Abstract
A wide range of arrhythmogenic phenotypes have been associated with heterogeneous mechanical dyskinesis. Pro-arrhythmic effects are often associated with dysregulated intra-cellular calcium handling, especially via the development of intra- and inter-cellular calcium waves. Experimental evidence suggests that mechanical strain can contribute to the generation and maintenance of these calcium waves via a variety of mechano-electric coupling mechanisms. Most model studies of mechano-electric coupling mechanisms have been focused on mechano-sensitive ion channels, even though experimental studies have shown that intra- and inter-cellular calcium waves triggered by mechanical perturbations are likely to be more prevalent pro-arrhythmic mechanisms in the diseased heart. A one-dimensional strongly coupled computational model of electromechanics in rabbit ventricular cardiomyocytes showed that specific myocyte stretch sequences can modulate the susceptibility threshold for delayed after-depolarizations. In simulations of mechanically-triggered calcium waves in cardiomyocytes coupled to fibroblasts, susceptibility to calcium wave propagation was reduced as the current through the gap junction caused current drain from the myocytes. In 1D multi-cellular arrays coupled via gap junctions, mechanically-induced waves may contribute to synchronizing arrhythmogenic calcium waves and after-depolarizations.
Highlights
Altered myocardial mechanics in disease may contribute to the triggering or maintenance of life-threatening reentrant ventricular arrhythmias via a variety of mechano-electric coupling mechanisms
These findings are largely consistent with many experimental reports of calcium waves, in which the extracellular calcium concentrations varied between ∼2.0 mM (Takamatsu and Wier, 1990; Wier and Blatter, 1991) and 15 mM (Capogrossi et al, 1986a; Cheng et al, 1996)
We investigated the ability of sub-cellular mechanical transients and heterogeneity and the effects of coupled fibroblasts to modify calcium wave velocity and the resulting calcium mediated delayed after-depolarizations (DADs)
Summary
Altered myocardial mechanics in disease may contribute to the triggering or maintenance of life-threatening reentrant ventricular arrhythmias via a variety of mechano-electric coupling mechanisms. Altered myocyte mechanics may cause pro-arrhythmic perturbations to cardiomyocyte electrophysiology (Franz et al, 1992; Kohl et al, 2011) These perturbations may generate currents that trigger arrhythmias or create a heterogenous myocardial electrical substrate that supports reentry (Taggart and Lab, 2008). To understand the mechanisms of mechanically-triggered arrhythmogenic currents, we must consider both how electrical excitation activates calcium-dependent muscle contraction [excitation-contraction coupling (ECC)] and the reverse processes by which stretch alters membrane currents [mechanoelectric coupling (MEC)] (Kohl et al, 1999). Despite intensive investigations at different levels, from single ion channels (Kohl and Sachs, 2001) to tissue (ter Keurs et al, 1998, 2006a,b; Kohl et al, 2001), the contributions of MEC to arrhythmia generation is incompletely understood
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