Towards resolving the role of M-cells in electrophysiology

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At the 10th annual congress of the European Cardiac Arrhythmia Society (ECAS; 23–25 March, Munich, Germany), Fu Siong Ng (London, UK) and colleagues won the first prize for best oral abstract with their research on the role of M-cells in electrophysiology. Ng writes for Cardiac Rhythm News an overview of the subject and the results of their own research.

Over two decades since they were first discovered, there remains a great deal of controversy and debate surrounding the role of M-cells in humans. These cells were discovered in the Antzelevitch laboratory in experiments designed to assess the transmural dispersion of action potential duration.1 They found a previously undescribed group of cells in the midmyocardium that had significantly prolonged action potential durations, which they termed the M-cell, named after one of forefathers of cardiac electrophysiology, Gordon K Moe.

The prolonged action potential durations in these cells have been attributed to weaker repolarising currents (IKs) and stronger late sodium and sodium-calcium exchanger currents. These cells have been postulated to have significant physiological and pathophysiological roles, including underlying the T-wave and J-wave of the electrocardiogram, as well as accounting for the arrhythmogenic effects of transmural dispersion of repolarisation in conditions such as long QT syndrome.

However, over twenty years on, researchers disagree as to their potential functional significance in humans. This disagreement between esteemed and experienced researchers stems not from any reservations about the validity or reproducibility of the data, but rather a difference in interpretation of the data that have been generated on this subject.

This has arisen because many of the experiments demonstrating a functional role for M-cells have been in isolated cells or wedge preparation. However, when researchers subsequently tried to look for evidence of M-cells in vivo in humans, in intraoperative studies of patients undergoing cardiac surgery, they have not been able to demonstrate the presence of M-cells.2 This has led to the view in one group of researchers that M-cells can only be clearly demonstrated in artificial experimental preparations such as isolated cardiomyocytes and in the explanted wedge preparation, but do not have any functional significance in the intact heart in humans.3 The effective intercellular coupling that exists in intact myocardium is thought to mask the effects of M-cells, thus rendering them functionally insignificant in intact hearts. However, a second group of researchers that have consistently supported a functional role for these cells have pointed to a number of potential deficiencies in the intraoperative studies, citing the effects of general anaesthesia and the complex distribution of M-cells as the potential reasons why they were not detected in those human studies.4

We recently performed some studies to address these disagreements, which we presented at the European Cardiac Arrhythmia Society Congress in Munich, Germany.5 We reported data from optical mapping experiments on ventricular wedge preparations from explanted human hearts. In these studies, we subjected human myocardium to a gap junction uncoupler, carbenoxolone, and investigated the effects of gap junction uncoupling on the transmural dispersion of action potential duration. We found no evidence of midmyocardial islands or layers with prolonged action potential durations representing M-cells at baseline. However, in response to the gap junction uncoupler carbenoxolone, we were able to detect M-cell regions not seen at baseline. We concluded from these results that M-cells clearly exist in human myocardium. However, they do not exert any significant functional effects under physiological conditions as effective cell-to-cell coupling masks their effects, and they can be unmasked in the context of gap junction uncoupling.

Although these results from our current studies are unlikely to settle the ongoing debates about the functional significance of M-cells in humans, they have added to the wealth of data on the subject, and go some way towards reconciling the difference between the two sides of the M-cell debate by explaining why these cells have been detected under certain experimental conditions but not in the intact heart.

References

1. 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

2. Taggart P, Sutton PM, Opthof T, Coronel R, Trimlett R, Pugsley W, Kallis P. Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia. Cardiovasc Res. 2001;50:454–462

3. Janse MJ, Coronel R, Opthof T. Counterpoint: M cells do not have a functional role in the ventricular myocardium of the intact heart. HeartRhythm. 2011;8(6):934–937

4. Wilson LD, Jennings MM, Rosenbaum DS. Point: M cells are present in the ventricular myocardium. HeartRhythm. 2011;8:930–933

5. Ng FS, Sulkin MS, Peters NS, Efimov IR. Do M-cells play a functional role in humans? Insights from high-resolution optical mapping of explanted human hearts (Abstract). J Interv Card Electrophysiol. 2014;39:S22–S23

Fu Siong Ng isa National Institute for Health Research (NIHR) Clinical Lecturer in Cardiology, Imperial College London, UK, and a Specialist Registrar in Cardiology, Imperial College Healthcare NHS Trust

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