Landiolol, electrical remodeling, and the emerging biology of ventricular arrhythmia control

Abstract

In this editorial, we comment on the article by Hu et al published in the World Journal of Cardiology. Cardiac rhythm disturbances are common in sepsis and range from sinus tachycardia to more serious ventricular arrhythmias. These changes do not occur in isolation; they reflect the combined impact of inflammation, metabolic stress, and persistent adrenergic stimulation on myocardial tissue. Although landiolol has been used primarily to control heart rate, emerging experimental data suggest that its role may extend beyond simple chronotropic modulation. In a septic model, landiolol was associated with a lower ventricular arrhythmia burden and with changes in connexin-43 and NaV1.5, two proteins central to electrical conduction. These findings raise the possibility that selective β1-blockade may influence the arrhythmogenic substrate itself. Further studies are needed to clarify whether modulation of electrical remodeling can translate into meaningful clinical benefit in carefully selected patients.

Key Words: Sepsis; Landiolol; Ventricular arrhythmia; Electrical remodeling; Connexin-43; NaV1.5; β1-selective blockade; Conduction heterogeneity

Core Tip: Ventricular arrhythmias in sepsis may not be only a consequence of elevated heart rate, but rather the result of inflammation-driven electrical instability within the myocardium. Experimental data suggest that landiolol may influence this process by affecting key conduction proteins, including connexin-43 and NaV1.5. This perspective shifts the focus from simple rate control toward potential modulation of the arrhythmogenic substrate, highlighting the need for more targeted clinical investigation.

This editorial refers to “Landiolol modulates sodium 1.5 ion and connexin-43 to reduce sepsis ventricular arrhythmias” by Hu et al, 2026; https://doi.org/10.4330/wjc.v18.i3.117821.

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INTRODUCTION

In patients with sepsis, cardiac function frequently deviates from normal physiologic patterns. The myocardium, which under healthy conditions conducts electrical impulses in a coordinated and synchronized manner, may develop electrical instability[1]. Sinus tachycardia is common, and more significant disturbances, including conduction abnormalities and ventricular arrhythmias, may also arise[2]. These alterations are multifactorial and reflect the combined effects of systemic inflammation, oxidative stress, metabolic derangements, and sustained adrenergic activation, all of which influence cardiomyocyte function and disrupt intercellular electrical coupling[1,3].

Landiolol has attracted attention in this clinical context because it allows selective control of sympathetic stimulation[4,5]. It is a highly β1-selective and ultra–short-acting agent[6,7]. For this reason, it can be carefully titrated and discontinued quickly if hypotension develops[8-10]. In unstable septic patients, this pharmacologic profile is particularly important[6,11,12]. However, the work published in the World Journal of Cardiology by Hu et al[13] suggests a concept that goes beyond simple heart rate control. Their study raises the possibility that landiolol may influence electrical remodeling of the myocardium. If this interpretation is correct, then β-blockade in sepsis may not only slow the heart rate but also modify the arrhythmogenic substrate.

CLINICAL CONTEXT AND SIGNIFICANCE

Sepsis is associated with increased incidence of both atrial and ventricular arrhythmias[2,14]. Observational studies have shown that these rhythm disturbances correlate with worse clinical outcomes[2]. Ventricular arrhythmias in sepsis are especially concerning because the clinical environment is complex[14,15]. Electrolyte imbalance, vasopressor therapy, myocardial ischemia without obstructive coronary disease, and inflammatory injury may coexist[15].

Although several clinical trials have examined the use of landiolol in sepsis, their results have not been entirely consistent. Differences in study design may partly explain these discrepancies. For example, the J-Land 3S trial enrolled patients with sepsis-related tachyarrhythmia who were relatively hemodynamically stable[16], whereas the STRESS-L trial focused on patients with established septic shock[17]. Timing of β-blocker administration, background vasopressor therapy, and the degree of cardiovascular compensation may therefore differ substantially across studies. In addition, septic shock represents a heterogeneous syndrome with varying degrees of inflammatory activation, myocardial dysfunction, and autonomic imbalance. These factors may influence whether β-blockade improves physiologic stability or instead interferes with compensatory sympathetic responses[4].

MECHANISTIC CONSIDERATIONS

The study by Hu et al[13] invites a shift in perspective: Ventricular arrhythmias in sepsis may not simply arise from transient physiologic stress, but from a dynamically evolving substrate shaped by inflammation, adrenergic signaling, and microstructural remodeling of the myocardium. In this framework, electrical instability reflects not only altered cellular excitability but also the disruption of the finely coordinated architecture that governs impulse propagation.

At the center of this process lies the intercalated disc, a specialized microdomain where mechanical and electrical coupling converge. Connexin-43 (Cx43), the principal gap junction protein in ventricular myocardium, plays a critical role in maintaining low-resistance cell-to-cell conduction[18,19]. Yet its function is highly context-dependent. Inflammatory signaling pathways activated in sepsis can alter Cx43 phosphorylation, promote its lateralization away from intercalated discs, and disrupt gap junction organization. These changes do not merely reduce coupling; they introduce spatial heterogeneity, a key substrate for re-entry[18,20].

Parallel to this, NaV1.5, the cardiac sodium channel responsible for rapid depolarization, operates within the same structural network. Increasing evidence suggests that NaV1.5 is not diffusely distributed across the sarcolemma but is preferentially localized within intercalated disc microdomains, where it interacts with scaffolding proteins such as ankyrin-G and βIV-spectrin[21]. This spatial organization is essential for preserving conduction velocity and safety. Inflammatory and oxidative stress may impair channel trafficking or membrane anchoring, effectively reducing local sodium current availability even in the absence of overt changes in total protein expression.

Importantly, these two systems, gap junction coupling and sodium channel function, are not independent. The emerging concept of the perinexus, a narrow extracellular cleft adjacent to gap junctions, suggests that ephaptic interactions between neighboring cells may contribute to conduction, particularly when gap junctional conductance is compromised. In this context, alterations in Cx43 distribution and NaV1.5 localization may synergistically amplify conduction heterogeneity, lowering the threshold for arrhythmia initiation[22].

The observations reported by Hu et al[13], showing modulation of both Cx43 and NaV1.5 in association with reduced ventricular arrhythmia burden, can therefore be interpreted within this broader framework of microdomain remodeling. Whether the observed changes reflect normalization of previously disordered architecture or suppression of maladaptive upregulation remains an open question. What appears more relevant is the potential restoration of spatial coherence in conduction.

These considerations also highlight an important methodological nuance. Measurements of protein abundance alone may not capture the functional state of the conduction system. Subcellular localization, post-translational modification, and microstructural organization are likely to be equally, if not more, important determinants of electrophysiologic behavior in sepsis.

From this perspective, the effect of landiolol may extend beyond heart rate control. By attenuating excessive β1-adrenergic stimulation, it may indirectly modulate inflammatory signaling, oxidative stress, and intracellular calcium handling; pathways that converge on the structural and functional integrity of the intercalated disc[23]. If so, its antiarrhythmic effect may reflect stabilization of the arrhythmogenic substrate rather than simple suppression of triggers.

Such a model helps reconcile an apparent paradox: Why β-blockade may reduce arrhythmias in some septic patients while proving neutral or even detrimental in others. If the underlying substrate has not yet transitioned toward electrical instability, early β-blockade may interfere with compensatory physiology. In contrast, in later stages-when adrenergic excess and inflammatory remodeling dominate—the same intervention may restore electrophysiologic balance.

TRANSLATIONAL IMPLICATIONS

If landiolol modifies electrical remodeling, then clinical endpoints should perhaps be reconsidered[24,25]. Many trials focused mainly on heart rate targets. However, heart rate alone may not reflect arrhythmogenic substrate[4]. Future studies may consider additional electrophysiologic markers, such as ventricular ectopy burden, QRS fragmentation, QT dispersion, or measures of conduction variability[26,27]. These parameters may better represent electrical stability. At the same time, previous trials remind us that tachycardia can sometimes be compensatory in septic shock[28]. Early or inappropriate β-blockade may worsen hemodynamics in patients who are preload-dependent or require increasing vasopressor support[29-31]. Therefore, patient selection is critical[16]. The hypothesis suggested by Hu et al[13] may help reconcile previous findings. Landiolol may be beneficial in patients who are hemodynamically stabilized but continue to experience adrenergic excess and evolving electrical remodeling. In contrast, in patients who are still in early unstable shock, β-blockade may not be appropriate.

CONCLUSION

The main strength of this study is its mechanistic focus. By examining Cx43 and NaV1.5, Hu et al[13] connect molecular alterations with arrhythmia susceptibility. This approach aligns with the current understanding that conduction depends on integrated microdomain organization within the intercalated disc.

The limitation is related to translation into human sepsis. Human patients are heterogeneous, and connexin behavior can vary depending on timing, severity, and measurement methods. Furthermore, previous clinical trials show that achieving heart rate control does not automatically lead to improved survival or organ function. Nevertheless, mechanistic clarification is valuable. It provides a direction for more targeted clinical investigation.

Future research may benefit from several considerations: Incorporation of electrophysiologic biomarkers in clinical trials, not only heart rate. Careful phenotype selection, focusing on patients with persistent adrenergic activation after stabilization. Bridging studies in humans to determine whether landiolol influences inflammatory signaling pathways related to electrical remodeling. Such approaches may help identify patients who could derive the most benefit.

Table 1 summarizes reported and biologically expected directional changes in key markers in sepsis and with landiolol, based on the Hu et al[13] in-press summary and broader sepsis electrophysiology literature; magnitudes and exact assay conditions should be taken from the final published manuscript.

Table 1 Summary of molecular and electrophysiologic changes in sepsis and with landiolol.

Domain	Sepsis (typical direction)	Landiolol in Hu et al[13] (direction)	Why this matters for ventricular arrhythmias
Inflammation (e.g., TNF-α, IL-6)	↑	↓	Cytokines and oxidative stress can destabilize myocardial electrophysiology and promote remodeling
Myocardial fibrosis/structural remodeling	↑	↓	Fibrosis increases conduction discontinuity and re-entry susceptibility
Cx43 remodeling	Context-dependent (often disordered localization; variable expression)	↓ (reported)	Altered coupling/hemichannel behavior and heterogeneity can widen dispersion and sustain re-entry
NaV1.5 remodeling	Variable; dysfunction/redistribution linked to conduction slowing/heterogeneity	↓ (reported)	Sodium current supports conduction reserve; disordered regulation can increase vulnerability to conduction block and re-entry
Conduction heterogeneity/dispersion	↑	↓	Dispersion is a substrate for re-entrant ventricular arrhythmias
Ventricular arrhythmia burden	↑	↓	Captures the clinically salient endpoint: Fewer malignant rhythms

TNF-α: Tumor necrosis factor-alpha; IL: Interleukin.