Can principles of the surface potential be combined with knowledge of natural products to reduce atrial rhythm disturbances?

Long-lasting or chronic electrophysiological abnormalities in human atria are significant contributors to morbidity during healthy ageing. Although both paroxysmal (brief) and chronic atrial fibrillation (AF) were considered to be benign, the notable association between maintained AF and stroke has resulted in AF now being a target for surgical intervention (ablation) and/or drug therapy. An interesting, forward-looking paper from the Elinder group1 in this issue of Acta Physiologica reveals novel pharmacological agents and principles that could be the basis for more effective antiarrhythmic therapies for AF. Salari et al.1 rigorously evaluate the possibility that altering the activity of not one, but several different transmembrane ionic currents that are essential for generation of the atrial action potential can reduce spontaneous firing and prolong the action potential. Salari et al.1 accomplish this by utilizing a surrogate for a mouse atrial myocyte (HL-1 cells) in culture and applying selected natural compounds (resin acids) that they have previously studied in other model systems.2 Their detailed electrophysiological testing (voltage clamp recordings) reveals that these small acids, when superfused at μm levels, can alter this HL-1-based arrhythmic substrate by simultaneously reducing Na+, and Ca2+ currents, while enhancing K+ currents, while enhancing K+ currents. These effects arise mainly from a common mechanism: the ability of these compounds (in particular isopimaric acid) to bind to discreet charged sites very near these ion channel gating regulators on the myocyte surface membrane (sarcolemma). In doing so, they alter the fixed or localized surface charges that strongly regulate the opening, closing and ‘availability’ of these channels.3, 4 These effects are concentration-dependent and reversible. Mathematical modelling suggests that they also can be predicted and understood based on the ability of these natural compounds to change the surface potential (or zeta potential), as opposed to altering the conventional electrochemical transmembrane voltage profile.4-6 Surface charge regulation of ion channel gating has a long history, much of which is tied closely to papers in this journal from a number of internationally acclaimed Scandinavian investigators. Frankenhaeuser and Hodgkin7 first identified and explained the functional importance of ‘surface potentials’ in their studies on the effects of divalent cations (with an emphasis on Ca2+) on the threshold for action potential firing and the conduction velocity in squid axons. Subsequent work by the Århem group4 and others documented these effects on Na+ channels in myelinated nerve, while also demonstrating similar changes in K+ channel gating and identifying its molecular basis.6 These findings can perhaps be put into a translational context by addressing the question: Would similar electrophysiological changes be observed in a human atrial myocyte, in response to the surface charge-mediated modifications of the ion channels reported by Salari et al.?1 Our mathematical simulations in Figure 1 provide some of this information. We have used the human atrial electrophysiology simulation resource8 published by our colleagues to introduce the isopimaric acid-induced changes in four of the transmembrane ionic currents that underlie the human atrial action potential. Sets of simulations have been carried out using both (i) the healthy or baseline mathematical model of a single left atrial human myocyte (left column) and (ii) a version of this mathematical model that incorporates many of the known AF-induced changes in the underlying ionic currents, producing altered action potential waveforms that are characteristic of chronic atrial fibrillation.9 In the first of four rows of Figure 1, one of the ion channel-specific isopimaric acid-induced hyperpolarizing shifts in the steady-state activation and inactivation relationships has been introduced in silico. Baseline (control) data are shown in black; results generated after incorporating a −5 mV shift in these variables are shown in red and the data produced by a −10 mV shift are illustrated by the blue broken lines. It is apparent that these isopimaric acid-induced changes in the Na+ current INa (panel a) and those in the Ca2+ current ICa-L (panel d) produce the most marked changes in the upstroke and phase I of the action potential or the AP waveforms. The data in panel (e) were computed based on a combination of all of these isopimaric acid-induced changes. Note that these changes are still prominent after the two K+ currents, Ito and IKr, that strongly regulate repolarization are modified in accordance with the findings of Salari et al.1 As shown in Figure 2, the changes in the action potential resulting from alterations in INa modify (i) the firing threshold and (ii) the maximum rate of depolarization (dv/dt). Careful inspection of the superimposed action potentials in panels (a) and (e) of Figure 1 also shows a reduction in the action potential overshoot. The ability of these changes to alter abnormal spontaneous firing in the human atrium myocyte model was not evaluated. However, it is apparent from the superimposed action potential waveforms in each panel of row (e) in Figure 1 that the observed changes would contribute to antiarrhythmic properties. Thus, excitability is reduced markedly and the action potential is prolonged significantly, both at baseline and in the setting of the in silico atrial fibrillation substrate. In combination, these two changes would be expected to increase the ‘wavelength of the human atrial impulse’ and therefore confer significant antiarrhythmic activity.10 It seems plausible, then, that the selected natural product family of ‘resin acids’ could provide electrophysiological stability in human atrium. However, additional work will be needed to document this interesting possibility by addressing a number of unresolved and (in some cases) confounding issues. These include the following: Atrial fibrillation is the most common form of cardiac rhythm disturbance and in otherwise healthy individuals is associated with increased incidence of stroke and other comorbidities. We commend the Elinder group1 for identifying an important health problem and then advancing the potential ‘toolkit’ for managing chronic AF based on a combination of elegant cellular electrophysiology and biophysics and evaluation of natural products as new therapeutic agents. There are no conflict of interests to declare for any of the authors. The Giles group is funded by the Canadian Institutes for Health Research, and the Zhang group is funded by the British Heart Foundation and the Engineering and Physical Science Research Council.

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