The M Cell:

Abstract

Characteristics of the M Cell. The discovery and characterization of the M cell, a unique cell type residing in the deep layers of the ventricular myocardium, has opened a new door in our understanding of the electrophysiology and pharmacolugy of the heart in both health and disease. The hallmark of the M cell is the ability of its action potential to prolong much more thau that of other ventricular myocardial cells in response to a slowing of rate and/or in response to agents that act to prolong action potential duration. Our goal in this review is to provide a comprehensive characterization of the M cell, its contribution to transmural heterogeneity, and its role in the normal electrical function of the heart. In the inscription of the ECG (particularly the T wave), and in the development of QT dispersion, T wave alternans, long QT intervals, and cardiac arrhythmias, such as torsades de pointes. Our secondary goal is to address the controversy that has arisen relative to the functional importance of the M cell in the normal heart. The controversy derives largely from the failure of some investigators to demonstrate transmural heterogeneity of repolarization in the dog in vivo under control conditions and after administration of quinidine. The inability to demonstrate transmural heterogeneity under these conditions may he due to the use of bipolar recording techniques that, in our experience, seriously underestimate transmural dispersion of repolarization (TDK). The use of sodium pentobarhital and a-chloralose as anesthesia also is problematic, becau.se these agents reduce or eliminate TDR by affecting a variety of ion channel currents. Finally, attempts to amplify transmural dispersion of repolarization with an agent such as quinidine must take into account that relatively high concentrations can result in effects opposite to those desired due to drug inhibition of multiple ion channels. These observations may explain the inability of earlier studies to detect the M cell.

Molecular basis for the transmural distribution of the transient outward current

“…Regional differences in I to , first suggested on the basis of action potential data, have now been demonstrated using voltage clamp techniques in canine, feline, rabbit, rat and human ventricular myocytes ( Fig. 1; see Antzelevitch et al 1999 for references). Transmural differences in the magnitude of the I tomediated action potential notch give rise to a transmural voltage gradient, which is responsible for the inscription of the electrocardiographic J wave.…”

“…Amplification of these electrical heterogeneities can lead to the development of life-threatening cardiac arrhythmias and sudden death. A number of ionic distinctions have been shown to contribute to the different action potential morphologies of epicardial, M and endocardial ventricular cells as well as to the distinctive responses of these three cell types to pharmacological agents and pathophysiological states (for reviews see Antzelevitch et al 1999;Antzelevitch & Dumaine, 2000). Ventricular M and epicardial cells, but not endocardial cells, typically display action potentials with a prominent notch or phase 1, due to the presence of a large 4-aminopyridine (4-AP)-sensitive transient outward current (I to ).…”

Ion Channels in the Heart

“…The amplified transmural APD heterogeneity may culminate into reentrant arrhythmias (17). Therefore, abnormalities in transmural repolarization can be distinguished on an ECG and can be used for prognosis and treatment (15, 16, 572). …”

Naming of the Waves in the ECG, With a Brief Account of Their Genesis

“…The M cells are found from the deep subendocardium to midmyocardium in the lateral ventricular wall and throughout the ventricular wall in the region of the outflow tracts. 12 The M cells are histologically similar to other myocytes, but they are electrophysiologically and pharmacologically different. For example, the action potential of the M cells lasts longer than that of other myocytes.…”

“…For example, the M cells and Purkinje cells respond in opposite ways to an ␣-adrenergic agonist. 12 Antzelevitch believes that normal U waves are produced by repolarization of the His-Purkinje cells. An abnormal U wave (large or inverted) is part of the T wave; it may be referred to as an interrupted T wave.…”