Action potential contour and inter-species differences

This editorial refers to ‘Action potential contour contributes to species differences in repolarization response to β-adrenergic stimulation’ by L. Sala et al., on pages 1543–1552. In the article by Sala et al.1, in this issue of EP-Europace, the action potential contour was found to be pivotal for species specificity of repolarization response to β-adrenergic stimulation. As crucial factors of action potential contour, the ‘spike-and-dome’ morphology and the level of the plateau phase were identified. The ‘spike-and-dome’ morphology is typical for canine as well as human (sub)epicardial and mid-myocardial ventricular myocytes,2–4 but in many other (experimental) species it does not occur. What is the primary function of this action potential morphology/phase and why is it species- and layer specific? Probably the most likely hypothesis suggests that it serves for an optimal synchronization of ventricular contraction.5,6 A large transient outward current (Ito) and consequent notch of the action potential due to a pronounced Phase 1 repolarization in epicardial myocytes allow a fast increase in the driving force of the L-type calcium current (ICaL). Consequently, the faster and bigger calcium trigger of calcium-induced calcium release may compensate for delayed activation of epicardial myocytes compared with the endocardial ones. Obviously, the need for transmural synchronization of contraction is more pronounced in large hearts (dogs and humans), in which the ‘spike-and-dome’ morphology typically occurs in epicardial myocytes with a prominent Ito current. In porcine heart, however, although it is similar to canine and human hearts in a number of aspects including size, the ‘spike-and-dome’ morphology of the epicardial action potential does not occur,7 which corresponds to the lack of functional Ito current.8 Nevertheless, the position of the plateau is somewhat less positive in porcine epicardial myocytes than in endocardial myocytes, increasing the driving force,7 which might be sufficient for better triggering. Anyways, other mechanisms than Ito-related notch must then be adequate, at least in the setting of the porcine myocardium, for optimal synchronization of ventricular contraction. In this line of thinking, β-adrenergic stimulation should reduce the transmural Phase 1–2 differences (‘spike and dome’) in canine cardiac myocytes. Although the effects of β-adrenergic stimulation on potassium Ito are questionable,9,ICaL is substantially enhanced, which should reduce the notch and shift the plateau to more positive potentials in epicardial myocytes. The results of Sala et al.1 are in a good agreement with this hypothesis: the plateau potential was at baseline less positive in epicardial than in endocardial myocytes, and after β-adrenergic stimulation with isoproterenol it was elevated more in epicardial myocytes, reaching levels comparable to that in endocardial myocytes. In small experimental animals (mice and rats), action potential duration is much shorter, and Ito represents the main repolarization current. Although the transmural heterogeneity is much less pronounced, it is still present and the principles outlined above are probably applicable also in small animal species. In mouse hearts, Ito densities are lower in endocardial than epicardial myocytes, which corresponds to longer action potential duration at 50% repolarization.10 In general, the action potential contour is a result of fine balance of inward and outward ionic currents, and the report by Sala et al.1 nicely shows how the early ‘spike-and-dome’ phase of the action potential sets the stage for fine balance of plateau currents. Rather inconspicuous changes of this early phase have important consequences for total action potential duration and significantly contribute to both inter-species and transmural action potential differences. Furthermore, the ‘spike-and-dome’ morphology of action potential is probably an important contributor to proper synchronization of ventricular contraction in terms of both calcium trigger in early phase of the action potential (setting the optimal driving force for early calcium entry) and calcium loading in later phases of the action potential (setting the optimal plateau level and duration). A notable aspect of the report by Sala et al.1 is the use of the dynamic clamp technique. By adding virtual Ito channels to a real biological cardiomyocyte, the authors were able to test whether the absence of fast repolarizing action of Ito channels is an essential discriminator between guinea pig and dog cardiomyocytes. In the earlier work, Wang and colleagues11,12 used the same approach to study the differences between guinea pig and dog cardiomyocytes, though in the absence of stimulation with isoproterenol. An interesting difference between the findings of Wang and colleagues and the article by Sala et al.1 is the effect of adding virtual Ito channels on action potential duration. While Sala et al.1 found that Ito had a small shortening effect on the guinea pig action potential (5.7 ms), earlier work observed prolongation of up to ∼20%. These contrasting findings might be explained by differences in the experimental conditions, which include the models used to simulate the virtual Ito channels. This is underlined by the fact that Sala et al.1 observed that addition of a sustained component to the Ito model did not result in shifting of the plateau phase, something that was indeed observed by Dong et al.12 when adding a sustained component of 16% of total peak Ito current. Ideally, dynamic clamp experiments should explore the effects of model structure and parameters systematically within each experiment, but this is practically very difficult, as a wet experiment has a limited lifetime, unlike pure in silico simulations that allow extensive sensitivity analyses. The report by Sala et al.1 approaches a physiologically relevant question—what is the role of the ‘spike-and-dome’ morphology in setting action potential duration under catecholaminergic stimulation—using a state-of-the-art combination of cardiac cellular electrophysiological tools that allow to delve further into the mechanisms of cardiac excitability. Conflict of interest: none declared.