Palpitations, potassium and the pump

Hypokalaemia (serum [K⁺] <3.5 mm) is the most common electrolyte abnormality in hospitalized patients, and has long been associated with an increased incidence of cardiac arrhythmias, often sensed as palpitations by patients. Despite increasing the driving force for outward current through K⁺ channels, hypokalaemia reduces repolarization reserve by decreasing the conductances of the inward rectifier K⁺ current I_K1, the rapid component of the delayed rectifier K⁺ current I_Kr and the transient outward K⁺ current I_to, thereby promoting early afterdepolarization (EAD)-mediated arrhythmias. Hypokalaemia also inhibits the Na⁺–K⁺ ATPase (NKA) pump, causing intracellular Na⁺ and Ca²⁺ overload, which promotes delayed afterdepolarization (DAD)-mediated arrhythmias. However, the external K⁺ binding site of the NKA pump is half-saturated at an extracellular [K⁺] (K_m) around 2.0 mm, implying that moderate hypokalaemia (2.5–3.0 mm) inhibits the NKA pump by significantly less than 50%. Perhaps for this reason, the role of NKA inhibition has received less attention as a clinically relevant arrhythmogenic factor except in severe hypokalaemia (<2.5 mm), which is relatively rare clinically compared to moderate hypokalaemia. In this issue of The Journal of Physiology, however, Aronsen et al. (2014) make a compelling case that NKA inhibition also plays an important arrhythmogenic role during moderate hypokalaemia. Using a variety of electrophysiological and fluorescent dye measurements in isolated rat ventricular myocytes, combined with computational modelling, they show convincingly that moderate hypokalaemia (2.7 mm) causes sufficient NKA pump inhibition to increase intracellular Na⁺ to a level promoting intracellular Ca²⁺ overload and Ca²⁺ waves, the cause of DADs. The reason is that in cardiac myocytes, hypokalaemia inhibits the NKA pump by two mechanisms. At a constant membrane potential (e.g. around −75 mV in their study), reducing extracellular [K⁺] to 2.7 mm reduced the total NKA pump current by about 20%, as can be directly measured from their Fig. 3B. However, by negatively shifting the K⁺ equilibrium potential, hypokalaemia also hyperpolarized the resting membrane potential to around −90 mV (their Fig. 2B). Because the NKA pump generates an outward current by exchanging 2 K⁺ for 3 Na⁺ ions, this hyperpolarization further inhibits the NKA pump. The combined effect of the K_m and hyperpolarization was to depress NKA pump current by more than 50% (as estimated from their Fig. 3B). Membrane hyperpolarization also enhances the ability of the Na⁺–Ca²⁺ exchanger (NCX) to remove Na⁺ from the myocyte, but NCX stimulation was not sufficient to compensate for the overall reduction in NKA pump activity, as validated in their myocyte computer model.

The authors also suggest that the NKA α₂ isoform, which requires a higher extracellular [K⁺] for half-maximal activation (K_m = 2.9 mm) than the NKA α₁ isoform (K_m = 1.9 mm) and therefore is more completely suppressed at 2.7 mm [K⁺], plays a preferential role in promoting intracellular Na⁺ and Ca²⁺ overload. Although the NKA α₂ isoform contributed less than 25% of total NKA pump current (the majority being generated by the more prevalent NKA α1 isoform), selective blockade of the NKA α₂ isoform with low-dose ouabain increased the Ca²⁺ transient amplitude under normokalaemic conditions, and prevented any further increase in the Ca²⁺ transient amplitude when [K⁺] was subsequently reduced to 2.7 mm. Moreover, unlike NKA α₁, which is distributed ubiquitously, the NKA α₂ isoform is preferentially localized in the t-tubules, similar to the NCX. This may be a hint that there is a preferential functional relationship between NKA α₂ and NCX, as suggested previously (Swift et al. 2008; Despa et al. 2012).

The implication of these findings is that, in addition to EAD-mediated arrhythmias, clinically relevant moderate hypokalaemia can also promote sufficient intracellular Na⁺ and Ca²⁺ overload by NKA inhibition to generate spontaneous diastolic Ca²⁺ waves leading to DAD-mediated arrhythmias. It could be argued that a weakness in this interpretation is that although moderate hypokalaemia increased the frequency of Ca²⁺ waves in isolated rat ventricular myocytes, the Ca²⁺ waves observed did not cause DADs of sufficient amplitude to induce triggered activity (at least as can be surmised from the example shown in their Fig. 1B). Moreover, the aforementioned Ca²⁺ waves were induced by rapid pacing trains, and did not appear until several seconds after termination of the train (their Fig. 1B). In contrast, the majority of hypokalaemia-induced atrial and ventricular ectopy in the clinical setting and intact heart models occurs during sinus rhythm in the absence of such long pauses. However, this discrepancy does not seriously detract from the overall significance of the present findings, because once Ca²⁺ overload develops, a variety of arrhythmia mechanisms, in addition to DADs, come into play. Relevant to this point, we recently reported that moderate hypokalaemia (also 2.7 mm) in isolated rat ventricular myocytes and intact rat hearts led to EAD-mediated arrhythmias that were effectively suppressed by Ca²⁺/calmodulin-dependent protein kinase (CaMK) inhibitors (Nivala et al. 2014). Consistent with the experimental findings reported here, our computational model predicted that NKA pump inhibition by moderate hypokalaemia played a key role in inducing intracellular Na⁺ and Ca²⁺ loading that activated CaMK, triggering EADs which further increased Ca²⁺ loading during the prolonged action potential. Thus, the initial NKA inhibition by moderate hypokalaemia triggered a positive feedback loop involving CaMK that ultimately culminated in ventricular fibrillation in intact isolated rat hearts. The key point is that once intracellular Ca²⁺ overload develops, its pleiotropic effects on many ion channels/transporters and signalling pathways can generate arrhythmias by a variety of synergistic mechanisms. By directly demonstrating significant NKA pump inhibition by moderate hypokalaemia, this study makes an invaluable contribution to our understanding of pathophysiology of arrhythmogenic complications arising from this common clinical condition.

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Competing interests

None declared.