Depolarization vs. repolarization: what is the mechanism of ventricular arrhythmogenesis underlying sodium channel haploinsufficiency in mouse hearts?

To the Editor: we read the review article published by Jeevaratnam et al. in February 2016, on sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis, with great interest. First of all, we acknowledge their contributions in elucidating the role of conduction abnormalities associated with structural change in Scn5a mouse hearts modeling Brugada syndrome. Both depolarization and repolarization hypotheses have been proposed to explain the arrhythmogenesis observed in Brugada syndrome, as summarized by Wilde et al. (2010). There is no doubt that Jeevaratnam et al. (2011, 2012) have made a strong argument for the role of abnormal conduction in mediating ventricular arrhythmias from their previous papers (Zhang et al. 2014). However, the data from the authors’ group on the repolarization are not convincing. Thus, Martin et al. (2010) obtained monophasic action potential (MAP) recordings from the epicardium or endocardium of the left ventricle (LV) or right ventricle (RV) in wild-type and Scn5a hearts. The MAP method is an ex vivo recording technique that has widely been used to study whole heart electrophysiology (Tse et al. 2016c). Martin et al. reported that ‘In WT hearts, flecainide shortened the APD values in all four ventricular regions investigated, but doing so significantly only for RV epicardium’. Their wording implied that no significant shortenings in APD values were observed in the LV epicardium, LV endocardium or RV endocardium. However, previous experiments from the same group found that flecainide not only shortened APD90 significantly but also shortened APD70 and APD50 significantly in the LV epicardium, and shortened only APD90 and APD70 but not APD50 significantly in the LV endocardium (Stokoe et al. 2007). Thus, these findings from both studies are in direct contradiction with each other. Many other discrepancies can be found. Thus, Martin et al. reported ‘In WT hearts, quinidine increased the APD values in all the ventricular regions studied, but did so most noticeably in the RV epicardium, reaching significance here for all three repolarizations’. Yet, quinidine was previously shown to prolong APD90 but not APD70 or APD50 at the LV epicardium. Moreover, the authors reported ‘quinidine lengthened the APDs in all ventricular regions in Scn5a hearts, again reaching significance specifically in the RV epicardium’. However, the previous study showed lengthening of LV endocardial APD90, but not in APD70 or APD50. If no agreement and no reproducibility can be observed between studies, then this may point to operator-dependent effects or intrinsic properties of the MAP recording technique (Tse et al. 2016c). Conclusions regarding activation latencies from MAPs are only valid if the interelectrode distance is not varied. Given the short distance, how did the authors ensure that the electrodes were not moved during the course of the experiments, and how was this distance measured? Whilst we do not doubt that the use of mouse models has advanced our understanding of the mechanisms underlying cardiac arrhythmogenesis (Tse et al. 2012, 2016a,b,d,e, Tse 2015, Tse & Yeo 2015), the limitations of the MAP technique must be recognized. Other techniques, such as multi-electrode and transmembrane membrane potential recordings, some of which have also been used by Jeevaratnam et al. previously, are needed to supplement findings from MAPs. What is clear is that both processes of depolarization and repolarization, which can be combined into a single parameter of excitation wavelength (k), are important for the determination of arrhythmic tendency (Tse & Yeo 2015), despite previous assertions that one process is more important than the other.