Ryanodine receptor 2 mutations in catecholaminergic polymorphic ventricular tachycardia: From molecular mechanisms to precision medicine

Table 1 Common ryanodine receptor 2 mutations and clinical characteristics

Mutation	Domain	Functional effect	Clinical severity1	Age of onset2	Penetrance3	β-blocker response	SOICR threshold4
R2474S	Central	Reduced threshold for Ca2+-induced Ca2+ release	Moderate-severe	Childhood-adolescence	80%-90%	Variable	Significantly reduced
N2386I	Central	Reduced threshold with enhanced sensitivity	Severe	Early childhood	95%	Poor	Markedly reduced
R4497C	Transmembrane	Channel structural instability	Mild-moderate	Adolescence-early adulthood	60%-70%	Good	Moderately reduced
S2246 L	Handle	Increased channel open probability	Moderate	Childhood	75%-85%	Good	Reduced
T2504M	Central	Enhanced SR Ca2+ leak with impaired termination	Severe	Early childhood	90%-95%	Variable	Severely reduced

¹Based on frequency of arrhythmic events and exercise tolerance.

²Typical age range when symptoms first appear.

³Percentage of mutation carriers who develop clinical manifestations.

⁴Relative threshold for store overload-induced calcium release activation.

SOICR: Store-overload-induced Ca²⁺ release; SR: Sarcoplasmic reticulum.

Table 2 Comparative efficacy of catecholaminergic Polymorphic Ventricular Tachycardia Therapies

Ref.	Treatment strategy	Arrhythmia reduction	SCD prevention	Side effects	Clinical use	Cost effectiveness
Mazzanti et al[44], 2022; Baltogiannis et al[45], 2019; Zhou et al[46], 2011	β-blockers alone	60%-70%	Moderate	Fatigue, bradycardia	First-line	High
Watanabe et al[48], 2011	β-blockers + Flecainide	80%-90%	High	Proarrhythmia risk	Refractory cases	Moderate
Kannankeril et al[50], 2017	Carvedilol	70%-80%	Moderate-high	Hypotension, fatigue	Alternative first line	High
Penttinen et al[52], 2015; Kobayashi et al[53], 2009	Dantrolene + β-blockers	75%-85%	High	Hepatotoxicity, weakness	Experimental	Unknown
van der Werf et al[55], 2011	ICD	> 95%	Very high	Device complications	High-risk patients	Low-moderate
De Ferrari et al[59], 2015; Hofferberth et al[60], 2014	LCSD	70%-80%	High	Surgical risks	β-blocker failure	Moderate

SCD: Sudden cardiac death; ICD: Implantable cardioverter defibrillator; LCSD: Left cardiac sympathetic denervation.