Experimental findings on mechanoelectric feedback in isolated myocardium and single cardiomyocytes have yielded a wide variety of stretch-induced changes in action potential duration (APD).

Earlier mathematical modelling has shown that APD responses may depend on stretch timing and the predominant mechano-sensitive mechanism activated. Thus early activation of stretch-activated ion channels (SACs) shortens APD, while late activation prolongs it. The opposite effects may be observed if the predominant target mechanism is troponin C (TnC) affinity for Ca²⁺ (Kohl et al. 1998).

To extend applicability of the model to contraction-related mechanical modulation of cardiomyocyte electrophysiology during various modes of contraction, we developed the Ekaterinburg/Oxford model which uses an improved description of cellular Ca²⁺ handling and mechanics, namely co-operative modulation of Ca²⁺ dissociation from TnC (Garny et al. 2001). This allowed us to relate changes in APD to length-dependent differences in Ca²⁺ dissociation from TnC and knock-on effects on Ca²⁺ transient and Na⁺-Ca²⁺ exchange current (i_NaCa). The model simulated a range of stretch effects, but not cross-over of repolarisation and late APD prolongation, or afterdepolarisation-like events during large stretch. Only then did the model produce these effects when we also included SAC currents (i_SAC).

We developed a routine that allows quantitative assessment of the influence of stretch-induced change in individual currents on AP shape. This is based on calculation of the cumulative effect (integral) of the difference Δi_k in the kth current during mechanical stimulation and control. The integrals contribute to AP change as in:

Comparison of integrals allows elucidation of the relative significance of individual currents for observed total AP change. Thus in the case of a small SAC conductance (0.03 nS for both control sarcomere length 1.9 mm and 5 % stretch), stretch-induced APD shortening is caused by a repolarising effect on AP of change in both i_NaCa and i_SAC (Fig. 1A). In the case of high SAC conductance (0.66 nS for 5 % stretch), the cross-over of repolarisation is driven by the opposite effects of these current changes (Fig. 1B).

This work is supported by The Wellcome Trust and the Russian Foundation for Basic Research.