© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Transmural repolarization gradients in vivo: the flukes and falls of the endocardium
Department of Cardiology, University Hospital Maastricht, Cardiovascular Research Institute Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
* Corresponding author. Tel.: +31-43-387-5097; fax: +31-43-387-5104 m.vos{at}cardio.azm.nl
Received 26 February 2001; accepted 26 February 2001
See article by Taggart et al. [3] (pages 454–462) in this issue.
In the early 90's the Antzelevitch group described the M-cell [1], in which the M originally refers to midmyocardium but has also been used for Masonic or Moe, as an acknowledgement to the people behind the initiative to perform research in Utica, NY. Since its introduction there has been accumulating in-vitro evidence that this cardiac cell type electrophysiologically and pharmacologically differs from (sub-)epi- and (sub-)endocardial cells of the left ventricular free wall.
In vitro studies revealed that the intrinsic differences in morphology and duration of the action potential (APD) of the different cell layers are emphasized under less physiological circumstances, such as bradycardia, sudden rate changes or acquired long QT, which can be induced by either drugs or pathological conditions. These M-cells could be an important arrhythmogenic factor, responsible for both initiation and perpetuation of ventricular arrhythmias.
The question whether dispersion of repolarization exists also in the in-vivo situation is keeping many researchers busy. Anyukhovosky et al. [2] have provided us with a theoretical explanation about the discrepancy in findings between groups on the basis of intercellular coupling. Because the intact heart cell-to-cell communication is considered optimal, absence or a very small transmural dispersion of repolarization will be seen. The greatest differences in APD will therefore be visualized in isolated myocytes obtained from the different layers.
However, there are important technical limitations, which will influence the visualization of repolarization within the myocardial wall. Understanding these limitations is crucial to determine the role of the M-cell in the repolarization gradients within the whole heart situation. The complex ventricular architecture, the repolarization parameter, the inter-electrode resolution, the location and regularity of the focus and the anesthesia are all of methodological importance.
The heterogeneity in the transmural APD is therefore difficult to visualize in situ, especially considering there is already a gradient existing between endo- and epicardium. A hypothetical contribution of the M-cell should give a biphasic pattern: an increase from (sub)endocardium to the M-layer(s), and a decrease from M to (sub)epicardium with an epicardial APD shorter than the APD of the (sub)endocardium (black bars; Fig. 1). Thus, the lack of consistency in describing such a biphasic gradient in vivo could be based on lack of definitions, discrepancies in methodology and absence of repolarization enhancing (patho)physiological circumstances.
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In this issue of Cardiovascular Research, Taggart and coworkers [3] are the first to investigate the repolarization gradient in a selected group of patients by using a plunge electrode with 5 recording sites showing electrograms and ARIs. We would like to compliment them with this tremendous effort to obtain signals from 21 subjects. They took basic research a step further by lifting the in-vivo search for the M-cell to the clinic.
Their technique, however, has limitations possibly prohibiting the visualization of the detailed transmural gradient of repolarization. To prove the contribution of the M-cell, the different layers to this gradient should be exactly recorded. According to textbook literature, a mean left ventricular free wall thickness in humans is 10.9±2 mm [4]. Until now, no data are available about the size of the endocardial, midmyocardial and epicardial layers. Based on a few experiments, we believe that the endocardial layer is thin (only 1 to 2 mm thick), so we are left with an enormous part of the transmural wall that belongs to the midmyocardium (Fig. 1). Therefore, caution should be taken to truly visualize the endocardium (or epicardium).
Two studies claim to have found the existence of M-cells with an unprecedented contribution to transmural APD heterogeneity in canine in vivo models [5,6]. Both studies used needle technology recording either APDs or unipolar electrograms from which activation recovery intervals (ARIs) were determined. In the study of Weissenburger et al. a needle with four recording electrodes was placed in the LV anterior wall with the most distal electrode (endocardial) not in contact with the wall but 1-2 mm inside the cavity. In their experiments, the application of sotalol prolonged the APD, with the largest increase sub-endocardially, in such a way that a gradual declining gradient from endo- to epicardium changed into a biphasic curve. El-Sherif et al. showed, with needles containing 8 electrodes, the longest ARI, after anthopleurin-A administration, to be located in the midmyocardium [6].
In our experiments in the chronic AV-block (CAVB) dog [7], we were able to describe both gradual declining and biphasic gradients going from sub-endo- to sub-epicardium with sometimes huge inter- and intra-individual differences present. The inter-electrode distance played a crucial role in defining the exact shape of the gradient. In a dog with compensated bi-ventricular hypertrophy (Fig. 1) we show that decreasing the inter-electrode distance from 3 to 1 mm the endocardial site revealed a change in gradient from gradual declining to biphasic. We confirmed that we reached the endocardium by pacing and visualizing the needle postmortem. Other options would be the registration of cavity potentials or the use of ultrasound.
Looking carefully at the study by Taggart, one may raise the question whether the endocardium truly has been visualized. A needle with a length of 7 mm (Fig. 1) could be too short to reach the endocardium. Therefore, their claim that the position of the most distal electrode is 2 mm from the endocardium can be questioned. Especially when one considers that angle of placement is important. Because if the needle enters the wall not completely perpendicular the distance will be larger than 2 mm. Moreover, the thickness of the endocardium could be overestimated. Therefore it could be possible that the decrease in APD from M-cell to endocardium is not seen due to lack of resolution or due to the inability to reach this part of the ventricular wall.
Finally, going from endo- to epicardium in the CAVB heart will show a change in T-wave morphology with negative, positive, and biphasic T-waves present (Fig. 2). By pacing from the right ventricle, the activation and rate will be kept stable during the course of the experiment. But a change in activation will have an influence on cardiac memory, which is possibly influencing ventricular APD. Normally, the site of earliest activation has the longest APD. If the activation pattern is changed this longest APD will be memorized for hours and repolarization measurements will not give a true value. Local T-wave morphology will change accordingly. The statement of the authors that they excluded signals with biphasic T-wave is in this regard worrisome, because these changes in T-wave morphology could contribute to the APD differences.
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So, although the discussion whether or not M-cells contribute to repolarization gradients and possibly to arrhythmogenesis in the human heart awaits further investigations, it are studies like this that provide important data for discussion.
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- Sicouri S., Antzelevitch C. A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. The M cell. Circ Res (1991) 68:1729–1741.
[Abstract/Free Full Text] - Anyukhovsky E.P., Sosunov E.A., Gainullin R.Z., Rosen M.R. The controversial M cell. J Cardiovasc Electrophysiol (1999) 10:244–260.[Web of Science][Medline]
- Taggart P., Sutton P., Opthof T., Coronel R., Trimlett R., Pugsley W.B., Kallis P. Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia. Cardiovasc Res (2001) 50:454–462.
[Abstract/Free Full Text] - Braunwald E. Heart disease: a textbook of cardiovascular medicine, 5th ed. W.B. Saunders Company, 1997, p. 426.
- Weissenburger M.D., Nesterenko V.V., Antzelevitch C. Transmural heterogeneity of ventricular repolarisation under basline and long QT conditions in the canine heart in vivo: Torsade de Pointes develops with halothane but not pentobarbital anesthesia. J Cardiovasc Electrophysiol (2000) 11:290–304.[Web of Science][Medline]
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- Jungschleger JG, Vos MA, de Bakker JM, van der Hulst FF, Anyukhovsky E, Opthof T, Wellens HJ. Transmural and transseptal repolarzation gradients in the chronic AV-block dog. Europace 2000;1:VII.2.
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[Abstract/Free Full Text]
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