Abstract
Mechanically-induced alterations in cardiac electrophysiology are referred to as mechano-electric feedback (MEF), and play an important role in electrical regulation of cardiac performance. The influence of mechanical stress and strain on electrophysiology has been investigated at all levels, however the role of MEF in arrhythmia remains poorly understood. During the normal contraction of the heart, mechano-sensitive processes are an implicit component of cardiac activity. Under abnormal mechanical events, stretch-activated mechanisms may contribute to local or global changes in electrophysiology (EP). While such mechanisms have been hypothesised to be involved in mechanically-initiated arrhythmias, the details of these mechanisms and their importance remain elusive.We assess the theoretical role of stretch mechanisms using coupled models of cellular electrophysiology and sarcomere contraction dynamics. Using models of single ventricular myocytes, we first investigated the potential MEF contributions of stretch-activated currents (SAC), and stretch-induced myofilament calcium release, to test how strain and fibrosis may alter cellular electrophysiology. For all models investigated, SACs were alone not sufficient to create a pro-arrhythmic perturbation of the action potential with stretch. However, when combined with stretch-induced myofilament calcium release, the action potential could be shortened depending on the timing of the strain. This effect was highly model dependent, with a canine epicardial EP model being the most sensitive.These model results suggest that known mechanisms of mechano-electric coupling in cardiac myocyte may be sufficient to be pro-arrhythmic, but only in combination and under specific strain patterns.
Highlights
IntroductionTo understand how mechanical changes can lead to arrhythmia, we must consider both the forward (excitation contraction coupling, ECC) and reverse processes (mechano-electric feedback, MEF) that couple electrical activity to mechanical function in cardiac cells and tissue
To understand how mechanical changes can lead to arrhythmia, we must consider both the forward and reverse processes that couple electrical activity to mechanical function in cardiac cells and tissue
Our intention was to understand whether the two mechano-electric feedback (MEF) mechanisms alter AP morphology or counteract each other, and whether this interaction depends upon the foundation EP model
Summary
To understand how mechanical changes can lead to arrhythmia, we must consider both the forward (excitation contraction coupling, ECC) and reverse processes (mechano-electric feedback, MEF) that couple electrical activity to mechanical function in cardiac cells and tissue. These interactions play an important role in electrical regulation of cardiac performance due to mechanical changes under normal conditions (Kohl et al, 1999). The interplay between forward (EP impacting calcium) and reverse (calcium impacting EP) processes in stretch-induced arrhythmia is intricate and likely to be highly context dependent
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