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Am J Physiol Heart Circ Physiol 281: H1968-H1975, 2001;
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Vol. 281, Issue 5, H1968-H1975, November 2001

Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization

Gan-Xin Yan1, Seth J. Rials3, Ying Wu1, Tengxian Liu1, Xiaoping Xu1, Roger A. Marinchak1,2, and Peter R. Kowey1,2

1 Main Line Health Heart Center, Wynnewood 19096; 2 Jefferson Medical College, Philadelphia, Pennsylvania 19107; and 3 HeartCare Incorporated, Columbus, Ohio 43215


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The effects of left ventricular hypertrophy (LVH) on the generation of phase 2 early afterdepolarization (EAD) and transmural dispersion of repolarization (TDR) were assessed using arterially perfused rabbit ventricular wedge preparations. Transmembrane action potentials from epicardium, subendocardium, and endocardium were simultaneously recorded together with a transmural ECG. Transmural action potential duration (APD) was also mapped. LVH (renovascular hypertension model) produced significant prolongation in ventricular APD and QT interval. Preferential APD prolongation in subendocardium and endocardium was associated with a marked increase in TDR. Phase 2 EADs were generated from subendocardium or endocardium in all LVH rabbits (15 of 15) in the absence of APD prolonging agents at basic cycle lengths of 2,000-4,000 ms. Phase 2 EAD could produce "R on T" extrasystoles, initiating polymorphic ventricular tachycardia (VT). This study provides the first direct evidence from intracellular recordings that phase 2 EAD could be generated from rabbit intact hypertrophied LV wall in the absence of APD prolonging agents, resulting in R on T extrasystoles capable of initiating polymorphic VT under enhanced TDR.

action potential; ventricular tachycardia; epicardium; endocardium


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

LEFT VENTRICULAR HYPERTROPHY (LVH) and failure afflict >2,000,000 Americans, and claim >200,000 lives annually in the United States. Of the deaths in patients with LVH and failure, up to 50% are sudden and unexpected, likely due to the onset of polymorphic ventricular tachycardia (VT) (19, 28). Although several ionic and cellular alterations in LVH demonstrated in isolated superfused and sliced ventricular tissue or single myocytes (9, 28) may contribute to arrhythmogenesis, little is known about electrophysiological alterations and the mechanisms responsible for the initiation and maintenance of polymorphic VT in intact hypertrophied ventricular wall.

The most striking and consistent electrical alteration associated with LVH observed in isolated ventricular tissues and single myocytes is prolongation of the action potential duration (APD) due to the downregulation of several K+ currents responsible for repolarization including inward rectifier K+ current (IK1), transient outward K+ current (Ito), and slowly activating delayed rectifier K+ current (IKs) (28, 33). The hypothesis that polymorphic VT in patients with LVH and failure might share similar mechanisms to that observed in patients with QT prolongation has been interestingly postulated (19). As demonstrated in acquired long QT syndrome, focal activities that originate from subendocardium or endocardium contribute importantly to the initiation of polymorphic VT (11). Phase 2 early afterdepolarization (EAD), oscillatory potential in final phases of the action potentials seen in isolated ventricular myocytes and tissue in the presence of APD prolonging agents, may potentially play an important role in the genesis of such an initiating beat under conditions of QT prolongation. Ventricular myocytes isolated from the hypertrophied ventricle, which show longer APD at baseline, exhibit increased susceptibility to phase 2 EAD in the presence of APD prolonging agents compared with those isolated from control canine hearts (21, 30). However, direct evidence that phase 2 EAD could induce a triggered beat in intact ventricular wall, in which all myocytes are electrically coupled, is still lacking, although EAD-like activities have been recorded using traditional Franz monophasic action potential (MAP) technique in in vivo conditions. Because the MAP electrode records a composite signal from local ventricular surface by applying appropriate pressure, EAD-like activities recorded by MAP may represent an artifact secondary to unstable electrode contact or local heterogeneous repolarization (12, 15, 16). Therefore, the studies using MAP have provided at best indirect evidence of EAD in in vivo conditions.

On the other hand, transmural functional reentry is believed to be responsible for the maintenance of polymorphic VT once it has been initiated (3, 4, 11, 35). Transmural dispersion of repolarization (TDR) secondary to the existence of cell types with distinct repolarization properties (i.e., epicardium, M cells, and endocardium) within ventricular myocardium plays an essential role in the development of such a transmural circus movement (3, 25, 35). Multiple ionic and cellular alterations in LVH may exert different influences among different cell types that may lead to an increase in TDR. However, alteration in repolarization across intact hypertrophied LV wall, in which myocardial layers are electrically coupled, remains poorly defined.

In the present study, we used an isolated arterially perfused rabbit LV wedge preparation to demonstrate, for the first time, that phase 2 EAD could be generated from intact hypertrophied LV wall in the absence of APD prolonging agents. Phase 2 EAD could propagate transmurally under conditions of markedly increased TDR in the setting of LVH, inducing an extrasystole on the downslope of the preceding T wave (i.e., malignant "R on T" phenomenon). Such an R on T extrasystole is capable of initiating polymorphic VT.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Renovascular hypertension model in rabbits with LVH. Adult New Zealand White rabbits (1.8-2.2 kg) underwent unilateral nephrectomy with contralateral renal artery banding to produce LVH, as reported previously (22, 33). Rabbits banded in this manner uniformly developed LVH within 3 mo. Control rabbits were matched for age. For each rabbit, the heart weight-to-body weight ratio (g/kg) was obtained before the experiment. Consistent with earlier studies (22), the heart weight-to-body weight ratio was elevated in the LVH group compared with the control group (2.90 ± 0.08 vs. 2.10 ± 0.05 g/kg, P < 0.01). The increase in heart weight has been shown to result primarily from a significant increase in LV thickness and weight (22).

Arterially perfused rabbit LV wedge preparations. The methods used for isolation, perfusion, and recording of transmembrane activity from the arterially perfused canine ventricular wedge preparation, as well as the viability and electrical stability of the preparation, are detailed in previous studies (34, 36). Preparation of isolated arterially perfused LV wedge from LVH rabbits is similar to that of the canine ventricular wedge. Briefly, transmural wedge preparations with a dimension of ~2 × 1.5 × 0.4 cm (control) and 2 × 1.5 × 0.7 cm (LVH) were dissected from rabbit LVs, cannulated via the first obtuse branch of left circumflex coronary artery and perfused with cardioplegic solution. The preparation was then placed in a tissue bath, perfused with Tyrode solution (35.7 ± 0.3°C), and paced at basic cycle lengths (BCL) from 500 to 4,000 ms. The control measurements were obtained after 1 h of equilibration of the preparations in the tissue bath.

Electrophysiological recordings. Transmembrane action potentials in rabbit LV wedge preparations were recorded simultaneously from epicardial, subendocardial (within one-third of the distance of the entire wall from endocardium), and endocardial sites by use of three separate intracellular floating microelectrodes. A transmural electrocardiogram (ECG) was recorded concurrently (36). In some initial experiments, transmural repolarization distribution was determined in LVH and control rabbits by recording APD across the LV wall. Because it is extremely difficult to maintain more than three floating intracellular electrodes, APD across LV wall was mapped by moving the intracellular recording electrodes at a certain interval, during which time ECG had no significant change. Because it is different from canine wedge preparation, it is very difficult to record transmural action potentials from the cutting surface of rabbit LV wedge. The recordings of subepicardial, midmyocardial, and subendocardial action potentials were accomplished by using long-shank intracellular electrodes that were forced into deep (>2 mm) myocardium through the cutting surface.

APD was measured at 90% repolarization (APD90) and analyzed by using computer software (Spike version 2, CED). TDR was defined as the difference between the longest and shortest repolarization times across the LV wall. This is closely approximated by the interval between the time from the peak to the end of the T wave (Tpeak-Tend interval) (3, 35). The QT interval was defined as the time from the onset of the QRS to the point at which the final downslope of the T wave crossed the isoelectric line.

Statistics. Statistical analysis of the data was performed using Student's t-test for paired parametric data in two groups or one-way analysis of variance coupled with Scheffé's test in three or more groups. For unpaired parametric data in two groups, i.e., comparison of APD and TDR between control and LVH groups, statistical analysis was performed using unpaired t-test. chi 2 test was used for the comparison between two groups for event incidence such as occurrence of phase 2 EAD, R on T extrasystole, and polymorphic VT. Data are presented as means ± SE unless otherwise indicated.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

APD and QT interval in setting of LVH. LVH rabbits exhibited significant frequency-dependent APD and QT interval prolongation compared with control rabbits. Simultaneous recordings of APD from endocardium, subendocardium, and epicardium together with ECG from typical experiments of control and LVH rabbits are shown in Fig. 1. Similar data obtained in control (n = 15) and LVH (n = 15) rabbits are summarized in Fig. 2. Interestingly, APD in all three myocardial layers and QT interval showed no further prolongation in control rabbits when BCL was increased from 2,000 to 4,000 ms, but APD in subendocardium and endocardium and QT interval continued to increase significantly in LVH rabbits (P < 0.05, Fig. 2). Preferential prolongation of subendocardium and endocardium in LVH rabbits at slower pacing rates was associated with a marked increase in T wave amplitude and width.


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  		Fig. 1.   Rate-dependent changes in transmembrane action potentials and transmural electrocardiogram (ECG) in the left ventricular (LV) wedges isolated from control (A) and LV hypertrophy (LVH) (B) rabbits. Each trace shows superimposed action potentials recorded simultaneously from endocardium (Endo), subendocardium (Subendo), and epicardium (Epi), together with an ECG. More significant and preferential prolongation of action potential duration (APD) in Subendo and Endo at slower pacing rate in LVH rabbits was associated with an increase in T wave amplitude and width. Phase 2 early afterdepolarizations (EADs) were seen in subendocardium and endocardium of LVH rabbits in the absence of APD prolonging agents at a basic cycle length (BCL) of 4,000 ms.



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  		Fig. 2.   Rate-dependent changes in QT interval and APD measured at 90% repolarization (APD90) in control (A) and LVH (B) rabbits (n = 15 in each group). Preferential prolongation of APD in Subendo and Endo in LVH rabbits resulted in a significant QT prolongation as well as an increase in dispersion of repolarization across the ventricular wall (i.e., increased separation of APD curves between Epi and Subendo or Endo).

As opposed to what was observed in canine LV (25, 36), APD recorded from subendocardium in either control or LVH rabbits was not significantly different from that recorded from endocardium (Figs. 1-3), a phenomenon that may indicate a strong electrotonic influence between subendocardial and endocardial layers within rabbit LV. For example, APD recorded from subendocardium and endocardium at a BCL of 2,000 ms was 222 ± 6 and 228 ± 7 ms, respectively, in control rabbits, and 285 ± 20 and 288 ± 18 ms, respectively, in LVH rabbits, exhibiting no statistically significant difference. To determine transmural repolarization time, APD90 across LV wall in LVH and control rabbits was mapped in some initial experiments, and the data are shown in Fig. 3.


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  		Fig. 3.   Comparison of distribution of APD90 across the LV wall between LVH (n = 9) and control (n = 8) rabbits. Transmural distances at 0 and 100% represent Epi and Endo, respectively. *P < 0.05 and **P < 0.01, respectively, compared with control group. BCL was 2,000 ms.

TDR in setting of LVH. Preferential prolongation of APD in subendocardium and endocardium in LVH rabbits was associated with a marked increase in TDR that was particularly striking at slower pacing rates (Fig. 4). An increase in TDR due to delayed repolarization in subendocardial and endocardial sites resulted in an increase in transmural voltage gradient that manifested as a positive, broad, and tall T wave on the transmural ECG (Fig. 1).


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  		Fig. 4.   Comparison of transmural dispersion of repolarization (TDR), a difference between the longest and shortest repolarization time across LV wall between control and LVH rabbits. TDR increased more significantly in LVH rabbits than control at slower pacing rates. n = 15 in each group. *P < 0.05 and **P < 0.01 respectively, compared with control group.

Phase 2 EAD and polymorphic VT in setting of LVH. In LVH rabbits with the heart weight-to-body weight ratio (g/kg) >= 2.5, phase 2 EADs were generated from subendocardium and endocardium in all preparations (15 of 15) at BCLs of 2,000 to 4,000 ms. In LVH rabbits with the heart weight-to-body weight ratio <2.5, phase 2 EADs were observed in three of five preparations. Phase 2 EADs occurred in only 1 of 15 control rabbits at a BCL of 2,000 ms (Table 1).

                              
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  		Table 1.   Comparison of generation of phase 2 EAD, "R on T" extrasystoles, and polymorphic VT between control and LVH rabbits

The generation of phase 2 EAD from subendocardium and endocardium was accompanied by a marked APD prolongation in these two ventricular layers but not epicardium, resulting in an increase in T wave height and width on the ECG (Fig. 5). If the magnitude of phase 2 EAD and TDR was great enough, EAD could produce an R on T extrasystole on the ECG (trace 5 in Fig. 5 and Table 1). R on T extrasystoles, which always originated on the downslope of the preceding T wave, could initiate the onset of polymorphic VT in hypertrophied LV wedge preparations (Fig. 6 and Table 1).


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  		Fig. 5.   Phase 2 EADs were generated from Endo in a LVH rabbit. Each trace shows superimposed action potentials recorded simultaneously from Endo, Epi, and transmural ECG. Traces 1-5, sequences in which action potentials and ECGs were recorded. Increase in EAD magnitude in endocardium was associated with an increase in T wave amplitude and width. When EAD magnitude was great enough, EAD propagated transmurally, resulting in an "R on T" extrasystole on the ECG (trace 5).



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  		Fig. 6.   Phase 2 EAD as a trigger to initiate a short run of polymorphic ventricular tachycardia (VT) in an isolated hypertrophied LV wedge preparation in the absence of APD prolonging agents. Fewer action potentials in Endo recording than in the Epi indicate intramural conduction block. Note that intracellular impalement in Epi is partially lost during VT. BCL was 2,300 ms.

Interestingly, some LVH rabbits displayed alteration of T wave morphology, magnitude, and QT interval in every other two or three beats, sometimes even every four beats at BCLs of 2,000 and 4,000 ms (Fig. 7A). Acceleration of pacing rates abolished this phenomenon that was seen in one-third of LHV rabbits (5 of 15) in the absence of APD prolonging agents.The rapidly activating delayed rectifier K+ current (IKr) blocker d-sotalol (1-3 µmol/l) induced T wave alternans in six additional LVH preparations. This type of T wave alternans is probably different from a classic T wave alternans induced by relatively fast pacing rates, during which the T wave morphology changes in every other beat (8, 24). In a complete cycle, phase 2 EAD from subendocardium or endocardium usually developed during a beat with longer APD, and produced an R on T extrasystole during a subsequent beat. A giant and positive T wave was present during the beat with phase 2 EAD, whereas the immediate beat after an R on T extrasystole usually exhibited a very short APD in all myocardial layers that resulted in a very brief QT interval. Interestingly, ryanodine (1 µmol/l) abolished this type of T wave alternans and phase 2 EAD within 10 min in 5 of 5 LVH preparations with and without the pretreatment of low doses of d-sotalol (Fig. 7B). Whereas T wave alternans and EADs remained through the entire experiment (usually 4-5 h) in those LVH preparations without administration of ryanodine (n = 4, P < 0.01).


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  		Fig. 7.   A: T wave shape and QT interval changed in every other two beats in a LVH rabbit. During a complete cycle, a ventricular beat that was immediately after an R on T extrasystole exhibited very short APD in Endo and Epi, therefore resulting in a very brief QT interval. In the second beat, phase 2 EAD was probably generated from Endo, producing a giant and positive T wave. Phase 2 EAD conducted across ventricular wall in the third beat, resulting in an R on T extrasystole on the ECG. B: ryanodine (1 µmol/l) abolished this type of T wave alternans and phase 2 EAD within ~10 min. BCL was 4,000 ms.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

With the use of a recently developed arterially perfused LV wedge preparation isolated from LVH rabbits, we provide the first direct evidence from intracellular recordings that phase 2 EADs can be generated from intact hypertrophied LV wall in the absence of APD prolonging agents. Phase 2 EAD is associated with a malignant R on T extrasystole on the ECG, probably due to transmural conduction of EAD. Our present study also demonstrates for the first time that LVH is associated with a significant increase in TDR. All of these electrophysiological alterations play important roles in the development of polymorphic VT in the setting of LVH.

An increase in QT interval observed in LVH rabbits is consistent with APD prolongation observed in single myocytes or sliced ventricular tissue isolated from LVH animals (28, 30). Recent studies (1, 25, 35) have demonstrated that the QT interval in the dog is normally determined by the repolarization time of subendocardium (M cell). However, there was no significant difference in APD observed between subendocardium and endocardium in either control or LVH rabbits (Fig. 3). This may indicate the following possibilities: 1) there are no M cells in the rabbit, 2) more likely, there is a strong electrotonic influence between subendocardium and endocardium in rabbits, or 3) endocardial cells may function (although not anatomically) as M cells in rabbit LV because of intrinsically weak IKs (33).

Recent studies (10, 13) have demonstrated that LVH results in an increase in APD dispersion regionally on epicardial surface that may contribute to the development of ventricular arrhythmias. On the other hand, one of the most important electrophysiological alterations associated with LVH (renovascular hypertension model) observed in the present study was preferential prolongation of APD in subendocardium and endocardium (Figs. 1-3) and a resultant increase in TDR (Fig. 4). Although the ionic basis for APD dispersion on the same myocardial layer is unknown, TDR has been demonstrated to be largely determined by different ratio of rapidly to slowly activating components of delayed rectifier K+ current (IKr/IKs) among epicardium, subendocardium, and endocardium (18, 29). Enhanced heterogeneity of repolarization across hypertrophied rabbit LV wall observed in the present study may be due to transmural alteration in the ratio of IKr/IKs. The evidence that IKs but not IKr is reduced in endocardium and epicardium of LVH rabbits seems to support this hypothesis (33). Several studies (20, 31) have reported that LVH leads to a reduction in Ito primarily in isolated epicardial myocytes. Theoretically, such a reduction in Ito in epicardium would cause a decrease in TDR. We (23) and others (17, 27) have found an increase in Ito density in hypertrophied myocytes. The discrepant findings are probably due to different methods for producing LVH. A marked increase in TDR is thought to serve as a substrate for functional reentry that contributes to the maintenance of polymorphic VT (2, 11, 25, 35), and may provide a widened vulnerable window in which an initiating beat can be generated. On the body surfacce ECG, the Tpeak-Tend interval (the down slope of T wave) represents this vulnerable window (3, 35).

Of note, an extrasystolic ventricular beat capable of initiating polymorphic VT almost always occurs on the downslope of the preceding T wave, i.e., so-called malignant R on T phenomenon (7, 30, 32). As demonstrated in the present study (Figs. 1 and 5), the downslope of a positive T wave represents a dynamic repolarization state, in which the epicardium has completed its repolarization but subendocardium and endocardium are still in their repolarization phase 2 and 3. Therefore, one potential candidate that could produce an R on T extrasystole is phase 2 EAD generated in myocardial layers with longer APD capable of inducing a new action potential in myocardial layers with shorter APD. This is supported by indirect evidence that phase 2 EADs occur in a single ventricular myocyte in the presence of APD prolonging agents, but are unable to initiate a new action potential in the same myocyte (30). However, conclusive evidence that phase 2 EAD could be generated under in vivo conditions and induce a triggered beat has been lacking. First, phase 2 EAD may be generated not as easily in in vivo as in in vitro conditions because strong electrical cell-to-cell coupling within intact ventricular wall would blunt the generation of any potential fluctuations such as phase 2 EAD. Second, intracellular access to endocardium and intramural sites is practically impossible under in vivo conditions. The interpretation of "humps" or "wobbles" in final phases of the action potentials as EADs in in vivo experiments with the use of MAP recording technique may have been misleading. These EAD-like electrical activities may potentially represent the artifacts of unstable electrode contact or a change in contact pressure during ventricular systole (for detailed review, see Ref. 12). In addition, local heterogeneous repolarization, which is associated with QT prolongation, has been demonstrated to cause EAD-like activities in MAP recordings (14, 15).

In the present study, phase 2 EADs were recorded by using floating intracellular electrodes, from endocardial surface or subendocardial sites in arterially perfused LVH rabbit LV wedge, in which cells are electrically coupled. Several electrophysiological alterations in LVH may facilitate the generation of phase 2 EADs and resultant triggered beats within intact ventricular wall. These alterations include APD or QT prolongation (19), greater intracellular Ca2+ transient (26), altered cell-to-cell coupling (9), and an increase in TDR, as shown in the present study. Enhanced intracellular Ca2+ transient in ventricular hypertrophy and failure is associated with an increase in the Na+/Ca+ exchange activity that may provide enough inward current for the generation of phase 2 EAD (26). This is supported by the experiments in the present study, in which ryanodine, an agent that reduces SR function and intracellular Ca2+ (6), abolished phase 2 EAD. The poor cell-to-cell electrical coupling associated with LVH that reduces the electrical load of myocytes within the ventricular wall may enhance the expression of EAD within the intact ventricular wall. An increase in TDR would, on the other hand, facilitate propagation of phase 2 EAD that leads to an R on T extrasystole. Therefore, a marked increase in TDR may not only provide a substrate for functional reentry but also be essential for the formation of the initiating beat for the development of polymorphic VT.

Another interesting finding associated with LVH observed in the present study was that T wave and QT interval changed very regularly in every other two, three, or even four beats. Within a complete cycle, phase 2 EAD and an R on T extrasystole occur during the beats with longer APD, which is always followed by a very short action potential. This phenomenon may be related to T wave alternans due to profound electrical remodeling that may be associated with a robust SR function (6). The longer APD would load the SR with more calcium for the release during a subsequent beat that would exert a strong feedback on membrane currents, such as the inhibition of L-type Ca2+ current or perhaps an increase in Ca2+-dependent outward K+ current. This may result in the abbreviation of APD under conditions of increased intracellular Ca2+ (6). Our data that elimination of SR function with ryanodine abolishes this type of T wave alternans, phase 2 EAD, and R on T extrasystoles seem to support this hypothesis. However, the relation of this phenomenon to classical T wave alternans and arrhythmogenesis such as the generation of phase 2 EAD is unknown, and further investigation is required.

Clinical implications. LVH and associated heart failure predispose to malignant ventricular arrhythmias, leading to sudden cardiac death (19, 28). Several interesting ECG manifestations observed in LVH rabbits in the present study may enhance our understanding of arrhythmogenic ECG markers in patients with LVH and failure.

Enhanced beat-to-beat QT variability or atypical T wave alternans in LVH rabbits is associated with a marked beat-to-beat change in transmural dispersion of repolarization that may facilitate the development of polymorphic VT. In patients with dilated cardiomyopathy who have higher incidence of malignant ventricular arrhythmias, QT interval fluctuation is significantly larger than that observed in normal individuals (5). The QT interval variability and T wave alternans may potentially serve as a marker of arrhythmogenesis in patients with LVH and heart failure.

Previous studies (35) demonstrated that the appearance of T waves of large amplitude denotes the presence of large transmural dispersion of repolarization and refractoriness. The data obtained from LVH rabbits indicate that a widened and tall T wave may also reflect the presence of phase 2 EAD in subendocardium and endocardium. Unfortunately, the appearance of a giant T wave due to phase 2 EAD is indistinguishable on the ECG from that simply due to an increase in transmural dispersion of repolarization. However, a gradual increase in T wave size and a subsequent R on T extrasystole strongly suggest the presence of phase 2 EADs and the imminence of polymorphic VT.

Study limitations. Although the location of the initial phase 2 EAD can be estimated based on simultaneously recording of transmembrane action potentials from epicardium, subendocardium, and endocardium, the exact origin of EAD cannot be determined. The possibility that phase 2 EAD seen in subendocardium or endocardium may originate from Purkinje fibers cannot be excluded based on our data. In addition, the transmural conduction path of phase 2 EAD, which is associated with an R on T extrasystole and polymorphic VT, cannot be constructed because of too few intracellular recording sites. However, the cause-and-effect relationship among phase 2 EADs, R on T extrasystoles, and polymorphic VT is clearly established in the present study despite these limitations.

In conclusion, LVH is associated with preferential prolongation of APD in subendocardium and endocardium that leads to a marked increase in the QT interval and transmural dispersion of repolarization. Phase 2 EAD can be generated from subendocardium or endocardium in the absence of APD prolonging agents and result in an "R on T" extrasystole that may initiate polymorphic VT.


    ACKNOWLEDGEMENTS

We are grateful to Roe Wells and Yvonne Wiley for assistance in the preparation of the manuscript.


    FOOTNOTES

This study was supported by grants-in-aid from the American Heart Association, the Fourjay Foundation, and the Sharpe Foundation.

Address for reprint requests and other correspondence: G.-X. Yan, Main Line Health Heart Center, 100 Lancaster Ave., Suite 558, Wynnewood, PA 19096 (E-mail: yanganxin{at}cs.com).

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.

Received 24 April 2001; accepted in final form 19 July 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 281(5):H1968-H1975
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


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