Cellular and Subcellular Mechanisms of Ventricular Mechano-Arrhythmogenesis

Intrinsic regulation of cardiac electrical and mechanical activity allows the heart to adjust its function to meet the metabolic demand of the body. This includes the acute feedback of cardiac mechanics to electrics (‘mechano-electric coupling’, MEC), which is achieved primarily through cellular and subcellular elements, including mechano-sensitive ion channels, biophysical signal transmitters and mechano-sensitive biochemical signalling pathways. While MEC is normally involved in fine-tuning of cardiac function, in disease states characterised by perturbations in the cardiac mechanical environment, myocardial mechanics or elements of MEC, it can instead drive arrhythmogenic changes in electrophysiology (‘mechano-arrhythmogenesis’), which can result in sustained ventricular tachyarrhythmias. This chapter briefly reviews essential aspects of MEC, discusses clinical evidence and experimental studies of ventricular mechano-arrhythmogenesis and describes the underlying cellular and subcellular elements involved. It then puts mechano-arrhythmogenesis into a clinical context by focussing on two pathological states that highlight the spatio-temporal dependence of mechano-arrhythmogenesis in the whole heart: one that is characterised by acute, local changes in cardiac electro-mechanics and MEC (acute regional myocardial ischaemia) and one that involves chronic, global changes (hypertension). Overall, an improved understanding of the mechanisms driving ventricular mechano-arrhythmogenesis is critical for the development of anti-arrhythmic therapies targeting MEC, such as modulation of tissue mechanics or alteration of subcellular mechano-sensitive components.