An optogenetic arrhythmia model to study catecholaminergic polymorphic ventricular tachycardia mutations.

Area of Science:

• Cardiovascular Physiology
• Genetics and Molecular Biology
• Pharmacology

Background:

• Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening arrhythmia linked to mutations in RyR2 or CASQ2.
• Studying specific CPVT mutations requires simple, analyzable models for drug development.
• The nematode *Caenorhabditis elegans* offers a potential model system due to its established optogenetically paced heart.

Purpose of the Study:

• To establish a *C. elegans* pharyngeal model for studying CPVT-inducing mutations.
• To characterize the functional impact of CPVT mutations in *csq-1* and *unc-68* genes.
• To evaluate the potential of this model for CPVT drug screening.

Main Methods:

• Introduction of CPVT-associated mutations into *csq-1* and *unc-68* genes in *C. elegans*.
• Electrophysiological recordings and video-microscopy to analyze pharyngeal pumping function under pacing.
• Assessment of drug efficacy using the benzothiazepine S107 to reverse induced arrhythmias.

Main Results:

• *csq-1* deletion impaired pharyngeal function, causing missed pumps during high-frequency pacing.
• Mutations in *unc-68* (RyR2 homologue), particularly UNC-68(R4743C), prevented worms from following 3.7 Hz pacing.
• The 'worm arrhythmia' was reversed by S107, demonstrating drug responsiveness.

Conclusions:

• The *C. elegans* pharynx serves as a viable model for studying CPVT-causing mutations in CASQ2 and RyR2.
• This nematode model recapitulates key features of CPVT arrhythmias and is suitable for high-throughput drug screening.
• The study validates the use of *C. elegans* for investigating cardiac channelopathies and testing therapeutic interventions.