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| Item Type: | Article |
|---|---|
| Title: | Innervated human cardiac muscle model reveals sympathetic drivers of KCNH2-associated arrhythmias |
| Creators: |
Schneider, Lennart Valentin  ORCID: https://orcid.org/0009-0007-1634-697X, Setya, Michael Gani, Bao, Guobin, Härtter, Daniel ORCID: https://orcid.org/0000-0002-9582-6141, Methi, Aditi, Krüger, Dennis ORCID: https://orcid.org/0000-0003-1950-9547, Schreiber, Marie Kristin ORCID: https://orcid.org/0000-0003-2965-1491, Jensen, Ole ORCID: https://orcid.org/0000-0001-9903-4769, Kanari, Elisavet, Schmoll, Kea Aline, Telugu, Narasimha Swamy ORCID: https://orcid.org/0000-0003-4509-7056, Sakib, Sadman, Kim, Eun Seo ORCID: https://orcid.org/0009-0008-7306-3009, Fahud, Aminath Luveysa ORCID: https://orcid.org/0000-0003-0613-4344, Novin, Maham, Seedorf, Aylin, Diecke, Sebastian ORCID: https://orcid.org/0000-0002-5219-5992, Fischer, André, Liaw, Norman Y. ORCID: https://orcid.org/0000-0001-7804-8133, Zimmermann, Wolfram-Hubertus ORCID: https://orcid.org/0000-0003-1190-4040 and Zafeiriou, Maria-Patapia ORCID: https://orcid.org/0000-0003-4604-4175
|
| Abstract: | Cardiac autonomic neurons regulate contractility. Autonomic nervous system dysregulation can cause sympathetic overdrive, leading to heart failure, and fatal arrhythmias. Here, we introduce innervated engineered human myocardium (iEHM), a model of neuro-cardiac junctions, constructed by fusing sympathetic neuronal organoids (SNO) and engineered human myocardium (EHM). Projections of sympathetic neurons formed presynaptic terminals in close proximity to cardiomyocytes and to the extensive vascular network co-developing in iEHM. Contractile responses to optogenetic stimulation of the accordingly engineered neuronal component demonstrated functional neuro-cardiac junctions. Modeling long-QT 2 in iEHM revealed sympathetic neuron hyperactivity and after depolarizations, underscoring a central role for sympathetic drive in KCNH2-associated arrhythmias. β-adrenoreceptor blockade was insufficient to rescue the pro-arrhythmic phenotype, while mexiletine targeting both neurons and cardiomyocytes, proved to be more effective. Collectively, our data establishes iEHM as a New Approach Methodology that provides a human-relevant, physiologically integrated model for mechanistic investigations and pharmacological testing. |
| Keywords: | Cardiac Arrhythmias, Cardiac Myocytes, ERG1 Potassium Channel, Heart, Myocardium, Neurons, Optogenetics, Sympathetic Nervous System |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 17 |
| Number: | 1 |
| Page Range: | 9404 |
| Date: | 2 September 2026 |
| Official Publication: | https://doi.org/10.1038/s41467-026-76956-9 |
| PubMed: | View item in PubMed |
| Related to: |
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