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Cardiovascular Research 2001 51(1):1-3; doi:10.1016/S0008-6363(01)00332-7
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Multiple interactions determine cellular electrical processes in the multicellular tissue

Yoram Rudy*

Cardiac Bioelectricity Research and Training Center, 509 Wickenden Building, Case Western Reserve University, Cleveland, OH 44106-7207, USA

yxr{at}po.cwru.edu

* Tel.: +1-216-368-4051; fax: +1-216-368-8672

Received 19 April 2001; See article by Verkerk et al. [5] (pages 30–40) in this issue.

"Things should be made as simple as possible, but not any simpler" Albert Einstein

The traditional classification of cardiac arrhythmias makes a distinction between focal mechanisms due to abnormal electrophysiological functioning of single cells, and propagation-related mechanisms due to abnormal conduction in the multicellular tissue [1]. Single-cell arrhythmogenecity is associated with triggered activity and after-depolarizations, which are subdivided into early (EAD) and delayed (DAD) afterdepolarizations based on their timing relative to the action potential (AP) [2]. Propagation-based arrhythmias include various types of reentry [3] and spiral-wave activity [4] that involve many interconnected cardiac cells and can occur on different spatial scales (e.g. micro- or macro-reentry). The above classification into single-cell and multicellular phenomena also reflects the commonly used reductionist experimental approach that studies cellular behavior in isolated-cell preparations, in the absence of the interactions with neighboring cells that occur in the intact myocardium. Similarly, on a smaller scale, ion-channel function is studied in membrane patches or expression systems (e.g. Xenopus oocyte), away from the complex cellular environment where they interact dynamically with other ionic processes to form the AP. Since cardiac arrhythmias occur in the intact myocardium, it is essential to develop systematic understanding of the underlying processes at increasing levels of complexity and integration from the ion channel, to the cell, to groups of interacting cells, to the multicellular tissue. Such step-by-step integration can be achieved through novel experimental strategies or the use of computer modeling.

The article by Verkerk et al. in this issue of Cardiovascular Research [5] uses an elegant experimental preparation, developed in Ron Joyner's laboratory and used previously [6–8], to simulate electrotonic interactions between a depolarized intramural ischemic region and surviving cells in the subepicardium or subendocardium. In this preparation, an electronic circuit represents the depolarized region, while a real myocyte (ventricular or Purkinje) represents the surviving (normal) cells during acute ischemia. The myocyte and the electronic circuit are coupled via a variable conductance that simulates alterations in the intercellular coupling. In some of the protocols, the cells were exposed to norepinephrine to simulate effects of catecholamine release during acute ischemia. Of course, this preparation does not represent fully the complex substrate of ischemic myocardium and its multiple electrophysiological manifestations. The strategy here is to use a simplified model that permits to study selectively, in a controlled fashion, the effects of alterations in coupling between a normal region and a depolarized (‘ischemic’) region with different levels of membrane depolarization. Such processes occur during the late phase (phase 1-b) of arrhythmias associated with acute ischemia (the period between 12 and 30 min following ischemia onset) [9]. Results demonstrate the importance of electrotonic influences from the depolarized region in determining the behavior of the normal cell. For a critical range of reduced coupling, arrhythmogenic afterdepolarizations form in the normal cell, suggesting a possible role for triggered activity in phase 1-b arrhythmias.

While the study provides specific insights on arrhythmogenecity during acute ischemia, it helps to illustrate a more general principle that the behavior of each building-block of the system (ion-channel, single cell) is modulated strongly by interactions with other components of the electrophysiological substrate. Here, electrical loading by the simulated depolarized region is shown to be a major determinant of the cell's response. For strong coupling, loading could render the cell completely inexcitable. Importantly, for a critical range (‘window’) of coupling and high depolarization levels (representing delayed action potentials in the ischemic region), EADs develop in the normal cell. Thus, the arrhythmogenic behavior of the cell is caused by its interaction with the surrounding environment (the multicellular tissue in the intact heart). This principle applies under a variety of circumstances. For example, a recent theoretical study [10] demonstrated that for simulated long-QT syndrome conditions, EADs develop in midmyocardial (M) cells [11] when the tissue is poorly coupled, while in well-coupled tissue they can form in endocardial cells as a result of strong electrotonic interactions [10].

The principle that the cellular behavior is modulated strongly by complex external interactions with its surroundings holds true for internal interactions between intracellular processes as well. Elegant experiments by January and Riddle [12] have demonstrated that the L-type calcium current, ICa(L), plays an essential role in the depolarization of EADs that develop from plateau potentials (‘plateau EADs’). Theoretical studies [13,14] have confirmed that ICa(L) carries the depolarizing charge that generates the EAD. For this to occur, the AP must be sufficiently prolonged at the plateau potential range (above the threshold for ICa(L) activation) to allow sufficient time for L-type channels to recover from inactivation and reactivate during the AP. Prolongation of the AP plateau prior to the EAD (a phase termed the ‘conditioning phase’) can be achieved through many nonspecific processes that shift the delicate balance of inward and outward currents in the inward (depolarizing) direction. In LQT3 this is achieved by a gain of late inward sodium current [15,16]; in LQT1 and LQT2 by loss of an outward potassium current [17–19]. Under conditions of augmented calcium release from the sarcoplasmic reticulum and sodium–calcium exchanger enhancement in its forward (depolarizing) mode (as occurs with β-adrenergic stimulation), the exchanger current contributes to prolongation of the AP plateau [14,20,21]. Independent of the mechanism that creates the conditions and sets the stage for EAD development, it is ICa(L) reactivation that causes the EAD depolarization. In the study of Verkerk et al. [5], prolongation of the AP plateau is caused by electrotonic current flow from the simulated depolarized region. This causes "prolongation of the time spent in the potential range of window Ca2+current. Recovery from inactivation and reactivation of the Ca2+ channels may then occur, resulting in a transient depolarization" (quote from Ref. [5]). Here an external process (the electrotonic current) interacts with intrinsic cellular processes to result in generation of arrhythmogenic EADs.

The principle that cellular mechanisms are strongly modulated by interactions with the multicellular electrophysiological substrate applies not only to the AP but to its propagation in the tissue as well. Experiments have demonstrated that in poorly coupled tissue, AP propagation can be strongly influenced by drugs that block or enhance ICa(L) [22–25]. These findings expand the traditional view that in a fully excitable tissue the fast sodium current provides all the depolarizing charge needed for successful AP conduction. Theoretical studies [26,27] have confirmed that in a poorly-coupled tissue, in the presence of long local conduction delays, charge contribution from ICa(L) is indeed necessary for successful AP propagation. Again, an external influence (cell-to-cell uncoupling) has interacted with cellular processes, this time to modulate the ionic mechanism of conduction in the multicellular tissue.

In summary, there is an increasing appreciation of the importance of complex interactions between various building blocks of cardiac tissue in determining normal excitation and arrhythmogenesis. Clear understanding of this interactive system at the tissue level is essential to the understanding of excitation and arrhythmia in the whole heart. We should design studies to characterize the system with a step-by-step increase in the level of complexity and integration. The study by Verkerk et al. in this issue of Cardiovascular Research is an important contribution to such an effort.


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