Intercellular coupling through gap junctions masks M cells in the human heart

Conrath, Chantal E.; Wilders, Ronald; Coronel, Ruben; Bakker, Jacques M.T. de; Taggart, Peter; Groot, Joris R. de; Opthof, Tobias

doi:10.1016/j.cardiores.2004.02.016

Cited by 101 publications

(50 citation statements)

References 34 publications

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“…For instance, measurement of the human ventricles during cardiac surgery, rather than isolated cells or a ventricular wedge, produced no significant transmural heterogeneity of repolarization (42). The electronic cancellation effect introduced by intercellular coupling through gap junctions is considered the cause of these observations in intact preparations (5,41), although experimental artifact has also been suggested (1). During surgery or in animal experiments, subjects receive anesthetic agents that may block sodium and/or delayed rectifier potassium currents, causing preferential shortening of the APD of M cells (31).…”

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confidence: 99%

Transmural and apicobasal gradients in repolarization contribute to T-wave genesis in human surface ECG

Okada

Washio

Maehara

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The cellular basis of the T-wave morphology of surface ECG remains controversial in clinical cardiology. We examined the effect of action potential duration (APD) distribution on T-wave morphology using a realistic model of the human ventricle and torso. We developed a finite-element model of the ventricle consisting of ϳ26 million elements, including the conduction system, each implemented with the ion current model of cardiomyocytes. This model was embedded in a torso model with distinct organ structures to obtain the standard ECG leads. The APD distribution was changed in the transmural direction by locating the M cells in either the endocardial or epicardial region. We also introduced apicobasal gradients by modifying the ion channel parameters. Both the transmural gradient (with M cells on the endocardial side) and the apicobasal gradient produced positive T waves, although a very large gradient was required for the apicobasal gradient. By contrast, T waves obtained with the transmural gradient were highly symmetric and, therefore, did not represent the true physiological state. Only combination of the transmural and the moderate apicobasal gradients produced physiological T waves in surface ECG. Positive T waves in surface ECG mainly originated from the transmural distribution of APD with M cells on the endocardial side, although the apicobasal gradient was also required to attain the physiological waveform.electrocardiogram; computer simulation; T wave; body surface map; M cells DESPITE ITS LONG HISTORY AND worldwide use in clinical cardiology for the diagnosis of various heart diseases, the cellular origin of the ECG waveform is not fully established. In particular, the genesis of the T wave remains controversial, largely because of its implication in arrhythmogenesis (1,4,20,22). The T wave was originally considered to result from the heterogeneity of repolarization of the ventricle in the apicobasal direction (19). However, more recently, the transmural difference (gradient) of repolarization is considered important, as supported by the discovery of M cells isolated from the canine ventricular wall (2, 32). M cells are distributed in the deep subendocardium in the anterior wall, but are shifted to the deep subepicardium in the posterior wall, and are characterized by a longer action potential duration (APD) compared with the epicardial and endocardial myocytes, creating a significant gradient (1). Subsequent studies identified similar type of cells in guinea pig, rabbit, pig, and human ventricular tissues (8,33,35,51).However, when measurements are made in more intact preparations, there is accumulating evidence that the APD of M cells becomes shorter, resulting in smaller transmural dispersion (23). For instance, measurement of the human ventricles during cardiac surgery, rather than isolated cells or a ventricular wedge, produced no significant transmural heterogeneity of repolarization (42). The electronic cancellation effect introduced by intercellular coupling through gap junctions is considered t...

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confidence: 99%

Transmural and apicobasal gradients in repolarization contribute to T-wave genesis in human surface ECG

Okada

Washio

Maehara

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…3, panel IV, as well as in previous studies (Yan et al, 1998b;Gima and Rudy, 2002;Idriss and Wolf, 2004;Ritsema van Eck et al, 2005). It should be noted however, that, while there is a large body of evidence supporting the existence of transmural heterogeneities in ionic currents and electrophysiological properties of ventricular tissue, some experimental studies have documented little or no transmural differences in APD in vivo (Anyukhovsky et al, 1996(Anyukhovsky et al, ,1999Taggart et al, 2001;Conrath et al;.…”

Section: Transmural Electrophysiological Heterogeneities In the Ventrmentioning

confidence: 54%

The role of transmural ventricular heterogeneities in cardiac vulnerability to electric shocks

Maharaj

Blake

Trayanova

et al. 2008

Progress in Biophysics and Molecular Biology

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Transmural electrophysiological heterogeneities have been shown to contribute to arrhythmia induction in the heart; however, their role in defibrillation failure has never been examined. The goal of this study is to investigate how transmural heterogeneities in ionic currents and gap-junctional coupling contribute to arrhythmia generation following defibrillation strength shocks. This study used a 3D anatomically realistic bidomain model of the rabbit ventricles. Transmural heterogeneity in ionic currents and reduced sub-epicardial intercellular coupling were incorporated based on experimental data. The ventricles were paced apically, and truncated-exponential monophasic shocks of varying strength and timing were applied via large external electrodes. Simulations demonstrate that inclusion of transmural heterogeneity in ionic currents results in an increase in vulnerability to shocks, reflected in the increased upper limit of vulnerability, ULV, and the enlarged vulnerable window, VW. These changes in vulnerability stem from increased post-shock dispersion in repolarisation as it increases the likelihood of establishment of re-entrant circuits. In contrast, reduced sub-epicardial coupling results in decrease in both ULV and VW. This decrease is caused by altered virtual electrode polarisation around the region of sub-epicardal uncoupling, and specifically, by the increase in (1) the amount of positively polarised myocardium at shock-end and (2) the spatial extent of post-shock wavefronts.

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“…Numerous studies have demonstrated that the coupling of cardiac gap junction is related closely to transmural dispersion of repolarization (TDR), 6,[8][9][10] and the uncoupling of gap junction will lead to an amplification of TDR, which is considered as a substrate for cardiac arrhythmogenesis. The present study investigated the underlying mechanisms for PMA-induced arrhythmias and the antiarrhythmic effect of AAP10 on PMA- .…”

Section: Discussionmentioning

confidence: 99%

Antiarrhythmic Peptide AAP10 Prevents Arrhythmias Induced by Protein Kinase C Activation in Rabbit Left Ventricular Wedges

Ruan

Zhang

2015

Int. Heart J.

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SummaryAs the mechanisms underlying PKC activation induced arrhythmias are not yet fully verified, we investigated the role of gap junctions in arrhythmias induced by PKC activation.Arterially-perfused rabbit left ventricular preparations were randomly assigned to perfusion with phorbol ester (PMA) or in combination with AAP10. Transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded throughout all experiments. Changes in connexin43 (Cx43) and nonphosphorylated Cx43 on S368 were measured by Western blot analysis.In the PMA group, the QT interval was shortened, the interval from the peak to the end of the electrocardiographic T wave (Tp-e) and induced nonsustained ventricular tachycardia (VT) were increased, and the expressions of Cx43 and nonphosphorylated Cx43 on S368 were decreased compared with the control group. Compared with the PMA group, without significant changes in the QT interval and the expression of nonphosphorylated connexin43 on S368, Tp-e and induced VT decreased and the expression of Cx43 increased in the AAP10 group.AAP10 can prevent PMA-induced rabbit ventricular arrhythmias by attenuating the increase of Tp-e and the decrease of expression of Cx43. These data suggest that increasing gap junction coupling prevents arrhythmias induced by protein kinase C activation. (Int Heart J 2015; 56: 234-238)

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Intercellular coupling through gap junctions masks M cells in the human heart

Abstract: The manifestation of M cells is absent in the human heart, probably by effective intercellular coupling, turning them functionally "invisible".

Cited by 101 publications

References 34 publications

Transmural and apicobasal gradients in repolarization contribute to T-wave genesis in human surface ECG

Transmural and apicobasal gradients in repolarization contribute to T-wave genesis in human surface ECG

The role of transmural ventricular heterogeneities in cardiac vulnerability to electric shocks

Antiarrhythmic Peptide AAP10 Prevents Arrhythmias Induced by Protein Kinase C Activation in Rabbit Left Ventricular Wedges

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