Figure 10. Summary of the concept of wavelength restitution analysis exemplified by the murine Scn5a^+/− system following flecainide.

A, illustration of the voltage-gated Na⁺ channel, alterations in which ultimately form the basis of the arrhythmic tendency in hearts showing a 50% Na⁺ channel reduction (KO) in the RV. B, comparison of the consequent AP waveforms in untreated WT (continuous black lines), untreated Scn5a^+/− (dashed grey lines) and flecainide-treated Scn5a^+/− (dotted grey lines). The Scn5a^+/− RV epicardium shows longer latencies and shorter APs when compared to WT. Flecainide substantially increases latency but also increases APD. These differences demonstrate depolarisation and repolarisation disturbances that are rate dependent and assessed by conduction velocity (C) and APD restitution curves (D). C, right-sided conduction block exists in untreated Scn5a^+/− hearts compared to WT. This is exacerbated by flecainide. D, data taken from Matthews et al. (2012) demonstrates that untreated Scn5a^+/− and WT hearts have similar DI_crit(APD) values. However, flecainide markedly increases this value in Scn5a^+/− RV epicardium. E, both depolarisation and repolarisation disturbances unify to the λ restitution curve. These may show differences in maximum value but converge to a common point of instability λ′_0crit. However, the pacing rate required to achieve this point is significantly lower in the Scn5a^+/− RV epicardium when treated with flecainide. F, the gradients of the λ′ restitution curve map to the magnitude of λ′ alternans through a simple analytical equation which shows greater linearity over physiological heart rates than previously described for APD restitution. This results in alternating excitation wavelengths that may give rise to heterogeneities or risk of re-entry around an existing heterogeneity, and consequent re-entrant arrhythmia in the form of VT (G).