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Cardiovascular Research 2001 50(3):454-462; doi:10.1016/S0008-6363(01)00223-1
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Copyright © 2001, European Society of Cardiology

Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia

Peter Taggarta,*, Peter M.I Suttona, Tobias Opthofb, Ruben Coronelc, Richard Trimletta, Wilfred Pugsleya and Panny Kallisa

aDepartments of Cardiology and Cardiothoracic Surgery, The Middlesex Hospital, London, and Hatter Institute for Cardiovascular Studies, University College Hospital, Grafton Way, London WC1E 6DB, UK
bDepartment of Medical Physiology, University Medical Center, Utrecht, The Netherlands
cDepartment of Experimental and Molecular Cardiology, Academic Medical Center, Amsterdam, The Netherlands

* Corresponding author. Tel.: +44-207-380-9880; fax: +44-207-388-5095 peter.sutton{at}ucl.ac.uk

Received 22 December 2000; accepted 11 January 2001


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Background: Studies in isolated tissues and myocytes show different repolarisation properties in subepicardium, midmyocardium and subendocardium. Whether these differences are present in vivo and are relevant to humans has been the subject of controversy. Our objectives were (1) to ascertain whether transmural repolarisation gradients are present in humans, (2) to determine whether the greater sensitivity of subepicardial cells to ischaemia in vitro is manifest during early ischaemia in humans in vivo. Methods and results: We studied 21 patients during routine coronary artery surgery. Unipolar activation recovery intervals (ARI) were recorded from five transmural locations between subepicardium and subendocardium in the left ventricular wall. A pacing protocol spanned a range of cycle lengths from a cycle length of 300 ms to the maximum permitted by the intrinsic atrial activity. Following the onset of cardiopulmonary bypass recordings were obtained before (control) and during a 3-min period of global ischaemia. During control transmural ARIs were homogeneous between 300 and 1500 ms (ventricular pacing) and 750 and 1500 ms (atrial spontaneous beats). During ischaemia, ARIs shortened similarly at all transmural electrode sites and transmural homogeneity was maintained. Conclusions: Transmural repolarisation differences within the ventricular wall of the human heart were absent at cycle lengths within the physiological range but also during prolonged cycles. During early (global) ischaemia repolarisation changed equally in subepicardial and subendocardial regions and transmural homogeneity of repolarisation was preserved.

KEYWORDS Ischaemia; Repolarisation

This article is referred to in the Editorials by M.A. Vos and G.M. Jungschleger (pages 423–425) and C. Antzelevitch (pages 426–431) in this issue.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Studies in isolated tissues and myocytes from different layers within the ventricular wall show different electrophysiological properties [1–4]. Cells from the midmyocardial region characteristically exhibit greater prolongation of action potential duration at slower rates than cells from subepicardial or subendocardial locations. The presence of M cells has been confirmed in canines [5–10] as well as in guinea pig [11], rabbit [12], pig [13] and humans [14,15]. However, whether the transmural repolarisation gradients suggested by these in vitro studies are manifest in vivo at physiological heart rates and therefore may be relevant to humans has been the subject of ongoing controversy [16–18].

Several studies in in vivo animal models have been unable to detect physiologically significant transmural repolarisation gradients [8,19–21]. A proposed explanation was the presence of cell coupling and local electrotonic current flow tending to mask intrinsic repolarisation differences between individual cells and adjacent cell groups [22–24]. Other workers on the other hand, have reported transmural repolarisation gradients in ventricular wedge preparations [18] and in intact canines [25,26], but only at unphysiologically long cycle lengths.

This discrepancy has fuelled the suggestion that the inability to detect repolarisation gradients in some in vivo studies may relate to aspects of methodology [18]. In particular the use of pentobarbitone [27] or {alpha}-chloralose as anaesthetic agents and bipolar electrical recording techniques have been suggested to attenuate or underestimate intramural heterogeneity in repolarisation [18].

Despite its potential importance information in humans in vivo is lacking. In view of the electrophysiological differences between different animal species and the uncertainties of extrapolation we have performed measurements in patients. We measured activation recovery intervals at five intramural sites spanning subepicardium through mid myocardium to subendocardium in the left ventricular wall during routine cardiac surgery. Barbiturates were not used during the anaesthetic procedure and unipolar as distinct from bipolar recordings were made thereby eliminating two potentially important methodological difficulties. A series of heart rates was studied to encompass a clinically relevant range. In addition we have studied a short period of global ischaemia in order to determine whether the sensitivity of subepicardial compared to subendocardial regions to ischaemic conditions seen in animal preparations in vitro [28] is present during early ischaemia in human hearts in vivo. Global but not regional ischaemia permits assessment of intrinsic regional differences. Our study shows no relevant midmyocardial delay of repolarisation during physiological and prolonged cycle lengths, neither in control conditions, nor during early ischaemia.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
We studied 21 patients undergoing routine coronary artery surgery. Patient details are shown in Table 1. The study was approved by the Hospital Ethical Committee and written informed consent was obtained from all patients.


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  		Table 1 Patient detailsa

 
2.1 Anaesthesia and surgery
All patients were anaesthetised according to a standard technique. Drugs included morphine, hyoscine (premedication), midazolam, fentanyl, pancuronium, nitrous oxide in oxygen, and isoflurane. Barbiturates were not used during any part of the anaesthetic procedure. Following mid-line sternotomy, the left internal mammary artery was mobilised for subsequent anastomosis. Routine cardiopulmonary bypass was instituted using a membrane oxygenator (Bard Quantum) primed with 1.5 l of Hartman's solution (131 mM sodium, 5 mM potassium, 2 mM calcium, 111 mM chloride, 29 mM lactate). An ascending aortic cannula and a single right atrial venous cannula were placed and the patient was perfused at 2.4 l/m2/min with a Shiley Stockert or Jostra pump in a pulsatile mode. Normothermia was maintained. The studies were carried out before the routine surgical procedure was continued.

2.2 Electrogram recordings
Unipolar electrograms were recorded from the anterior left ventricular free wall using a plunge electrode with five electrode terminals spanning from subepicardium to subendocardium. We have previously described the use of the electrode to determine transmural activation orders during non-ischaemic and ischaemic conditions in patients during cardiac surgery [29]. In brief, the electrodes were platinum with an interelectrode spacing (centre to centre) of 1.5 mm and diameter of 0.3 mm. The shaft was constructed from a 21-Gauge stainless steel needle and attached to a flange with eyelets to enable the flange to be sutured to the epicardium. The most superficial (subepicardial) electrode was located 1 mm from the flange which was flush with the epicardium. As the diameter of the electrodes was 0.3 mm the most superficial recording terminal was 0.85 mm from the flange. In addition the width of the epicardium and subepicardial fat is estimated at 0.5–1.0 mm. Therefore, the recording at the subepicardial terminal is effectively an epicardial measurement. The needle electrode was manufactured based on known echocardiographic assessment of ventricular wall thickness in the area where the recordings were to be made (left ventricular anterior wall) [30]. On this basis we would anticipate that the subendocardial electrode would have been about 2 mm from the endocardial surface. The rib retractors served as attachment for the indifferent electrode. Signals were fed to a Gould isolated preamplifier model (11-5407-58) and then to a Gould Universal amplifier model (13-4615-58) with an input impedance of 109 {Omega} and an output of 1 V for 40 mV input and frequency response of 300 Hz. The signals were digitised at a sampling rate of 1000/s using a CED 1401-S (Cambridge Electronic Design).

2.3 Ischaemia
A surgical technique used to achieve a bloodless operating field during anastomosis of the coronary artery grafts is ‘aortic cross clamping’. When the patient is on cardiopulmonary bypass a clamp is placed across the aorta between the input from the pump oxygenator in the ascending aorta and the coronary arteries thereby obstructing blood flow to the coronary arteries while maintaining perfusion of the systemic circulation. This results in global ischaemia of the myocardium which is maintained during the time required for the anastomosis. It has been shown that a preliminary short period of ischaemia induces a preconditioning effect in these patients [31] and is, therefore, expected to be protective during the subsequent longer periods of ischaemia necessary for each coronary artery graft. Since the preconditioning effect on the myocardium does not occur until after a period of reflow following the preconditioning ischaemia it is therefore possible to use this period to study global ischaemia in unpreconditioned myocardium [29,32].

2.4 Protocol
The plunge electrode was inserted into the mid left ventricular wall shortly after sternotomy and secured in position using two sutures to the epicardium. The electrode remained in position during the preparatory surgery which allowed sufficient time (about 30–40 min) for the resolution of injury potentials [8] before recordings were made. On cardiopulmonary bypass right ventricular pacing was established at 2x diastolic threshold at 2-ms pulse width. We have previously observed a wide variation in sinus node activity and response time in these patients, not only between patients but also varying in the same patients over time. In order to acquire data during activation from a ventricular site and supraventricular site and incorporate the largest possible intervals without time consuming protocols the following two test sequences were used. During steady state right ventricular pacing at cycle length 500 ms (S1) an early test pulse (S2) was interpolated at a cycle length of 300 ms followed by a 2-s pause before pacing was resumed. The time interval between the last paced beat and the emergence of spontaneous atrial beats was noted. After a delay of 20 cycles, a second test sequence was introduced in which the S2 pulse was changed from a short interval used in sequence 1 to the longest possible S1–S2 interval possible while maintaining capture, i.e. before the emergence of spontaneous atrial beats. A 3-min period of global ischaemia was then created and the two test pulse sequences repeated during the last 30 s of ischaemia. Normothermia was maintained at 36.5°C during the recordings. Intramural temperature in the mid anterior left ventricle was measured directly (Needle Probe type A-K20, Ellab, Denmark) in five patients and varied by less than 0.3°C from subendocardium to subepicardium there being no consistent pattern or discernible gradient.

2.5 Analysis of data
Activation recovery intervals (ARIs) were measured from dV/dtmin of the initial downstroke to dV/dtmax of the T wave using an interactive computer program. Only signals which met accepted criteria were used [33,34]. Specifically, recordings were not made from areas of infarction. Signals in which the first derivative of the T wave was biphasic or did not show a clear dV/dtmax were excluded from the analysis. Data are shown as mean±S.E.M. Analysis of variance (ANOVA) was used for multiple comparisons.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
Fig. 1 shows electrograms recorded at the five intramural electrodes during control (left hand panel) and during ischaemia (right hand panel). During control the range of ARIs is 14 ms. Moreover, the ARIs at the midmyocardial electrodes 2, 3 and 4 were all shorter than at the subendocardial electrode. During ischaemia ARIs show the expected shortening at each electrode and the range of ARIs remains unchanged at 12 ms. Again, all three midmyocardial electrodes display a shorter ARI than at the subendocardial electrode despite the possibility of decreased intracellular coupling due to ischaemia. In only two of 21 patients was the longest ARI observed at one of the midmyocardial electrodes 2, 3 or 4 during control and ischaemia. In these two patients the maximum difference in ARI between electrode sites 2, 3 or 4 on the one hand and 1 or 2 on the other was 8 and 14 ms, respectively.


Figure 1
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  		Fig. 1 Electrograms recorded at five intramural sites between subepicardium (sub epi) and subendocardium (sub endo) from the mid left ventricular wall during right ventricular pacing in a patient with coronary heart disease. This example is from patient 12 who had no previous MI, good ventricular function and no haemodynamically significant stenosis of the coronary vessel supplying the recording site. Values for ARIs are shown for each electrogram. During control only a small ARI gradient is present (left hand column). During ischemia ARIs shorten but the transmural gradient remains similar to control (cycle length 750 ms).

 
3.1 Normoxia
Cumulative data for activation recovery intervals (ARIs) during control right ventricular pacing are shown in Fig. 2. ARIs were homogeneous at each of the five intramural electrode terminals. This was the case for each of the cycle lengths tested, i.e. the steady state cycle of 500 ms, interpolated short cycles of 300 ms and the long cycles (976±123 ms). As the long cycles span a range of cycle lengths from 700 to 1500 ms these data were subdivided into those below 1000 ms (mean 810±91 ms) and those above 1000 ms (mean 1161±158 ms) in order to uncover prolongation of ARIs in the midmyocardium due to M cells at the longer cycle lengths, which proved not to be the case. ARIs for atrial spontaneous beats during control are shown in Fig. 3. Again there was no significant difference in mean ARI between any transmural electrode site either for the group as a whole (mean cycle length 1043±106 ms) or when the data were subdivided as in Fig. 2 into cycle lengths below 1000 ms (mean 852±92 ms) and above 1000 ms (mean 1259±122 ms). Statistical analysis of transmural gradients under all conditions studied revealed no statistically significant differences between any of the electrode sites (Fig. 3).


Figure 2
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  		Fig. 2 Activation recovery intervals (ARIs) at the five transmural electrode terminals spanning from subepicardium (Epi-electrode 1) through mid myocardium to subendocardium (Endo-electrode 5). All values are shown for steady state ventricular pacing (cycle length 500 ms), for interpolated early test pulses (cycle length 300 ms), and for interpolated long intervals (mean cycle length 976±123 ms). The data for the long intervals are subdivided into those with cycle lengths above 1000 ms and below 1000 ms (dashed lines). No significant transmural ARI differences were present at any cycle length. n for individual points: (filled circles) range 16–20, and for subdivided data (hollow circles) range 8–10.

 

Figure 3
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  		Fig. 3 Activation recovery intervals (ARIs) at the five transmural electrode terminals spanning from subepicardium (Epi-electrode 1) through subendocardium (Endo-electrode 5). ARI values are shown for spontaneous atrial beats (mean cycle length 1043±106 ms). The data are subdivided into those with cycle lengths above 1000 ms and below 1000 ms (dashed lines). No significant transmural ARI differences were present. n for individual points: (filled circles) range 16–17, (hollow circles) range 8–9.

 
3.2 Ischaemia
Our second objective was to ascertain whether the greater sensitivity of isolated canine myocytes from subepicardial regions compared to cells from subendocardial regions to ischaemic conditions is evident during the first minutes of ischaemia in humans in vivo. Fig. 4 shows that during a 3-min period of global ischaemia ARIs shortened homogeneously at all cycle lengths. Figs. 5 and 6Go show that the transmural homogeneity of ARI observed under control conditions persisted during early ischaemia. No statistically significant differences were seen between the five intramural electrode sites during right ventricular pacing at the short cycles (300 ms), at steady state (500 ms), and long cycles (983±230 ms) (Fig. 5). During atrial spontaneous beats (cycle length 1029±176 ms) similar observations were made (Fig. 6). Again subdivision of the data into cycle lengths below and above 1000 ms, i.e. 830±83 and 1193±195 ms for right ventricular pacing and 881±69 and 1178±108 ms for atrial beats did not disclose any statistically significant regional ARI differences (Figs. 5 and 6Go).


Figure 4
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  		Fig. 4 Activation recovery intervals (ARIs) during control and after 2.5 min of global ischemia. Mean values are shown separately for subepicardium, mid myocardium and sub endocardium. During ischemia ARIs shorten to a comparable extent in all three regions at each of the cycle lengths tested.

 

Figure 5
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  		Fig. 5 Activation recovery intervals (ARIs) at the five transmural electrode terminals after 2.5 min of global ischemia. Data for ventricular paced beats are shown as in Fig. 2. No significant transmural ARI differences were present. n for individual points: (filled circles) range 14–20, and for subdivided data (hollow circles) range 7–11.

 

Figure 6
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  		Fig. 6 Activation recovery intervals (ARIs) at the five transmural electrode terminals after 2.5 min of global ischemia. Data for atrial spontaneous beats are shown as in Fig. 3. No significant transmural ARI differences were present. n for individual points: (filled circles) range 17–18, (hollow circles) range 8–9.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
This study shows that repolarisation across the left ventricular wall of human hearts during normal and prolonged cycle lengths is homogeneous both under control conditions and during early ischaemia. The striking heterogeneity of repolarisation observed in vitro in isolated tissues and myocytes from different locations within the ventricular wall was not evident in these human studies in vivo. A 2.5-min period of global ischaemia resulted in shortening of ARI intervals (Figs. 2 and 3Go). However the shortening was of similar magnitude in subepicardium and at other transmural sites (Figs. 2 and 3Go). We did not observe preferential ARI shortening in subepicardial regions despite the known greater sensitivity of ventricular myocytes isolated from subepicardium to ischaemic conditions compared to cells isolated from subendocardial regions [28].

The absence of any significant transmural repolarisation gradient that we observed under control conditions is in keeping with some in vitro studies in animal hearts [8,19–21] but in contrast to others [25,26]. Two studies employed refractory periods as a measure of repolarisation. Janse et al. [19] observed only small and inconsistent variation in effective refractory period at eight intramural sites in porcine hearts. Bauer et al. [21] recently reported the absence of intramural differences in refractory period at four intramural sites in canine heart either under control conditions or in the presence of propafenone, dofetilide or the Iks blocking agent chromanol 293b. Two studies by Anyukhovsky et al. [8,20] using ARI intervals in canines were unable to detect significant transmural repolarisation differences. On the other hand studies in canines by El Sherif et al. [25] using ARI intervals and another study using intramural monophasic action potentials [26] both reported transmural dispersion of repolarisation with later repolarisation in midmyocardium, but only at unphysiologically long cycle lengths. Factors related to cycle length, methodology and cellular coupling may underlie these conflicting reports and the lack of any demonstrable transmural repolarisation gradient we observed in the present study in humans.

4.1 Cycle length
Characteristic of cells from mid myocardium is a steep cycle length/APD relation such that at long cycles APD prolongs more than cells from endocardial or epicardial regions. This minimises dispersion of repolarisation at short cycles and maximises it at long cycles. One possibility therefore is that the cycle lengths we used were not long enough for intrinsic repolarisation differences to become manifest. However, in vitro studies show substantial repolarisation differences within the range of cycle lengths that we employed, for example Fig. 5 in Ref. [1] and Fig. 4 in Ref. [14]. At a cycle length of 1000 ms, i.e. within the range of cycle lengths in the present study, APD in human ventricular myocytes from different intramural layers varied by in excess of 100 ms [14] while the in vivo difference in the present study was about 10 ms. Although Anyukhovsky and co-workers [8,20] were unable to show any significant repolarisation gradient in canines at a longer cycle length in vivo (2000 ms) they demonstrated significant repolarisation gradients at a shorter cycle length in vitro (1000 ms). These investigators suggested the reason for the differences between in vivo and in vitro preparations lay in decreased cellular coupling in the latter. This demonstrates that in vivo–in vitro differences predominate over cycle length differences.

4.2 Methodology
Several methodologic aspects have been proposed to underlie the absence of demonstrable transmural repolarisation gradients in in vivo studies. Some anaesthetic agents have been shown to reduce transmural heterogeneity of repolarisation, notably pentobarbitone and {alpha}-chloralose [18,27]. Barbiturates were not used for any part of the anaesthetic procedure in our studies in patients reported here. In our patients anaesthesia was maintained with isoflurane as used by El Sherif et al. [25] in canines in which repolarisation gradients were observed. Isoflurane does cause a degree of cellular uncoupling [35] and therefore produces optimal conditions for the detection of transmural repolarisation gradients. In spite of this, no significant transmural repolarisation gradients were detected in our study. It has been suggested that the absence of prolonged ARIs in the intramural tissue layer results from the use of bipolar recording techniques [18]. Therefore we have used unipolar recording techniques. This renders optimal circumstances for the detection of small transmural ARI differences. Nevertheless such differences were not observed.

4.3 Electrical coupling
We have observed neither physiological nor statistically significant transmural differences, although this study was performed in patients with compromised and possibly remodeled myocardium. It can be anticipated for reasons explained below that in more effectively coupled healthy myocardium transmural differences are absent as well. In cells that are well coupled electrically local current flow exerts an averaging effect on APD tending to shorten the longer action potentials and lengthen the shorter action potentials [22,23]. This would be consistent with the presence of large APD differences between isolated cells harvested from different transmural sites and a smaller repolarisation gradient in tissue slices or isolated perfused multicellular preparations where intercellular coupling is decreased. Consequently, repolarisation gradients are absent or trivial in intact hearts as previously suggested by Anyakovsky et al. [17] and Coronel et al. [24] The absence of preferential shortening of ARI in subepicardium during ischaemia in this study, in spite of the known greater sensitivity of ventricular myocytes to an ischaemic environment in vitro [28] could be explained by electrotonic current to the subepicardium from a large volume of underlying myocardium with a lesser intrinsic sensitivity to ischaemia. In the whole heart environment myocytes are also mechanically coupled and subject to repetitive wall stress the nature and intensity of which varies between endocardium and epicardium. It is possible, although speculative, that the sequence of contraction may play a regulatory role in the sequence and timing of repolarisation which is absent in in vitro preparations [36].

4.4 Methodological considerations
Several aspects of methodology and study design require mention. Patients with previous MI were included. Although we did not record from the infarcted territory the presence of previous MI may have affected the properties of adjacent tissue due to remodeling. The duration of ischaemia in these studies was very short, whereas in clinical practice periods of ischaemia may be very much longer. Electrophysiological effects would be expected to change over time particularly with the development of uncoupling which may then unmask intrinsic transmural repolarisation gradients. Patients referred for surgery are an inhomogeneous group in many ways such as medication etc. However the absence of repolarisation gradients was a consistent finding. The present studies were performed while the patients were on cardiopulmonary bypass, i.e. the heart was in a non-working state. It is likely that this resulted in a small prolongation of action potential duration as a result of absence of mechano-electrical feedback [37]. In other non-working mammalian preparations (like, e.g. the wedge preparation) transmural gradients have been described. Indeed unloading may uncover such gradients. The fact that in these human hearts gradients were absent, despite the presence of conditions which would be expected to increase transmural gradients, underscores that intercellular coupling even in compromised hearts is strong enough to abolish intrinsic transmural gradients. It may be argued that averaging of the data of disparate groups of patients or of myocardial tissue with different characteristics (e.g. normally perfused and poorly perfused) may mask underlying transmural gradients. However, this is not the case. In patients with good myocardial perfusion transmural gradients were not different from patients with poor myocardial perfusion. Fig. 1 illustrates the absence of a gradient at a site with normal perfusion. Our findings appear to be at variance with classical teaching that an endocardial to epicardial gradient of repolarisation is the cause of the body surface T-wave. We only observed about 10–20 ms difference in repolarisation time. However, larger endocardium to epicardial gradients may be present between apical and basal endocardium or epicardium. Our study was designed to detect intramurally increased delayed moments of repolarisation rather than the maximum difference between an endocardial and an epicardial site which may occur at not directly opposed myocardial sites. Only one site was monitored in each patient and therefore we cannot exclude the possibility that other regions might have demonstrated some degree of heterogeneity. However the results we obtained were similar in all patients studied.

4.5 Clinical relevance
Our findings may have implications for arrhythmias in which dispersion of repolarisation is important. Our data suggest that the intrinsic transmural differences in repolarisation are not likely to be unmasked by bradycardia or sinus pauses. During ischaemia, heterogeneity created by repolarisation differences across the lateral border zone may be more arrhythmogenic than that across the wall. One of the implications of our finding is that a critical degree of cellular uncoupling between myocardial cell layers is a prerequisite for creation of an arrhythmogenic substrate [38]. The situation may be different in circumstances that substantially increase the magnitude of intrinsic cellular repolarisation differences (e.g. drugs with class III action, more severe ischaemia) or reduce the influence of cell coupling (e.g. severe ischaemia) but on the other hand recent data in intact canine ventricle do not support this [21]. By and large, transmural differences in the moment of recovery of excitability seem less important under normal conditions, in the presence of agents with class III action, as well as early during acute ischaemia than previously assumed.

Time for primary review 39 days. Dr. M.R. Rosen acted as guest-editor for this article.


   Acknowledgements
 
We would like to express our thanks to the staff off the operating theatres for their help; and to W. Potter for technical electronic expertise. This work was supported by the British Heart Foundation (PT).


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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