Determination of action potential wavelength restitution in Scn5a+/− mouse hearts modelling human Brugada syndrome

Brugada syndrome is a primary electrical disorder of the heart, predisposing affected individuals to potentially lethal, ventricular tachy-arrhythmias. A number of mechanisms have been identified as being important increasing the risk of these rhythms. Wavelength (λ) restitution has been suggested to predict the onset of action potential duration (APD) alternans in mouse Scn5a hearts modelling Brugada syndrome. Classical APD restitution analysis yielded mixed success in its ability to predict the onset of APD alternans and arrhythmogenicity. APD restitution relates APD to the previous diastolic interval (DI). APD restitution gradients > 1 is associated with the emergence of APD alternans, and increased arrhythmogenicity in a number of different genetic and pharmacological mouse models, such as Brugada syndrome, long QT syndrome type 3 and hypokalaemia. Matthews and colleagues previously demonstrated a non-linear relationship between APD alternans and APD restitution gradient and underestimated the extent of APD alternans, suggesting that it may partly underlie its lack of success in predicting arrhythmogenicity. Another reason is that effective refractory period (ERP) can be altered independently of APD.  The lack of predictive power of APD restitution led Matthews and colleagues to devise a novel λ restitution analysis by recording monophasic action potential (MAP) recordings in wild-type and Scn5a hearts during dynamic pacing, which introduced a stepwise increase in pacing rate. The MAP method is an ex vivo recording technique that has widely been used to study whole heart electrophysiology in Langendorff systems. Activation latencies and APDs were derived from the MAPs obtained from the ventricles, with conduction velocity (θ) approximated by the reciprocal of activation latency, θ’. This in turn enabled the