1.1. Hypokalaemia: Aetiology and Prevalence

Hypokalaemia is conventionally defined as serum potassium (K⁺) levels < 3.5 mmol/L and presents as a major burden in the health care setting, affecting an estimated 20% of hospitalised patients [2]. Critically, observational studies indicate that arrhythmic and mortality risk rise at even low-normal K⁺ levels (<4.0), suggesting the traditional threshold may be an underestimation [3,4].

The primary aetiology of hypokalaemia in cardiovascular patients is iatrogenic, driven mainly by non-potassium sparing diuretics [5]. Loop diuretics and thiazide diuretics inhibit sodium (Na⁺) and K⁺ reabsorption in the ascending limb and distal tubule respectively, increasing urinary potassium excretion. These populations demonstrate considerable variation in hypokalaemia prevalence, ranging from 7–56% based on pharmacological factors such as drug class, dose and duration of treatment [5]. The risk is further exacerbated in heart failure patients, where disruptions in the Renin-Angiotensin-Aldosterone System (RAAS) result in pathological increases in renal potassium excretion. This dual-pathway mechanism explains the elevated hypokalaemia burden in heart failure cohorts [6]. Neurohormonal activation in heart failure and intracellular potassium redistribution mediated by insulin or β-adrenergic stimulation can further reduce extracellular potassium, while inherited renal tubulopathies, such as Gitelman syndrome, represents a less common cause, often presenting in younger populations with atypical clinical patterns [1,7].

1.2. The Clinical Gap

There is a clear association between hypokalaemia and SCD [1], but current management is largely reactive, restricted to monitoring serum electrolytes and administering potassium supplements. This approach is fundamentally flawed as repletion is often low, poorly tolerated, and does not address the underlying molecular modification which is observed in cardiomyocytes during hypokalaemia [8]. Furthermore, studies document that 24% of hospitalised patients receive inadequate management by published guidelines, highlighting the need for novel therapies [8]. Importantly, as will be detailed in this review, low extracellular [K⁺] causes a physical reduction in the density of hERG (Kv11.1) channels on the cell membrane, functioning as an acquired channelopathy [9,10,11]. This vulnerability can persist even with fluctuating serum levels thus, there is an unmet clinical requirement for therapies to stabilise the membrane effects of hypokalaemia, independent of systemic electrolyte control [9].

3.1. Triggered Activity

Triggered activity refers to the generation of ectopic impulses driven by pathological oscillations in membrane potential, commonly referred to as afterdepolarisations. Unlike automaticity, these events are not self-generating and require a preceding action potential to ‘trigger’ the instability [16]. The cause of triggered action potential is usually defined by two distinct types based on the timing of the oscillation relative to the repolarisation phase: early afterdepolarisation (EAD) and delayed afterdepolarisation (DAD) [16].

EADs typically occur during the plateau (phase 2) and rapid repolarisation phase (phase 3) of the action potential [16,17]. The pathophysiology involves disruption to the normal balance between inward (depolarising) and outward (repolarising) currents, resulting in the lengthening of the action potential. This delay in repolarisation maintains the membrane potential within a critical ‘window’ voltage range (approximately −30 to 0 mV) (Figure 1) [16,17]. In this zone, L-type calcium channels recover from inactivation yet remain in a voltage range sufficient for reactivation. This allows a subset of channels to reopen (re-activate), generating a secondary inward current that reverses repolarisation through calcium influx. While this EAD is localised within the myocyte, its arrhythmogenic consequence requires electronic transmission via gap junction, allowing neighbouring cells which have recovered from repolarisation to generate its own action potential, which can then propagate through the tissue [16,17].

DADs occur after full repolarisation of the action potential (phase 4) and are therefore observed in diastole [18]. These depolarisations are driven by a process called spontaneous calcium release (SCR) from the sarcoplasmic reticulum (SR), which, by definition occurs independently of an action potential during diastole (contrary to systolic calcium release that is triggered by an action potential) [19]. SCR is initiated when SR calcium ion (Ca²⁺) content reaches a critical concentration for release, also known as the threshold for SCR. SCR does not occur synchronously throughout the cell but rather begins in one area and propagates across the cell as a wave of calcium release. As this wave of calcium release propagates, it activates the electrogenic Na⁺/Ca²⁺ Exchanger (NCX), which removes one intracellular Ca²⁺ in exchange for three extracellular Na⁺, producing a net inward transient current (TI) [16]. This inward current underlies the membrane depolarisation that we record as a DAD. The onset of SCR depends on the interplay between SR Ca²⁺ content (concentration of Ca²⁺ in the SR) and the threshold for SCR [20]. Factors that increase ryanodine receptor type 2 (RyR2) open probability—such as CaMKII-mediated phosphorylation, certain naturally occurring mutations or caffeine—can lower the threshold for SCR and thereby increase the likelihood of DADs [21]. As we will see later, hypokalaemia can enhance both SR Ca²⁺ content and RyR2 open probability. The DADs ultimately can trigger a full ectopic action potential (AP) when the DAD amplitude reaches the threshold for activation of voltage-gated Na⁺ channels [16,18].

If spontaneous SR calcium release occurs during the repolarisation phase rather than in diastole, and the resulting inward NCX current is sufficiently large to overcome the outward potassium currents, the membrane voltage will reverse direction before complete repolarisation, manifesting as phase 3 EADs [16,18]. Late phase 3 EADs represent a less common variant occurring at very negative potentials wherein NCX-mediated depolarisation can trigger action potentials [16,18].

Figure 1. The ‘calcium window’ in EAD generation. Depicts steady-state activation (blue line) and inactivation (red line) curves for L-type Ca²⁺ channels plotted against membrane voltage. The cross-hatched region (Window I_Ca,L) represents the voltage range (−30 to 0 mV) where simultaneous channel activation and reduced inactivation permit continuous calcium influx.

3.2. Re-Entry

Re-entry occurs when a cardiac impulse propagates in a circular pathway around an anatomical or functional obstacle, repeatedly re-exciting tissue that has recovered excitability, rather than extinguishing after depolarizing the heart [22,23]. For this to occur, three fundamental prerequisites must be met. First, a unidirectional conduction block, in which an impulse fails to conduct in one direction (typically due to tissue refractoriness) but can conduct in the opposite direction through an alternate pathway. Second, slow conduction through this alternate pathway, which provides sufficient delay to allow recovery of refractoriness at the site of initial block. Finally, an excitable gap, a temporal window during the re-entry cycle in which tissue downstream of the block site has recovered excitability and can be re-excited when the wavefront returns [22,23]. The excitation wavelength, defined as λ = conduction velocity (CV) × effective refractory period (ERP), is critical to re-entry mechanics because it defines the minimum path length required for a circuit. A reduction of wavelength, through either decreased CV or shortened refractoriness, permits re-entry around smaller anatomical obstacles or purely electrophysiological heterogeneity (functional re-entry) [22,23]. Re-entry can circulate around fixed anatomical barriers (scars, accessory pathways) or around functional cores consisting solely of heterogeneous tissue with disparate refractoriness and conduction properties [22,23]. Brugada syndrome is a clinically relevant example in which re-entry can arise from both functional and structural abnormalities in the right ventricular outflow tract [24].

4.1. Na⁺/K⁺-ATPase Inhibition in Hypokalaemia

An important consequence of hypokalaemia is inhibition of the Na⁺/K⁺ -ATPase (NKA) (Figure 2), one of the suggested main contributors to calcium-mediated arrhythmogenesis [26]. The NKA is the cell’s principal regulator of intracellular Na⁺ and K⁺ concentration gradients essential for electrical excitability and calcium handling, functioning by hydrolysing ATP to extrude three Na⁺ in exchange for two K⁺ [27]. The action of this pump is essential in maintaining the resting membrane potential and provides the driving force for the action potential [27].

Figure 2. Integrated Mechanisms of hypokalaemia-induced arrhythmogenesis. Low extracellular [K⁺] initiates parallel pathways of Na⁺/K⁺ ATPase (NKA) inhibition, potassium current suppression and I_k1 rectification, resulting in the main mechanisms of arrhythmia, highlighted in purple boxes. Solid arrows indicate causal relations; Red dotted line demonstrates positive feedback loop. Abbreviations: APD, action potential duration; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; CV, conduction velocity; ERP, effective refractory period; EAD, early afterdepolarisation; DAD, delayed afterdepolarisation; I_Ca,_L, L-type Ca²⁺ current; INa, sodium current; RyR2, ryanodine receptor type 2; RMP, resting membrane potential.

A seminal study by Aronsen and colleagues demonstrated that reducing extracellular [K⁺] in rat ventricular myocytes from 5 mM to 2.7 mM reduced NKA pump current by approximately 25% at constant membrane potential, further increasing to around 48% when the resting membrane potential (RMP) hyperpolarisation was accounted for [28]. This reduction can be explained through various physiological changes observed in hypokalaemia. First, the reduced extracellular [K⁺] and increased cytosolic [Na⁺] reduces the driving force for potassium uptake by the pump, reducing its forward activity [28]. Secondly, the hyperpolarisation of the resting membrane potential itself, which is expected according to the Nernst equation when extracellular [K⁺] is reduced, opposes the pump’s electrogenic activity, further inhibiting pump current [28].

The inhibition of NKA activity has two main consequences on electrolyte regulation and arrhythmia substrate formation. First, the intracellular Na⁺ accumulates due to the reduction in Na⁺ extrusion [26]. This rise in Na⁺ directly impairs the forward mode of the Na⁺/Ca²⁺ exchanger (NCX), which normally removes one intracellular Ca²⁺ ion in exchange for three Na⁺ ions, severely impairing the exchanger’s ability to extrude calcium (Figure 2) [26]. Under severe Na⁺ loading conditions, the NCX may even reverse direction, operating in the reverse mode, importing calcium into the cell and further exacerbating calcium overload [26]. Second, due to the electrogenic characteristic of the pump, its inhibition removes an important repolarising current from the action potential, directly contributing to APD prolongation (Figure 2) [26]. This maintains the membrane potential within the critical voltage window for, L-type Ca²⁺ channels, directly facilitating the generation of EADs (Figure 2) [26]. Thus, inhibition of NKA could establish the initiating events for the arrhythmogenic cascade of hypokalaemia through two parallel mechanisms: calcium overload and APD prolongation. These attributes prime the cell for triggered activity and activate downstream calcium mediated mechanisms, serving as a foundation.

4.2. Potassium Conductance

While NKA inhibition initiates the arrhythmogenic cascade, a second and complementary mechanism occurs—dysregulation of the repolarising K⁺ current which functions to terminate an action potential and return the resting membrane potential (Figure 2) [25]. This reduction in potassium current occurs paradoxically despite hyperpolarisation of the resting membrane potential and increased electrochemical driving force for potassium efflux [25]. This dysregulation is instead driven by the suppression of core repolarising potassium currents: the inward rectifier current (I_K1), the delayed rectifier currents (I_Kr and I_Ks), and the transient outward current (I_to) [25]. Although cumulatively they create a loss of repolarisation reserve, each current has its unique mechanisms by which it is suppressed.

I_K1, encoded primarily by Kir2.x genes, is the primary stabiliser of diastolic resting membrane potential and essential in myocyte repolarisation [29]. Mechanistically, low extracellular [K⁺] increases the stability of intracellular blocking cations (magnesium and polyamines) within the inward rectifier pore, preventing the normal electrostatic displacement of the blockers by extracellular [K⁺] [25]. Consequently, despite the increased electrochemical driving force for potassium efflux, the outward driving force is reduced [25]. This loss of repolarising current is also a critical contributor to the paradoxical depolarisation of the resting membrane potential which further exacerbates arrhythmogenesis [30].

The delayed inward rectifier currents consist of the I_Kr and I_Ks, comprised mainly by the pore forming alpha subunits hERG (encoded by KCNH2) and KvLQT1 (encoded by KCNQ1/KCNE1), and are essential for ventricular repolarisation and determining APD [31,32]. In hypokalaemia I_Kr is suppressed through accelerated inactivation kinetics and reduced recovery from inactivation, both resulting from low extracellular [K⁺] [31,32]. Additionally, critical for this review, the surface density of hERG channels is reduced through mechanisms involving conformational changes and endocytic degradation [31,32]. I_Ks is similarly affected, although the mechanism is more complex. Although I_Ks shows relative resistance to acute hypokalaemia when expressed alone, its suppression is accelerated parallel to I_Kr loss [31]. This can be explained by the macromolecular complex formed between hERG and KCNQ1 at the plasma membrane [31]. When endocytic degradation of hERG occurs, the co-assembled KCNQ1 (and KCNE1) are co-ordinately internalised and degraded [31]. Experimentally, it was demonstrated that HEK cells exposed to 0 mM extracellular [K⁺] for 6 h had reduced hERG-mediated I_Kr by approximately 55% and KCNQ1-mediated I_Ks by 76%, compared to only 20% reduction in I_Ks when KCNQ1 was expressed alone [31]. Importantly, the study also illustrated KCNQ1 delayed the acute reduction of hERG current, attributing a stabilising interaction between the channels, although this was lost following initial hERG degradation [31]. The suppression of both delayed rectifier components prolongs the action potential phase, delaying the return of the membrane potential to rest and maintaining the membrane within the voltage window for L-type calcium channel reactivation [25,31,32].

The transient outward current (I_to), mediated primarily by Kv4.2 and Kv4.3 channels, is responsible for the rapid phase 1 repolarisation (early outward current) following the action potential upstroke and contributes to the plateau voltage. Hypokalaemia has been suggested to slow reactivation of Ito in human atrial cells and further prolong APD [33]. However, compared with evidence for I_Kr and I_K1, the contribution of I_to remains less clearly defined. Therefore, it would be beneficial to further investigate the channel’s role in ventricular hypokalaemia-based arrhythmias.

Overall, the combined suppression of potassium conductance creates a profound loss of repolarisation reserve. Critically, potassium current suppression alone is ineffective at causing EADs in isolated myocytes and rather synergistically acts with the calcium overload initiated by NKA inhibition [26]. As discussed, prolongation of APD maintains the membrane potential within the ‘calcium window’ voltage range, generating EADs. Furthermore, the reduced repolarisation removes the essential suppression of depolarising currents, allowing inward currents to dominate and exert great influence on the membrane potential. The prolongation of repolarisation also allows more time for calcium accumulation in the sarcoplasmic reticulum (SR), increasing the likelihood of spontaneous calcium release. Thus, suppression of repolarising potassium currents acts synergistically with other key mechanisms to establish a highly arrhythmogenic substrate [25].

4.3. Depolarisation of the Resting Membrane Potential

Although low extracellular [K⁺] is expected to hyperpolarise the membrane potential in accordance with the Nernst equation, at least initially, a paradoxical depolarisation of the resting membrane potential (RMP) is observed under sustained hypokalaemia conditions [30]. This counterintuitive phenomenon can be credited primarily to the non-linear nature of the inward rectifier current (I_K1), mediated by Kir2.1 channels [30]. During hypokalaemia, the rectifying properties of the channel at depolarised potentials become pathological, shifting the balance between inward and outward currents at the resting potential, manifesting as depolarisation toward more positive voltages (Figure 2) [30]. An experimental study using human iPSC-derived cardiomyocytes outlined overexpressing Kir2.1 channels manifested as depolarisation of the RMP while the mutant channels, lacking the rectification component, displayed hyperpolarised RMP [30].

This depolarisation of the RMP could carry significant consequences for conduction. By shifting the membrane potential closer to threshold for Na⁺-channel inactivation, there could be a reduction in the number of Nav1.5 channels available to open during phase 0 of the action potential, thereby decreasing the upstroke velocity and local CV while prolonging the ERP. In spatially heterogeneous tissues, regions of slower conduction are more prone to unidirectional block and supporting re-entry [22,23,30]. As this progression has not been demonstrated fully within a tissue model, it should be interpreted as a mechanistically supported pathway requiring confirmation in multicellular preparations with more mature conduction properties.

4.4. CaMKII Activation and Downstream Phosphorylation

The progressive accumulation of calcium through NKA inhibition and APD prolongation increase the amount of calcium stored in the SR and, therefore, increases systolic calcium release. This sustained systolic elevation triggers activation of calcium/calmodulin-dependent protein kinase II (CaMKII), a protein that integrates calcium signalling with phosphorylation of multiple downstream targets and pathways [26,34,35]. Each of these phosphorylation events further contributes to the destabilisation of cardiac electrophysiology, forming the vicious cycle of calcium overload and arrhythmia formation [26,34,35].

4.5. Re-Entry and Hypokalaemia

The cascade of electrophysiological changes outlined do not merely trigger isolated premature beats but rather establish a tissue level substrate permissive for re-entrant arrhythmias. The core mechanisms which facilitate this likely involve simultaneously creating spatial heterogeneity in refractoriness and CV, thereby reducing the excitation wavelength, all of which are essential for re-entry initiation and maintenance [12,25].

The suppression of repolarising potassium currents in hypokalaemia is not uniformly distributed across cardiac tissue [12,15,25]. Heterogeneous expression of hERG, I_K1, and I_to channels across the ventricular wall and between cardiac chambers creates regions with disparate repolarisation kinetics and action potential durations (Figure 2) [18,25]. Consequently, adjacent tissue regions may recover excitability at markedly different rates, establishing the necessary spatial gradient in refractoriness that permits unidirectional conduction block—a prerequisite for re-entry [12,25].

Although APD prolongation would be expected to increase the absolute refractory period, experimental evidence demonstrates that changes in the ERP are often heterogeneous and depend on the resting membrane potential [15,30,37]. More importantly, depolarisation-induced reductions in Na⁺ channel ability and consequent conduction slowing, together with spatial differences in ADP/ERP, could play a major role in creating the conditions necessary for unidirectional block and re-entry.

4.6. Age-Related Changes

Experimental work in Langendorff-perfused rat hearts has illustrated the profound effect of age-associated fibrosis in lowering the threshold for EAD-mediated ventricular arrhythmias in angiotensin II-induced oxidative stress and, critically, hypokalaemia [38]. In this model, the aged ventricles exhibited interstitial fibrosis and reduced connexin-43 density, with most developing EAD-mediated VF secondary to a reduction in extracellular potassium compared to young hearts which consistently observed sinus rhythm or required a longer stress exposure before VF [38]. However, patch-clamp recordings from isolated myocytes illustrated a broadly similar tendency for both young and old cells to promote EADs and triggered activity, implying that cellular electrophysiological remodelling alone does not explain the pronounced age-dependent differences in VF susceptibility [38]. Rather, the age-related changes between cells alter source-sink relationships such that afterdepolarisations that would normally be suppressed by neighbouring cells can escape, propagate as premature beats and degenerate into VF [38]. This is consistent with a “multi-hit” paradigm, where structural remodelling is the first hit and reduced repolarisation reserve the second to induce VF [38].

This finding integrates closely with the mechanisms previously described in this review, with intracellular calcium overload acting as the “second hit” necessary to initiate arrhythmias alongside reduced repolarisation reserve. This convergence of structural and ionic remodelling may outline how more modest hypokalaemia can be particularly malignant in elderly patients with fibrotic cardiomyopathy and highlights the need for therapies that address both components of the substrate.

4.7. Integrated Ionic and Signalling Mechanisms

From the available evidence, the arrhythmogenic consequence of hypokalaemia is likely an integrated network rather than a signal-channel disorder. Reduced NKA activity promotes intracellular Na⁺ accumulation and impaired Ca²⁺ extrusion through the NCX, suppression of I_K1, I_Kr and I_Ks and potentially I_to reduce the repolarisation reserve and activation of CaMKII amplifies inward current and spontaneous release. These processes converge to promote triggered activity, conduction slowing and spatially heterogenous recovery of excitability.

Within this network, evidence strongly supports NKA inhibition as a critical pathway for EAD formation and arrhythmogenesis. However, these findings alone do not establish NKA inhibition as the universal initiating or dominant mechanism of hypokalaemia-induced arrhythmia, as the relative contributions of individual pathways are likely to vary by biological context. Loss of I_Kr may have greater importance when repolarisation reserve is already compromised, such as exposure to hERG-blocking drugs. Conversely, CaMKII signalling may contribute more prominently in settings characterised by pre-existing Na⁺ and Ca²⁺ loading, including heart failure [39]. Hypokalaemia should therefore be regarded as a context-dependent, multi-hit process in which altered repolarisation, intracellular Ca²⁺ handling and the tissue substrate interact to determine arrhythmic risk.

5.1. Historical Identification

The human ether-à-go-go-related gene (KCNH2), widely known as hERG (Kv11.1), was first identified in 1994 by Warmke and Ganetzky [42,43] and, over the decades since its discovery, has been identified to play a major role in the action potential by conducting the rapid component of the delayed rectifier K⁺ current [44]. With the concurrent identification of the complementary slow component, I_Ks [45], the distinctive properties of hERG, particularly its rapid inactivation followed by slow deactivation (commonly recognised as the characteristic hook-tail or inward rectification), highlighted is physiological importance [46]. This inward rectification enables hERG to conduct maximal repolarising current during late phases of the action potential when the membrane potential becomes negative, making hERG the primary repolarisation reserve current in cardiomyocytes [43].

5.2. Structural Characterisation

5.2.1. Tetrameric Architecture and Domain Organisation

As a member of the voltage-gated K⁺ channel family (Kv), hERG is a tetrameric protein composed of four identical α-subunits [43,47]. Each subunit contains six transmembrane segments (S1–S6), where S1–S4 form the voltage-sensing domain (VSD), and S5–S6 constitute the pore domain (PD), consisting of the selectivity filter (SF) responsible for K⁺ specificity (Figure 3) [43,47]. Within the VSD, S4 plays a vital role, being the primary voltage sensor through its positively charged residues that respond to the transmembrane potential changes (Figure 3) [48]. A distinctive feature of KCNH family channels, including hERG, is the presence of two critical cytoplasmic domains: an N-terminal Per-Arnt-Sim (PAS), essential for channel stability when present, and a C-terminal cyclic nucleotide-binding domain (CNBD) that regulates gating kinetics and deactivation (Figure 3) [43,49].

Figure 3. Schematic architecture of a single hERG (Kv11.1) channel subunit. Cartoon representation of one hERG subunit embedded in the plasma membrane, showing transmembrane α-helices (S1–S6) with intracellular N-and C- termini. Segments S1–S4 (red) form the voltage-sensing domain, with S4 containing regularly spaced positively charged residues that detect membrane potential, while S5–S6 (blue) form the pore domain responsible for K⁺ selective conductance. The N-terminal Per-Arnt-Sim (PAS) domain and C-terminal cyclic nucleotide-binding domain (CNBD) are shown in the cytoplasm. Created in biorender [50].

Early electrophysiological and mutagenesis studies identified key functional residues such as Y652 and F656 within the pore as high-affinity drug-binding sites [51,52] and, critically, F627 in the selectivity filter as the primary mediator of rapid C-type inactivation [43,53].

5.3. Gating Kinetics

The physiological significance of hERG as a major contributor to repolarisation reserve current is fundamentally determined by its distinctive gating kinetics: slow activation, rapid inactivation, rapid recovery from inactivation and slow deactivation [44,48]. This specific kinetic profile enables hERG to preserve the depolarising currents of the action potential while simultaneously generating the inward tail currents essential for repolarisation.

5.4. Dysregulation of hERG in Low Extracellular [K⁺]

The dependence of hERG on extracellular [K⁺] was recognised shortly after its initial cloning and was initially attributed to the rectification properties intrinsic to the channel’s rapid inactivation kinetics, specifically, the voltage-dependent trapping of the channel in a non-conducting, inactivated state [46]. However, over the past two decades, this understanding has undergone a fundamental shift, driven by the discovery of a coordinated dysregulation of plasma membrane (PM) hERG expression through accelerated endocytosis and protein degradation [9]. This system presents a second, independent mechanism of hERG current loss, operating in parallel with the acute kinetic suppression [32].

5.4.1. Acute Conformational Destabilization of the Selectivity Filter

The initial mechanism by which low extracellular [K⁺] initiates hERG internalisation involves conformational destabilisation of the mature channel protein (Figure 4). Massaeli and colleagues demonstrated through site directed mutagenesis and functional analysis that specific residues within the hERG selectivity filter are critical for the K⁺-dependent stabilisation of the hERG protein [10]. At physiological extracellular [K⁺] (5 mM), these residues can maintain a stable, plasma membrane (PM) bound channel configuration. However, at low extracellular [K⁺], the selectivity filter loses K⁺ coordination geometry, resulting in conformation destabilisation and a non-conducting state of the channel (Figure 4) [10]. Critically, this acute suppression is reversible with recovered hERG current in ~6 min of restoring normal low extracellular [K⁺] [10].

Figure 4. hERG internalisation in hypokalaemia. Lowering extracellular K⁺ destabilizes the hERG selectivity filter and induces non-conducting gating changes, causing an acute but reversible reduction in I_kr upon restoration of normal K⁺. Persistent hypokalaemia promotes CHIP-mediated K48/K63 polyubiquitination of hERG, clathrin-independent endocytosis, ESCRT/multivesicular body sorting and lysosomal degradation, resulting in decreased cell-surface hERG density and sustained loss of I_kr. Created in BioRender.com [59].

Parallel to the conformational destabilisation, low extracellular [K⁺] disrupts the gating kinetics properties previously discussed [32]. The compromised selectivity filter geometry accelerates inactivation and slows recovery from inactivation, producing functional I_Kr loss before trafficking mechanisms engage [32]. This acute kinetic suppression compounds the electrochemical gradient loss from hypokalaemia itself [32].

6.1. Potassium Supplementation

Despite these developments in the mechanistic understanding of hypokalaemia-induced arrhythmia, current management remains fundamentally limited to potassium supplementation. Recent evidence does confirm that potassium repletion is effective for arrhythmia prevention, particularly in high-risk populations, demonstrating that targeting high normal K⁺ (4.5–5.0 mmol/L) reduced arrhythmia burden by 24% in implantable cardioverter-defibrillator (ICD) patients [63]. However, this repletion alone addresses only the acute electrochemical phase of hypokalaemia-induced dysfunction and has no preventative effect on the chronic structural remodelling of hERG channels or the calcium-mediated mechanisms that operate in parallel.

The mechanistic complexity of hypokalaemia creates multiple therapeutic targets rather than a single solution. Unlike traditional thinking that frames hypokalaemia management as a K⁺ problem, modern understanding reveals that multimodal intervention targeting different mechanisms simultaneously likely provides superior arrhythmia prevention compared to a simpler approach. This section reviews the current pharmacological landscape for hypokalaemia-induced arrhythmia prevention, discussing emerging agents.

6.2. hERG-Blocking Drugs during Hypokalaemia

A critical paradox defines hypokalaemia pharmacotherapy as many antiarrhythmics block hERG channels, the same channel already suppressed by hypokalaemia. The most striking evidence for this comes from Pezhouman and colleagues, demonstrating that dofetilide (a class III antiarrhythmic drug) worsens hypokalaemia-induced arrhythmia in isolated rabbit hearts [26]. At K⁺ 2.7mmol/L, around 50% of cardiomyocytes developed VT/VF compared to 80% in a population treated with 1 μM dofetilide, with additional prolongation of APD observed [26]. Dofetilide achieves this by adding additional hERG blockade through preferential binding to inactivated state of depolarisation. Furthermore, other studies reported that dofetilide, and other similar class III antiarrhythmics, could also have a synergistic effect of activating I_Na,L through phosphoinositide 3-kinase inhibition [64]. These effects compound with the additional properties of hypokalaemia to promote EAD formation and arrhythmia.

6.3. Preclinical Emerging Agents

The recognition that arrhythmia in hypokalaemia involves intracellular Na⁺ and Ca²⁺ loading in addition to reduced repolarisation reserve has identified several potential therapeutic targets including CaMKII, I_Na and RyR2. However, most of these approaches remain preclinical, deriving principally from isolated cardiomyocytes and Langendorff-perfused animal hearts [26,65].

6.4. Translational Gap

A substantial gap separates mechanistic evidence from clinical application. Current potassium replacement is supported by clinical practice and human outcome data while the therapies discussed are mostly experimental strategies. Progression towards clinical testing will require efficacy under clinically relevant degrees and durations of hypokalaemia, confirmation in mature human cardiomyocytes, multicellular cardiac preparations and simultaneous assessment of the ion channels involved in hypokalaemia.