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Preprint WatchModerateOctober 28th, 2026

Roles of Neuromedin-U and Endothelin-1 in human cardiac organoid differentiation

Snabel, R. R.; Cofino-Fabres, C.; Baltissen, M.; Schwach, V.; Passier, R.; Veenstra, G. J. C.

Endothelin-1 acting through EDNRA increased atrial cardiomyocyte numbers while reducing ventricular cardiomyocyte numbers, shortening repolarisation times and raising contraction frequency in human cardiac organoids.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The preprint reports that endothelin-1 signalling through EDNRA shifts human cardiac organoid differentiation, increasing atrial cardiomyocyte numbers while reducing ventricular cardiomyocyte numbers, shortening repolarisation times and raising contraction frequency. Claidex holds one EDNRA failure, zibotentan-ednra-cirrhosis-portal-hypertension-zeal-phase2-hvpg, an efficacy failure of the endothelin A receptor antagonist zibotentan in cirrhosis with portal hypertension. The preprint describes EDNRA biology in a cardiac developmental system rather than in liver vasculature, so it neither supports nor refutes that trial directly. It does document chamber-specific and electrophysiological consequences of modulating this receptor, which is relevant to how systemic EDNRA antagonism is monitored. Flagged MODERATE because the single matching failure was an efficacy failure.

Abstract excerpt

During recent years, many new culture methods have been established to generate cardiomyocytes, using signaling and patterning factors that play important roles in mammalian heart development. Here, we identify two additional pathways of interest using a cardiac differentiation roadmap that we have generated, involving the endothelin 1 receptor EDNRA gene, and the Neuromedin family signaling peptide gene NMU. Treatment with NMU had most effect in ventricular lineages where it normally is not abundantly expressed, leading to a significant shift from ventricular cardiomyocyte (vCM) differentiation to non-myocytes, as shown with reporters and cell type-specific markers, which was associated with an increased beating frequency. This was not observed in atrial cultures. Treating atrial cultures with endothelin 1 (ET-1, EDN1) increased the number of atrial cardiomyocytes (aCM), while reducing repolarization times, increasing the contraction frequencies and altering the patterns of action potential propagations across the tissue. In ventricular cultures, a reduction in ventricular cardiomyocyte (vCM) numbers was observed, suggesting a combinatorial effect of ET-1 and retinoic acid (RA) on cardiomyocyte differentiation. These results identify ET-1 and NMU as important signaling factors for cardiomyocyte differentiation and electrophysiology of cardiac organoids, with ET-1 enhancing aCM differentiation when added around the time of posteriorization of the second heart field. NMU added without RA reduces the number of vCMs in the culture while it changes the organoids to exhibit a more atrial-like beating frequency.

Matching Claidex post-mortems

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.