Landiolol and septic ventricular arrhythmias: Revisiting the inflammation-fibrosis-Nav1.5/Cx43 electro-structural axis

Abstract

Sepsis-associated ventricular arrhythmias (VAs) are uncommon, but frequently catastrophic, and their biology remains incompletely defined. Beyond triggers such as catecholamine excess, hypoxia, acid-base and electrolyte derangements, the propensity to develop malignant VAs likely reflects an arrhythmogenic substrate shaped by inflammation-driven electro-structural remodeling. In a cecal ligation and puncture rat model, Hu et al’s study published in the World Journal of Cardiology showed that landiolol, an ultra-short-acting, highly β1-selective blocker, reduces VA burden while attenuating myocardial inflammation, apoptosis and fibrosis, and concurrently normalizes conduction heterogeneity. Mechanistically, sepsis increased ventricular Cx43 and expression of the cardiac sodium channel Nav1.5, whereas landiolol reversed these changes. However, the available data primarily demonstrate associations among reduced inflammation/fibrosis, altered Cx43/Nav1.5 expression, and improved conduction heterogeneity; direct functional evidence, including INa measurements and gap-junction or hemichannel assays, is still required to establish causality. This study is nonetheless important because it reframes landiolol from a rate-control tool to a potential modifier of an inflammatory electro-structural axis. In this editorial, we focus on how inflammation and fibrosis may interact with Cx43 biology and Nav1.5 microdomain organization to promote conduction dispersion and reentry, and we outline a pragmatic translational roadmap centered on phenotype-guided patient selection, dose and time-window definition, and electrophysiology-aware monitoring.

Key Words: Sepsis; Ventricular arrhythmia; Landiolol; β1-blocker; Cx43; Nav1.5; Conduction dispersion; Fibrosis; Electro-structural remodeling; Precision critical care

Core Tip: Hu et al demonstrated that landiolol reduced ventricular arrhythmia burden in a septic rat model while attenuating inflammation, apoptosis, and fibrosis, improving conduction heterogeneity, and being accompanied by reciprocal changes in Cx43 and Nav1.5 expression. The key message is conceptual rather than definitive: Ultra-short-acting beta1 blockade may benefit selected septic patients by modulating an inflammation-fibrosis-Nav1.5/Cx43 electro-structural axis, not merely by slowing heart rate. Future studies should explicitly link expression to function through INa and gap-junction or hemichannel assays, define the safe dose and time window, and translate this framework through phenotype-guided clinical implementation.

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

Sepsis-related arrhythmias remain a substantial challenge in critical care medicine. Although atrial tachyarrhythmias are encountered more commonly, ventricular arrhythmias (VAs), ranging from frequent premature ventricular complexes and non- sustained ventricular tachycardia to sustained ventricular tachycardia and ventricular fibrillation, carry a disproportionate risk of hemodynamic collapse and death.

Conventional explanations have largely focused on acute precipitating factors, including catecholamine excess, hypoxia, acidosis, electrolyte disturbances, drug exposure, and sepsis-induced myocardial dysfunction. However, these triggers alone do not adequately explain why only a subset of septic patients develop malignant VAs. This discrepancy suggests that, beyond transient triggers, a vulnerable arrhythmogenic substrate, either pre-existing or rapidly acquired during sepsis, plays a central role in determining ventricular electrical instability. Currently, growing attention has shifted from simple heart-rate control to the broader concept of electro-structural remodeling in sepsis. Inflammatory activation microcirculatory disturbance, cardiomyocyte injury, interstitial edema, and extracellular matrix remodeling may collectively create a heterogeneous myocardial substrate that favors conduction dispersion and reentry. Within this framework, Cx43, which governs intercellular electrical coupling and may also participate through hemichannel activity, and the cardiac sodium channel Nav1.5, a key determinant of membrane excitability and conduction safety, emerge as plausible mechanistic nodes linking inflammation, fibrosis, and ventricular arrhythmogenesis. Thus, the critical question is no longer merely whether β-blockade slows heart rate in sepsis, but whether it can modify the arrhythmogenic substrate itself.

The experimental study by Hu et al[1] published in the World Journal of Cardiology provides an important mechanistic entry point into this issue. Using a cecal ligation and puncture rat model of sepsis, the authors showed that 24 hours of landiolol treatment reduced circulating tumor necrosis factor-α and interleukin-6 levels, attenuated myocardial disorganization, edema, inflammatory infiltration, apoptosis, and fibrosis, and decreased VA episodes on electrocardiographic assessment. Electrical mapping further suggested that sepsis was associated with increased conduction heterogeneity, whereas landiolol reduced dispersion and partially normalized conduction parameters. At the molecular level, sepsis increased ventricular Cx43 and Nav1.5 expression, changes that were reversed by landiolol[1]. These findings are noteworthy because they extend the potential role of landiolol beyond chronotropic control and raise the possibility that ultra-short-acting β1 blockade may reset a sepsis-induced electro-structural axis underlying VA susceptibility. Importantly, the current data primarily show associations among reduced inflammation and fibrosis, altered Cx43/Nav1.5 expression, and improved conduction heterogeneity; direct functional evidence, such as patch-clamp assessment of INa, gap-junction or hemichannel assays, and higher-resolution mapping, remains necessary before causality can be established. This perspective is particularly timely because ultra-short-acting beta1-blockers, including esmolol and landiolol, have regained interest in the management of septic tachycardia by enabling precisely titratable sympathetic unloading. However, mixed signals from clinical studies indicate that benefit cannot be assumed across all septic phenotypes[2-6]. A mechanistically grounded interpretation is therefore needed to identify who may benefit, when treatment should be initiated, and how antiarrhythmic and hemodynamic effects should be monitored. Against this background, the study by Hu et al[1] deserves attention not simply as a pharmacologic observation, but as a stimulus to reconsider septic VAs through the lens of inflammation-driven electro-structural remodeling.

In brief, systemic inflammation drives interstitial edema and extracellular matrix remodeling, leading to myocardial fibrosis, which in turn alters the distribution and function of Cx43 and Nav1.5, thereby increasing conduction heterogeneity and creating a substrate for reentrant VAs. Understanding whether β1 blockade can modify this axis, rather than merely control heart rate, is the central question motivating the present editorial.

REFRAMING SEPTIC VAS: THE INFLAMMATION-FIBROSIS-NAV1.5/CX43 ELECTRO-STRUCTURAL AXIS

We propose that septic VAs can be usefully conceptualized through an “electro-structural axis” in which inflammatory signaling drives interstitial edema, extracellular matrix remodeling and fibrosis, which in turn amplify spatial heterogeneity in conduction. Within this remodeled tissue, two coupled determinants of propagation become central: (1) Cell-to-cell coupling via Cx43-based gap junctions and potentially hemichannels; and (2) Membrane excitability and conduction safety factor governed largely by Nav1.5-mediated fast INa. Disturbance of either component, especially when discordant across microdomains, increases conduction dispersion and reentry susceptibility (Figure 1)[7-11].

Figure 1 Inflammation-fibrosis-Nav1.5/Cx43 electro-structural axis in septic ventricular arrhythmias and putative landiolol-mediated modulation. Sepsis triggers inflammatory cytokine excess and microcirculatory maldistribution, leading to cardiomyocyte injury, interstitial edema, and extracellular matrix remodeling and fibrosis, thereby generating a structurally heterogeneous substrate. In parallel, remodeling of Cx43-including gap-junction coupling and potential hemichannel activity, both influenced by subcellular localization and phosphorylation-and remodeling of Nav1.5, a key determinant of membrane excitability and conduction safety, may alter propagation dynamics, increase conduction dispersion, and enhance reentry susceptibility, ultimately promoting ventricular arrhythmias. The study discussed here supports associations between landiolol treatment, reduced inflammation and fibrosis, reciprocal changes in Cx43 and Nav1.5 expression, and improved electrophysiologic heterogeneity, consistent with a putative modulation of this electro-structural axis. However, direct functional validation by patch-clamp assessment of INa and by gap-junction or hemichannel assays is still required to establish causality. In the final artwork, evidence-based links should be depicted with solid arrows and more speculative links with dashed arrows. VA: Ventricular arrhythmias.

CX43: BEYOND ABUNDANCE-PHOSPHORYLATION, LOCALIZATION AND HEMICHANNEL BIOLOGY

In many cardiac diseases, the arrhythmogenic relevance of Cx43 is determined less by total protein abundance than by its phosphorylation state, subcellular localization (intercalated disc vs lateralized distribution), and channel composition/function. In sepsis, systemic inflammation may alter kinase/phosphatase balance, oxidative stress and membrane trafficking, favoring gap-junction uncoupling and conduction slowing in some contexts, while immune-cell Cx43 upregulation and hemichannel opening can propagate inflammation through ATP release and inflammasome activation. This dualism implies that simply “up” or “down” regulation is an incomplete descriptor; functional assays (dye transfer, junctional conductance, hemichannel inhibitors) are needed to interpret the net electrophysiologic consequence[12-15].

NAV1.5 MICRODOMAINS: COUPLING EXCITABILITY TO THE INTERCALATED DISC

Nav1.5 channels are organized into distinct pools, particularly at the intercalated disc and lateral membrane, embedded within macromolecular complexes that link sodium-channel availability to structural junctional proteins. Emerging evidence indicates that Cx43 and associated scaffolding elements influence Nav1.5 clustering and stability at the intercalated disc, providing a mechanistic bridge between coupling and excitability. Therefore, septic remodeling that perturbs junctional architecture may secondarily alter Nav1.5 distribution and gating, translating structural injury into conduction vulnerability[16-18].

HOW MIGHT LANDIOLOL MODULATE THE AXIS?

Three non-exclusive mechanisms may explain landiolol’s apparent modulation of the axis. First, β1 blockade reduces catecholamine-driven metabolic demand and may dampen inflammatory signaling cascades, thereby limiting fibrosis and edema that promote heterogeneity. Second, sympathetic unloading can improve ventricular-arterial coupling and microcirculatory balance in selected patients, indirectly stabilizing myocardial electrophysiology. Third, landiolol may exert signaling effects beyond heart-rate reduction, potentially influencing kinase pathways that regulate Cx43 phosphorylation/trafficking and Nav1.5 complex stability. These mechanisms remain plausible rather than proven, and disentangling them will require experiments that separate chronotropic from direct tissue effects (e.g., paced preparations, receptor-specific antagonism, and downstream signaling interrogation)[5,6].

CRITICAL APPRAISAL: STRENGTHS AND LIMITATIONS

Strengths of the Hu et al[1] study include the integrated assessment of inflammation, histopathology, fibrosis, mapping-derived conduction indices, and channel expression within the same septic model. Their data support an association between landiolol treatment and reduced inflammation and fibrosis, altered Cx43 and Nav1.5 expression, and improved conduction heterogeneity. Nonetheless, key limitations constrain mechanistic inference. Most importantly, changes in Nav1.5 expression were not paired with direct INa measurements (patch clamp) or detailed gating kinetics, leaving uncertainty about whether altered protein abundance translated into altered functional current or conduction safety. Similarly, Cx43 biology was inferred largely from expression rather than from direct assessment of junctional conductance, phosphorylation pattern, subcellular localization, or hemichannel behavior. These unresolved steps are central if the proposed electro-structural axis is to move from a compelling hypothesis to a causally established mechanism.

Additionally, conduction mapping findings (including the directionality of conduction velocity changes) warrant cautious interpretation and replication with higher-resolution optical mapping and fibrosis distribution co-registration[1,12-18].

TRANSLATIONAL IMPLICATIONS: FROM “SHOULD WE β-BLOCK” TO “WHO, WHEN, HOW”

Clinical translation should move from a binary question (“use β-blockers in sepsis or not”) to an operational framework: Who benefits, when to start, what dose range is safe and effective, and how to monitor. Randomized trials demonstrate the feasibility of heart-rate control, but heterogeneity of septic shock phenotypes and evolving myocardial function likely explain discordant outcome signals. A brief phenotype contrast is clinically useful. Patients with hyperdynamic septic shock, persistent sinus tachycardia (heart rate > 120 beats/minutes), preserved perfusion, and a relevant burden of ventricular ectopy or non-sustained ventricular tachycardia may represent a more favorable phenotype for carefully titrated landiolol[6,19,21]. In contrast, patients with low-output septic cardiomyopathy, escalating vasopressor requirements, hyperlactatemia, and borderline tissue perfusion are more likely to experience hemodynamic compromise with β1 blockade[2,6,21]. Current guideline statements and contemporary trial data remain cautious regarding routine beta-blocker use in septic shock, underscoring that indiscriminate administration may be unsafe and that implementation should remain phenotype-guided and trial-informed[22,23]. Accordingly, precision deployment should integrate: (1) Hemodynamic phenotype (hyperdynamic tachycardic vs low-output myocardial depression); (2) Arrhythmia phenotype (atrial vs ventricular; burden and triggers); (3) Vasopressor dose and lactate trajectory; and (4) An electrophysiologic substrate signature (baseline QRS/QTc, conduction dispersion proxies, prior structural heart disease)[2-9,24-28]. Recent studies, including several World Journal of Cardiology articles on arrhythmic syncope, risk stratification, inherited arrhythmias, and myocardial injury pathways, provide complementary clinical frameworks and mechanistic context for phenotype-guided implementation in critical care[24-28].

A TESTABLE ROADMAP

To validate the electro-structural axis and landiolol’s position within it, we propose the following staged program: (1) Molecular/function layer: Measure INa (peak, availability, late current), Nav1.5 trafficking, and Cx43 phosphorylation/Localization; quantify gapjunction conductance and hemichannel activity under septic stressors (inflammation, acidosis, hyperthermia); (2) Tissue layer: High-density mapping or optical mapping to quantify conduction velocity, dispersion and reentry threshold; co-register with spatial fibrosis/edema maps to derive structure-function coupling metrics; (3) Translational layer: Prospective phenotyping to define dose/time windows, with protocolized titration and stop rules guided by mean arterial pressure (MAP), lactate, vasopressor requirement, echocardiography, and rhythm burden; and (4) Clinical trials: Enrichment strategies that recruit patients with demonstrable tachycardia-associated electrical instability but preserved perfusion reserve, and incorporate electrophysiology-anchored endpoints (VA burden, dispersion surrogates) alongside organ failure outcomes[12-18].

CONCLUSION

Hu et al[1] provide timely experimental evidence that landiolol reduces septic VAs and attenuates inflammatory and fibrotic remodeling, accompanied by reciprocal changes in Cx43 and Nav1.5 expression and improved conduction heterogeneity. The principal contribution is conceptua: Ultra-short-acting β1 blockade may act as a modulator of an inflammation-fibrosis-Nav1.5/Cx43 electro-structural axis rather than a pure chronotropic intervention. Bridging expression to function and establishing phenotype-guided implementation will be essential to translate this mechanistic promise into safe, reproducible benefit for patients[1-9].