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Decoding intracellular signaling in atrial fibrillation — From the magic lens of Western blot to clinical practice Cover

Decoding intracellular signaling in atrial fibrillation — From the magic lens of Western blot to clinical practice

Romanian Journal of Cardiology
AHEAD OF PRINT
By: Alkora Ioana Balan,  Elena Butoi,  Mihaela Vadana,  Miruna Larisa Naie,  Andreea Cristina Mihaila and  Alina Scridon  
Open Access
|Apr 2026
Figures & tables

Figures & Tables

Figure 1

Schematic representation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathway in atrial fibrillation (AF). Schematic representation of CaMKII activation and its downstream effects on atrial electrical remodeling. Increased intracellular Ca2+, sympathetic stimulation, and oxidative stress promote CaMKII activation, leading to altered phosphorylation of ion channels and Ca2+-handling proteins, including RyR2 and phospholamban/sarcolipin. These changes favor sarcoplasmic reticulum Ca2+ leak, triggered activity, and shortening of atrial refractoriness, thereby contributing to the initiation and maintenance of AF. AF – atrial fibrillation; ICa,L – L-type Ca2+ current; IK1 – inward rectifier K+ current; IK,Ca – Ca2+-activated K+ current; IKur – ultra-rapid delayed rectifier K+ current; INa – Na+ current; Ito – transient outward K+ current; NCX – Na+– Ca2+ exchanger; NHE – Na+-H+ exchanger; PLB/SLN – phospholamban/sarcolipin; RyR – ryanodine receptor

Figure 2

Integrated intracellular signaling network underlying atrial remodeling in atrial fibrillation. Atrial fibrillation (AF) results from the convergence of multiple intracellular signaling pathways that collectively generate an arrhythmogenic electrical and structural substrate. Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a central role in electrical remodeling by promoting Ca2+-handling abnormalities and triggered activity. Structural remodeling is driven predominantly by profibrotic signaling through the TGF-β/Smad pathway, with amplification by mitogen-activated protein kinases (MAPK) and inflammatory NF-κB signaling. The PI3K/AKT/mTOR pathway exerts context-dependent effects, supporting cardiomyocyte survival while promoting fibroblast proliferation under pathological conditions. Oxidative stress and inflammatory mediators act as common upstream drivers and reinforce pathway crosstalk. The integrated activity of these signaling networks promotes atrial fibrosis, conduction heterogeneity, and sustained AF. AKT – protein kinase B; CaMKII – calcium/calmodulin-dependent protein kinase II; ERK – extracellular signal-regulated kinase; IN, late – late sodium channel current; JNK – c-Jun N-terminal kinase; MAPK – mitogen-activated protein kinase; mTOR – mammalian target of rapamycin; NF-κB – nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K – phosphatidylinositol 3-kinase; ROS – reactive oxygen species; RyR – ryanodine receptor; Smad – suppressor of mothers against decapentaplegic; TGF-β1 – transforming growth factor beta 1

Figure 3

Western blot as a molecular window into atrial fibrillation signaling. Western blot analysis enables the detection of protein expression and post-translational modifications in atrial tissue samples obtained from experimental models or patients with atrial fibrillation (AF). Following total protein extraction from heterogeneous atrial tissue, Western blot allows the relative quantification of signaling proteins and their phosphorylated forms, providing insights into the activation status of key intracellular pathways involved in electrical and structural remodeling. However, this technique does not preserve spatial resolution, cell-type specificity, or temporal dynamics of signaling events. Therefore, Western blot findings should be interpreted as reflecting global pathway activation and are best integrated with functional, imagingbased, and electrophysiological approaches to fully characterize the AF substrate. AF – atrial fibrillation; AKT – protein kinase B; CaMKII – calcium/calmodulin-dependent protein kinase II; ERK – extracellular signal-regulated kinase; RyR2 – ryanodine receptor 2; Smad – suppressor of mothers against decapentaplegic

Therapeutic strategies targeting signaling pathways involved in atrial fibrillation_

Signaling pathwayDrug class / examplesMain molecular effectsEffects on atrial remodelingClinical AF outcomesReferences
Ca2+/CaMKIIβ–blockers↓ sympathetic tone; indirect ↓ CaMKII activationImproved Ca2+ handling; ↓ triggered activityReduced AF burden; limited efficacy in persistent AF[36]
Ca2+ channel blockers↓ ICa,L; ↓ Ca2+ influxElectrical stabilization; minimal structural effectsRate control; no prevention of AF progression[36]
MAPKACE inhibitors / ARBs↓ ERK, p38 activation; ↓ Ang II signaling↓ atrial fibrosis; ↓ fibroblast activationReduced new–onset AF; modest effect in established AF[35,1]
MAPK/TGF–βMineralocorticoid receptor antagonists (eplerenone)↓ ERK, ↓ TGF–β signalingReduced atrial fibrosis; improved conduction homogeneityReduced AF recurrence in selected populations[34,37]
PI3K/AKT /mTORStatinsAnti-inflammatory; ↓ oxidative stress; indirect AKT modulationAttenuation of structural remodelingInconsistent AF prevention; benefit mainly in postoperative AF[38,39]
mTOR inhibitors (rapamycin)↓ mTORC1 activity; ↑ autophagyReduced atrial fibrosis (experimental)No established clinical role[40,41]
NF–κBAnti–inflammatory agents↓ NF–κB activation; ↓ cytokine expressionReduced inflammatory atrial remodelingNo consistent benefit in AF prevention[42,43]
TGF–β/SmadARBs, MRAs↓ Smad phosphorylation↓ profibrotic gene transcriptionReduced AF susceptibility; limited reversal of advanced fibrosis[44,45]
MultipleStatins, RAAS blockers↓ oxidative stress; ↓ inflammationSubstrate modification rather than rhythm controlExplains delayed and modest clinical effects(39,44–46)
DOI: https://doi.org/10.2478/rjc-2026-0010 | Journal eISSN: 2734-6382 | Journal ISSN: 1220-658X
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Language: English
Published on: Apr 18, 2026
Published by: Romanian Society of Cardiology
In partnership with: Paradigm Publishing Services
Publication frequency: 4 issues per year
Keywords:
atrial fibrillation,
atrial fibrosis,
atrial remodeling,
intracellular signaling,
Western blot
Related subjects:
Medicine,
Clinical medicine,
Internal medicine,
Cardiology,
Surgery,
Cardiac surgery,
Pediatrics and juvenile medicine,
Paediatric cardiology

© 2026 Alkora Ioana Balan, Elena Butoi, Mihaela Vadana, Miruna Larisa Naie, Andreea Cristina Mihaila, Alina Scridon, published by Romanian Society of Cardiology
This work is licensed under the Creative Commons Attribution 4.0 License.

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