RyR2-Dependent Calcium Leak Drives the Acute Cardiovascular Manifestations of Ciguatera Poisoning: implications for an emerging climate-sensitive cardiotoxic disease
- 1Physiology and Experimental Medicine of Heart and Muscles, Universite de Montpellier, Inserm, CNRS, Montpellier, France
Abstract
Background: Ciguatera is the most prevalent non-bacterial seafood poisoning worldwide. It results from the consumption of fish contaminated with ciguatoxins (CTXs). Cardiovascular manifestations are frequently reported in affected patients; however, the molecular mechanisms underlying CTX-induced cardiac dysfunction remain poorly understood. Methods: We investigated the effects of purified CTX-1B and CTX-3C on human induced pluripotent stem-cell-derived ventricular cardiomyocytes. Electrophysiology, intracellular calcium cycling and contractility, and cellular structure were assessed. The RyR2 channel activity was studied in planar lipid bilayers, and molecular docking was used to identify a potential CTX-1B interaction site. Consequences on cardiac function were assessed in rats using echocardiography and EKG. Findings: We found that ciguatoxin exposure rapidly increased diastolic intracellular calcium, with severe impacts on the cardiac excitation-contraction coupling, and caused sarcomeric disorganization in human cardiomyocytes. Single-channel recordings indicated that CTX-1B prolonged RyR2 openings at resting cytosolic calcium and altered ATP-dependent gating. These findings are consistent with a state-dependent remodeling of RyR2 gating rather than uniform potentiation. Docking placed CTX-1B within the RyR2 transmembrane region, near ATP-associated regulatory elements. In rats, CTX-1B caused premature atrial contractions, ventricular ectopy, and acute cardiac dysfunction, with impaired relaxation. Interpretation: These findings identify RyR2-dependent calcium leak as a plausible contributor to ciguatoxin cardiotoxicity and extend the established model based on sodium-channel activation and altered sarcolemmal ion handling. Combined disruption of membrane excitability and intracellular calcium release could explain the rapid electrical and mechanical abnormalities associated with ciguatera. As intensive international shipping traffic and the global dispersal of harmful microalgae via ballast water expand exposure risk alongside the international seafood trade, ciguatera should be considered an emerging global cardiovascular hazard.
Related
- Cardiovascular Manifestations of Cystic Fibrosis
- Class effect beyond glucose: Implications of the LEGEND‐T2DM findings for cardiovascular outcomes
- A Literature Review on the Waist Circumference Criteria for Metabolic Syndrome in Japan: Evidence and Implications for Cardiovascular Risk Stratification
- The Connection of Immune Response and cGAS-STING Pathway in Cardiovascular Disease: From Basic Mechanism to Therapeutic Implications
- Integrated Use of Extracorporeal Membrane Oxygenation and Molecular Adsorbent Recirculating System for Refractory Cardiotoxic Ingestion: A Single-Center Case Series
BibTeX
@misc{benoit2026ryr2dependent,
title = {{RyR2-Dependent Calcium Leak Drives the Acute Cardiovascular Manifestations of Ciguatera Poisoning: implications for an emerging climate-sensitive cardiotoxic disease}},
author = {H. Benoit and I. Choukri and P. Sicard and E. Bounasri and G. Labesse and L. Alburquerque and M. Laabir and J. Mercier and J. Thireau and A. Lacampagne and A. C. Meli},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.748269},
url = {https://www.biorxiv.org/content/10.64898/2026.08.31.748269v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - RyR2-Dependent Calcium Leak Drives the Acute Cardiovascular Manifestations of Ciguatera Poisoning: implications for an emerging climate-sensitive cardiotoxic disease
AU - H. Benoit
AU - I. Choukri
AU - P. Sicard
AU - E. Bounasri
AU - G. Labesse
AU - L. Alburquerque
AU - M. Laabir
AU - J. Mercier
AU - J. Thireau
AU - A. Lacampagne
AU - A. C. Meli
PY - 2026
DA - 2026/08/31
PB - bioRxiv
DO - 10.64898/2026.08.31.748269
UR - https://www.biorxiv.org/content/10.64898/2026.08.31.748269v1
AB - Background: Ciguatera is the most prevalent non-bacterial seafood poisoning worldwide. It results from the consumption of fish contaminated with ciguatoxins (CTXs). Cardiovascular manifestations are frequently reported in affected patients; however, the molecular mechanisms underlying CTX-induced cardiac dysfunction remain poorly understood. Methods: We investigated the effects of purified CTX-1B and CTX-3C on human induced pluripotent stem-cell-derived ventricular cardiomyocytes. Electrophysiology, intracellular calcium cycling and contractility, and cellular structure were assessed. The RyR2 channel activity was studied in planar lipid bilayers, and molecular docking was used to identify a potential CTX-1B interaction site. Consequences on cardiac function were assessed in rats using echocardiography and EKG. Findings: We found that ciguatoxin exposure rapidly increased diastolic intracellular calcium, with severe impacts on the cardiac excitation-contraction coupling, and caused sarcomeric disorganization in human cardiomyocytes. Single-channel recordings indicated that CTX-1B prolonged RyR2 openings at resting cytosolic calcium and altered ATP-dependent gating. These findings are consistent with a state-dependent remodeling of RyR2 gating rather than uniform potentiation. Docking placed CTX-1B within the RyR2 transmembrane region, near ATP-associated regulatory elements. In rats, CTX-1B caused premature atrial contractions, ventricular ectopy, and acute cardiac dysfunction, with impaired relaxation. Interpretation: These findings identify RyR2-dependent calcium leak as a plausible contributor to ciguatoxin cardiotoxicity and extend the established model based on sodium-channel activation and altered sarcolemmal ion handling. Combined disruption of membrane excitability and intracellular calcium release could explain the rapid electrical and mechanical abnormalities associated with ciguatera. As intensive international shipping traffic and the global dispersal of harmful microalgae via ballast water expand exposure risk alongside the international seafood trade, ciguatera should be considered an emerging global cardiovascular hazard.
ER -