syndrome. Circulation 96: 4392–4399, 1997.[Abstract/Free Full Text]
11. Gilmour RF Jr and Zipes DP. Different electrophysiological responses of canine endocardium and epicardium to combined hyperkalemia, hypoxia, and acidosis. Circ Res 46: 814–815, 1980.[Free Full Text]
12. January CT and Riddle JM. Early afterdepolarizations: mechanism of induction and block. Circ Res 64: 977–990, 1989.[Abstract/Free Full Text]
13. Jalife J, Morley GE, Tallini NY, and Vaidya D. A fungal metabolite that eliminates motion artifacts. J Cardiovasc Electrophysiol 9: 1358–1362, 1998.[ISI][Medline]
14. Kaplinsky E, Ogawa S, Balke W, and Dreifus LS. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation 60: 397–403, 1979.[Abstract/Free Full Text]
15. Kleber AG, Janse MJ, Wilms-Schopmann FJ, Wilde AA, and Coronel R. Changes in conduction velocity during acute ischemia in ventricular myocardium of the isolated porcine heart. Circulation 73: 189–198, 1986.[Abstract/Free Full Text]
16. Martins JB and Zipes DP. Effects of sympathetic and vagal nerves on recovery properties of the endocardium and epicardium of the canine left ventricle. Circ Res 46: 100–110, 1980.[Free Full Text]
17. Merot J, Charpentier F, Poirier JM, Coutris G, and Weissenburger J. Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol. Cardiovasc Res 44: 303–314, 1999.[Abstract/Free Full Text]
18. Roden DM. Pharmacogenetics and drug-induced arrhythmias. Cardiovasc Res 50: 224–231, 2001.[Abstract/Free Full Text]
19. Shimizu W and Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation 99: 1499–1507, 1999.[Abstract/Free Full Text]
20. Shimizu W and Antzelevitch C. Effects of a K⁺ channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT1, LQT2, and LQT3 models of the long-QT syndrome. Circulation 102: 706–712, 2000.[Abstract/Free Full Text]
21. Surawicz B. Electrophysiologic substrate of torsade de pointes: dispersion of repolarization or early afterdepolarization? J Am Coll Cardiol 14: 172–184, 1989.[Abstract]
22. Taggart P, Sutton PM, Opthof T, Coronel R, Trimlett R, Pugsley W, and Kallis P. Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia. Cardiovasc Res 50: 454–462, 2001.[Abstract/Free Full Text]
23. Taggart P, Sutton P, Opthof T, Coronel R, and Kallis P. Electrotonic cancellation of transmural electrical gradients in the left ventricle in man. Prog Biophys Mol Biol 82: 243–254, 2003.[CrossRef][ISI][Medline]
24. Tomaselli GF and Zipes DP. What causes sudden death in heart failure? Circ Res 95: 754–763, 2004.[Abstract/Free Full Text]
25. Ueda N, Zipes DP, and Wu J. Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT 3. Cardiovasc Res 63: 69–76, 2004.[Abstract/Free Full Text]
26. Ueda N, Zipes DP, and Wu J. Functional and transmural modulation of M cell behavior in canine ventricular wall. Am J Physiol Heart Circ Physiol 287: H2569–H2575, 2004.[Abstract/Free Full Text]
27. Ueda N, Zipes DP, and Wu J. Epicardial but not endocardial premature stimulation initiates ventricular tachyarrhythmia in canine in vitro model of long QT syndrome. Heart Rhythm 1: 684–694, 2004.[CrossRef][Medline]
28. Verkerk AO, Veldkamp MW, Van Ginneken ACG, and Bouman LN. Biphasic response of action potential duration to metabolic inhibition in rabbit and human ventricular myocytes: role of transient outward current and ATP-regulated potassium current. J Mol Cell Cardiol 28: 2443–2456, 1996.[CrossRef][ISI][Medline]
29. Watanabe IA, Kanda A, Engle CL, and Gettes LS. Comparison of the effects of regional ischemia and hyperkalemia on the membrane action potentials of the in situ pig heart. J Cardiovasc Electrophysiol 8: 1229–1236, 1997.[ISI][Medline]
30. Workman AJ, MacKenzie I, and Northover BJ. Do K_ATP channels open as a prominent and early feature during ischaemia in the Langendorff-perfused rat heart? Basic Res Cardiol 95: 250–260, 2000.[CrossRef][ISI][Medline]
31. Wu J, Wu J, and Zipes DP. Early afterdepolarizations, U waves, and torsade de pointes. Circulation 105: 675–676, 2002.[Free Full Text]
32. Wu J, Biermann M, Rubart M, and Zipes DP. Cytochalasin D as excitation-contraction uncoupler for optically mapping action potentials in wedges of ventricular myocardium. J Cardiovasc Electrophysiol 9: 1336–1347, 1998.[ISI][Medline]
33. Wu J and Zipes DP. Transmural reentry during global acute ischemia and reperfusion in canine ventricular muscle. Am J Physiol Heart Circ Physiol 280: H2717–H2725, 2001.[Abstract/Free Full Text]
34. Wu J and Zipes DP. Transmural reentry triggered by epicardial stimulation during acute ischemia in canine ventricular muscle. Am J Physiol Heart Circ Physiol 283: H2004–H2011, 2002.[Abstract/Free Full Text]
35. Yan GX and Antzelevitch C. Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation 98: 1928–1936, 1998.[Abstract/Free Full Text]
36. Yang X, Salas PJ, Pham TV, Wasserlauf BJ, Smets MJD, Myerburg RJ, Gelband H, Hoffman BF, and Bassett AL. Cytoskeletal actin microfilaments and the transient outward potassium current in hypertrophied rat ventriculocytes. J Physiol 541: 411–421, 2002.[Abstract/Free Full Text]
37. Zabel M, Hohnloser SH, Behrens S, Li YG, Woosley RL, and Franz MR. Electrophysiological features of torsade de pointes: insights from a new isolated rabbit heart model. J Cardiovasc Electrophysiol 8: 1148–1158, 1997.[ISI][Medline]
38. Zicha S, Moss I, Allen B, Varro A, Papp J, Dumaine R, Antzelevitch C, and Nattel S. Molecular basis of species-specific expression of repolarization K⁺ currents in the heart. Am J Physiol Heart Circ Physiol 285: H1641–H1649, 2003.[Abstract/Free Full Text]

This article has been cited by other articles:

				S. T. Morita, D. P. Zipes, H. Morita, and J. Wu Analysis of action potentials in the canine ventricular septum: No phenotypic expression of M cells Cardiovasc Res, April 1, 2007; 74(1): 96 - 103. [Abstract] [Full Text] [PDF]

				J. C. Lopshire and D. P. Zipes Sudden Cardiac Death: Better Understanding of Risks, Mechanisms, and Treatment Circulation, September 12, 2006; 114(11): 1134 - 1136. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 290/2/H607    most recent 00699.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Ueda, N. Articles by Wu, J. Search for Related Content PubMed PubMed Citation Articles by Ueda, N. Articles by Wu, J.