Key result
EL20 (500 nmol/L) reduced diastolic Ca2+ spark frequency by 78% in CPVT patient-derived R176Q iPSC-CMs.
Why the study?
EL20 was shown to inhibit mutant RyR2 and suppress arrhythmias in mice, but whether it normalizes SR Ca2+ handling and arrhythmic events in human CPVT iPSC-CMs was unknown.
Does the tetracaine derivative RyR2 inhibitor EL20 normalize diastolic sarcoplasmic reticulum Ca2+ handling and suppress arrhythmogenic activity without impairing systolic Ca2+ handling in iPSC-derived cardiomyocytes from a patient with RyR2-R176Q catecholaminergic polymorphic ventricular tachycardia?
Does the tetracaine derivative RyR2 inhibitor EL20 normalize diastolic sarcoplasmic reticulum Ca2+ handling and suppress arrhythmogenic activity without impairing systolic Ca2+ handling in iPSC-derived cardiomyocytes from a patient with RyR2-R176Q catecholaminergic polymorphic ventricular tachycardia?
Answers are grounded in this paper and cite their sources.
First demonstration in human CPVT patient-derived cardiomyocytes that the selective RyR2 inhibitor EL20 suppresses arrhythmogenic diastolic Ca2+ leak at low nanomolar concentrations (IC50 = 82 nM) without impairing systolic Ca2+ handling.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal‐dominant variants in the cardiac ryanodine receptor type‐2 ( RYR2) gene. Mutations in RYR2 promote calcium (Ca 2+ ) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca 2+ handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca 2+ handling and arrhythmic events in induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg‐176‐Glu (R176Q) and a mutation‐negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC‐CMs were derived using the Stemdiff TM kit. Confocal Ca 2+ imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC‐CMs harbouring the R176Q variant demonstrated spontaneous SR Ca 2+ release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC 50 = 82 nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca 2+ handling in control iPSC‐CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca 2+ handling and suppresses arrhythmogenic activity in iPSC‐CMs derived from a CPVT patient. Hence, this study confirms that this RyR2‐inhibitor represents a promising therapeutic candidate for treatment of CPVT.
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Word et al. (2021) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT) (n=2). EL20 (tetracaine derivative RyR2 inhibitor) vs. Vehicle and mutation-negative control iPSC-CMs was evaluated on Diastolic Ca2+ spark frequency (CaSpF, sparks/100 um/s) in evoked R176Q iPSC-CMs in the presence of 100 nmol/L isoproterenol (p=<0.001). EL20 (500 nmol/L) reduced diastolic Ca2+ spark frequency by 78% in CPVT patient-derived R176Q iPSC-CMs.
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