ArticleEuropace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology2026
DENND3-p.R534S disrupts dyadic microdomain architecture to drive potentially pro-arrhythmic calcium and electrophysiologic instability.
Article in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors.
Funding
Abstract
aimsInherited ventricular arrhythmias (VAs) frequently occur in the absence of pathogenic variants in canonical ion channel genes, suggesting alternative mechanisms of electrical instability. DENND3 is a guanine nucleotide exchange factor that regulates Rab GTPase-mediated trafficking, but its role in cardiac excitation-contraction coupling and membrane microdomain organization remains undefined. METHODS AND
resultsWe studied induced pluripotent stem cell-derived cardiomyocytes generated from a CRISPR/CAS9-engineered ultra-rare DENND3-p.R534S variant-inserted line (previously identified in an idiopathic ventricular fibrillation pedigree) and matched isogenic controls. Multielectrode array recordings, live-cell calcium imaging, super-resolution imaging using expansion microscopy, and biochemical analyses were used to assess electrical activity, calcium handling, membrane architecture, and calcium release unit organization. Potentially therapeutic studies were performed using genetic and pharmacologic inhibition of Rab11b. DENND3-p.R534S induced pluripotent stem cell-derived cardiomyocytes exhibited multicellular electrical instability characterized by increased beat-to-beat variability, arrhythmic activity, conduction slowing, and prolonged excitation-contraction delay. These abnormalities were accompanied by heterogeneous and dyssynchronous calcium cycling despite preserved expression of major calcium-handling proteins. Super-resolution imaging revealed disruption of BIN1-dependent membrane architecture and nanoscale uncoupling of Cav1.2 and RyR2. Inhibition of Rab11b restored BIN1 organization, re-established dyadic coupling, normalized calcium cycling, and improved electrical stability.
conclusionThese findings support a model in which altered trafficking balance contributes to disruption of membrane microdomain organization, leading to dyadic uncoupling, calcium instability, and electrical dysfunction. Modulation of the Rab11b-mediated trafficking pathway restored structural and functional abnormalities, supporting the trafficking-associated pathway as a potential therapeutic target in DENND3-associated ventricular arrhythmia.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.