Catecholaminergic polymorphic ventricular tachycardia: A narrative review of recent advances in genetics, mechanisms, diagnosis, and treatment

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but potentially lethal inherited arrhythmia syndrome. It is characterized by exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia, which can lead to recurrent syncope and even sudden death. CPVT is mainly caused by mutations in genes related to calcium homeostasis regulation, with ryanodine receptor 2 and calsequestrin 2 gene mutations being the most common. In recent years, with the development of molecular biology techniques and in-depth clinical research, the understanding of CPVT has been continuously deepened. This review summarizes the latest advances in CPVT research, focusing on molecular genetic mechanisms, pathogenesis, clinical manifestations, diagnostic approaches, and treatment strategies. We examine the complex interplay between genetic mutations and arrhythmogenic mechanisms, highlighting insights from heterologous, animal, and human induced pluripotent stem cell-derived models. The review also addresses current therapeutic approaches, from pharmacological interventions to device therapy and sympathetic denervation, while exploring future research directions that may lead to improved patient outcomes through gene-specific and precision medicine approaches.

1. Introduction

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by malignant ventricular arrhythmias induced by exercise or emotional stress^[1]. Although the incidence is estimated to be approximately 1:10,000 worldwide, it carries an extremely high risk of death, with a mortality rate of up to 30% to 50% before the age of 40 in untreated individuals^[1,2]. The disease usually first occurs in childhood, with an average age of onset of 7 to 9 years, and is one of the important causes of sudden death in young people, especially children and adolescents^[3]. The clinical importance of CPVT is mainly reflected in its high lethality, early onset, diagnostic difficulties, and treatment challenges^[4]. Even under modern treatment conditions, there is still a significant risk of death. The disease usually occurs first in childhood, affecting quality of life. Resting electrocardiogram (ECG) is often normal, making it easy to miss or misdiagnose^[3,5]. Moreover, CPVT requires lifelong treatment, and the treatment effect varies greatly among individuals^[5].

In recent years, with the deepening of molecular genetic research, the understanding of CPVT has been continuously improved. Currently, multiple pathogenic genes have been discovered, among which ryanodine receptor type 2 (RyR2) gene mutations are inherited through an autosomal dominant manner, accounting for 55% to 65% of identified cases, while calsequestrin 2 (CASQ2) gene mutations are inherited through an autosomal recessive manner, accounting for about 2% to 5% of identified cases^[3]. These findings provide an important basis for understanding disease mechanisms and developing new treatment strategies.

This review aims to summarize the latest advances in the field of CPVT research, specifically by systematically elucidating the molecular genetic mechanisms and pathogenesis of CPVT; describing the clinical manifestations and diagnostic strategies; and presenting the advantages and disadvantages of existing treatment options. Through this review, we provide a complete overview of current understanding in CPVT research, highlighting key advances in genetics, pathophysiology, diagnosis, and treatment approaches.

2. Search strategy

For this narrative review, literature research was performed using PubMed from 2000 to 2025. The following keywords were used: (“Polymorphic Catecholaminergic Ventricular Tachycardia”[MeSH Terms] OR “catecholaminergic polymorphic ventricular tachycardia”[Title/Abstract] OR “CPVT”[Title/Abstract]) AND (“Ryanodine Receptor Calcium Release Channel “[MeSH Terms] OR “ryanodine receptor 2”[Title/Abstract] OR “RyR2”[Title/Abstract] OR “Calsequestrin”[MeSH Terms] OR “calsequestrin 2”[Title/Abstract] OR “CASQ2”[Title/Abstract] OR “Calmodulin”[MeSH Terms] OR “calmodulin”[Title/Abstract] OR “CALM1”[Title/Abstract] OR “CALM2”[Title/Abstract] OR “CALM3”[Title/Abstract] OR “Triadin”[Title/Abstract] OR “TRDN”[Title/Abstract] OR “TECRL”[Title/Abstract]) AND (“Genetics”[MeSH Terms] OR “Mutation”[MeSH Terms] OR “Pathogenesis”[Title/Abstract] OR “Diagnosis”[MeSH Terms] OR “Therapeutics”[MeSH Terms] OR “treatment”[Title/Abstract] OR “management”[Title/Abstract]) AND (“2000/01/01”[Date - Publication]: “2025/01/01”[Date - Publication]). After removing irrelevant and duplicate records, the titles and abstracts were screened, and articles deemed unrelated or unnecessary were excluded.

3. Genetics of catecholaminergic polymorphic ventricular tachycardia

CPVT is a genetically heterogeneous disease, and multiple causative genes have been discovered to date. A deep understanding of the characteristics of these gene mutations and their functional impact is of great significance for the diagnosis, risk assessment, and treatment selection of the disease.

3.1. Primary pathogenic gene: ryanodine receptor type 2

3.1.1. Ryanodine receptor type 2 gene mutation types, distribution, and functional impact

The RyR2 gene is located on the long arm of chromosome 1 (1q43), comprising 105 exons and encoding the RyR2 protein consisting of 4967 amino acids^[6]. RyR2 functions as a calcium release channel on the sarcoplasmic reticulum (SR) of cardiac myocytes, playing a crucial role in excitation–contraction coupling^[7]. RyR2 interacts with multiple regulatory proteins including CASQ2, Triadin, Junctin, Calmodulin, Junctophilin, and FK506-binding protein 12.6 (FKBP 12/12.6), which normally stabilizes its closed state. To date, far over 150 RyR2 mutations have been identified in CPVT patients^[8] (Table 1), with the following key characteristics:

Table 1.

RyR2 mutations related to catecholaminergic polymorphic ventricular tachycardia.

Variant	Loc	Model	Findings/mechanism	Reference
Exon3 del	NT	HL-1, HEK293	↓Threshold for Ca2+ release termination ↑Fractional Ca2+ release	Tang et al.[9]
		hiPSC-CM	↓APD ↓AP amplitude ↓Upstroke velocity ↑DADs and EADs after adrenaline exposure	Pölönen et al.[10]
F13L	NT	hiPSC-CM	↑Ca2+ spark ↑[Ca2+]i transient amplitude	Stutzman et al.[11]
L14P		hiPSC-CM
R15P		hiPSC-CM
A77V	NT	HL-1, HEK293	↓Threshold for Ca2+ release termination ↑Fractional Ca2+ release	Tang et al.[9]
R176Q	NT	HL-1, HEK293	↓Threshold for Ca2+ release termination ↑Fractional Ca2+ release	Tang et al.[9]
		HEK293	↓Threshold for SOICR	Jones et al.[12]
		hiPSC-CM	↑Abnormal diastolic Ca2+ release Ameliorated by CaMKII inhibition	Bezzerides et al.[13]
		hiPSC-CM	↑SR diastolic Ca2+ release events. Diminished by RyR2 inhibitor EL20 ↓SR Ca2+ load	Word et al.[14]
		hiPSC-CM	↑Ca2+ spark	Stutzman et al.[11]
G230C	NT	HEK293	↓Calstabin 2 binding ↑Sensitivity of cytosolic Ca2+	Meli et al.[15]
		HEK293	↓Threshold for SOICR ↑Sensitivity of single RyR2 channels to both cytosolic and luminal Ca2+ activation	Liu et al.[16]
G357S	NT	HEK293	↓Thresholds for the activation and termination of SOICR ↓Thermal stability of the N-terminal domain of RyR2 ↓Protein expression of the full-length RyR2	Liu et al.[17]
		HEK293	↑Caffeine sensitivity and SOICR activity	Wangüemert et al[18]
S406L	NT	hiPSC-CM	↑Diastolic [Ca2+]i by ISO ↓SR Ca2+ content ↑DADs, ↑Frequency and duration of Ca2+ sparks	Jung et al.[19]
		hiPSC-CM	↑SR diastolic Ca2+ release events Ameliorated by activating mitochondrial Ca2+ uptake	Schweitzer et al[20]
R420W	NT	Mice	Impairs depolarization-induced Ca2+ oscillation	Okudaira et al.[21]
R420Q	NT	HEK293	↓Ca2+ release	Domingo et al.[22]
		hiPSC-CM	ISO: failure to ↑[Ca2+]i transient amplitude but ↑diastolic [Ca2+]i or induced arrhythmias	Novak et al.[23]
		Mice/hiPSC-CM	↑DADs ↑Ca2+ waves ↑Fractional Ca2+ release Longer Ca2+ sparks Widened junctional SR Impaired binding of RyR2 and junctophilin-2	Yin et al.[24]
		hiPSC-CM	↑Irregular, long-lasting Ca2+ sparks	Zhang et al.[25]
		Mice	↑EADs during β-adrenergic stimulation ↑APD	Zissimopoulos et al.[26]
L433P	NT	HEK293/HL-1	↑SOICR ↑Sensitivity to luminal Ca2+ activation	Jiang et al.[27]
		Mice	↑Frequency Ca2+ sparks ↓SR Ca2+ load	Shan et al.[28]
		HEK293	Impairs tetramerization of the full-length channel Altered sensitivity to Ca2+ activation Prolonged Ca2+ transients ↓Ca2+ store content	Seidel et al.[29]
N771D	Ctr	hiPSC-CM	↓ICa ↓RyR2 Ca2+ leak ↑CICR gain Normal Fractional release ↑DADs ↑Ca2+ sparks	Fernández-Morales et al.[30]
A1107M	Ctr	HEK293	↑Threshold for Ca2+ release termination ↓Fractional Ca2+ release	Tang et al.[9]
R1760W	Ctr	HEK293	↑SOICR ↓Activation and termination thresholds of spontaneous Ca2+ release ↑Sensitivity to cytosolic Ca2+ activation	Li et al.[31]
A1855D	Ctr	hiPSC-CM	Premature spontaneous SR [Ca2+]i transients ↓RyR2 expression ↑Action potential duration	Zhou et al.[32]
G2145R	Ctr	HEK293	↑RyR2 open probability	Marjamaa et al.[33]
S2246L	Ctr	HL-1	↑Ca2+ release	George et al.[34]
		HEK293/HL-1	↑SOICR ↑Sensitivity to lumina Ca2+ activation	Jiang et al.[27]
		HEK293	↓Threshold for SOICR	Jones et al.[12]
E2311D	Ctr	hiPSC-CM	↑DADs and triggered activity both resting and β-adrenergic stimulation Ameliorated by CaMKII inhibition	Di Pasquale et al.[35]
P2328S	Ctr	HEK293	↓Binding of JPH2	Lehnart et al.[36]
		Mice	↑Diastolic Ca2+ release	Zhang et al.[37]
		hiPSC-CM	↓SR Ca2+ content ↑Fractional release ↑Diastolic [Ca2+]i with adrenaline ↑DADs, ↑EADs	Kujala et al.[38]
		Mice	↑DADs and ectopic APs ↑Interatrial conduction delays ↓Epicardial conduction velocity ↓dV/dt	King et al.[39]
		Mice	↓Nav1.5 expression and Na+ channel function	King et al.[40]
		hiPSC-CM	↑Diastolic [Ca2+]i by adrenaline ↑Ca2+ abnormalities, reduced by dantrolene	Penttinen et al.[41]
		hiPSC-CM	↑Variability of Ca2+ transients under ISO Slower depolarization in epinephrine	Paavola et al.[42]
		Mice	↑Activated and inactivated activities of RyR2	Salvage et al.[43]
H2464D	Ctr	hiPSC-CM	↑Maximum contractile strain ↓Contraction rate	Stempien et al.[44]
F2483I	Ctr	hiPSC-CM	↑DADs after sympathetic stimulation ↑Amplitude and duration of diastolic [Ca2+]i release, abolished by Forskolin	Fatima et al.[45]
		hiPSC-CM	↑CICR gain ↓SR Ca2+ load Longer and propagating Ca2+ sparks	Zhang et al.[46]
		hiPSC-CM	Longer and propagating Ca2+ sparks ↓SR Ca2+ load	Wei et al.[47]
		hiPSC-CM	↑SR Ca2+ release, suppressed by JTV519 and reduced by flecainide and dantrolene ↓SR Ca2+ load	Zhang et al.[25]
N2386I	Ctr	Mice	↑Diastolic SR Ca2+ leak	Shan et al.[28]
R2474S	Ctr	HEK293/HL-1	↑SOICR ↑Sensitivity to lumina Ca2+ activation No alteration of the FKBP12.6-RyR2 interaction	Jiang et al.[27]
		Mice	The interaction between the N-terminal and central domains of the RyR2 was weakened	Uchinoumi et al.[48]
		Mice	↓CaM-binding affinity Defective interdomain interaction between the N-terminal and the central domain of the RyR2	Xu et al.[49]
		Mice	↑Ca2+ spark frequency after β-adrenergic stimulation, which can be attenuated by dantrolene	Kobayashi et al.[50]
		Mice	Exercise training reduces ventricular tachycardia	Manotheepan et al.[51]
V2475F	Ctr	Mice	↑Cytosolic and luminal Ca2+ activation Abnormal PKA phosphorylation ↑Spontaneous Ca2+ release events	Loaiza et al.[52]
F2483I	Ctr	hiPSC-CM	↑DADs Higher amplitudes and longer durations of spontaneous Ca2+ release	Fatima et al.[45]
		hiPSC-CM	Aberrant unitary Ca2+ signaling ↓SR stores ↑CICR gains Sensitized adrenergic regulation	Zhang et al.[46]
		hiPSC-CM	Longer Ca2+ sparks ↑Diastolic Ca2+ leaks	Wei et al.[47]
		hiPSC-CM	↑Fractional Ca2+ release	Zhang et al.[25]
T2538R	Ctr	hiPSC-CM	↑Ca2+ abnormalities, reduced by dantrolene	Penttinen et al.[41]
D3638A	Ctr	hiPSC-CM	3D conformational defects ↑Aberrant Ca2+ transients ↑SR Ca2+ leak Weaker response to ISO in force contraction ↑PKA phosphorylation of RyR2, prevented by S107	Acimovic et al.[53]
L3741P	CT	hiPSC-CM	↑DADs in response to ISO ↓SR Ca2+ load ↑SR Ca2+ leak ↑Fractional Ca2+ release ↑Ca2+ wave, reduced by flecainide ↑Ca2+ spark, reduced by flecainide	Preininger et al.[54]
E3848A	CT	hiPSC-CM	Homozygous: block of CICR, insensitive to 5 mM caffeine	Xia et al.[55]
Q3925E		hiPSC-CM	Heterozygous: ↓CICR and caffeine-triggered Ca2+ release
E4076K	CT	hiPSC-CM	↑SR Ca2+ leak, rescued by S36	Mohamed et al.[56]
N4104K	CT	HEK293	↑SOICR ↑Sensitivity of activation by luminal Ca2+	Jiang et al.[57]
M4109R	CT	hiPSC-CM	↑DADs with or without adrenergic stimulation ↑Triggered activity ↑Irregular [Ca2+] i transient ↓SOICR threshold	Itzhaki et al.[58]
L4115F	CT	hiPSC-CM	↑Ca2+ abnormalities, mostly irresponsive to dantrolene	Penttinen et al.[41]
		hiPSC-CM	↑Ca2+ abnormalities, can be reduced by carvedilol	Pölönen et al.[59]
		hiPSC-CM	↑DADs and EADs after adrenaline exposure ↑Discordant negatively coupled alternans ↑Arrhythmias, can be cured by carvedilol	Pölönen et al.[10]
Q4201R	CT	hiPSC-CM	↑SR Ca2+ release, suppressed by JTV519 and reduced by flecainide and dantrolene ↓SR Ca2+ load ↑CICR gain ↑Fractional release	Zhang et al.[25]
R4496C	CT	HEK293	↑RyR2 sensitivity to activation by Ca2+ and by caffeine	Jiang et al.[60]
		Mice	↑DADs No alteration of RyR2–FKBP12.6 interaction	Liu et al.[61]
		Mice	↑Spontaneous Ca2+ sparks frequency ↓SR Ca2+ load ↑Abnormal diastolic Ca2+ release ↑DADs ↑Triggered activity ↑Ca2+ sensitivity of RyR2	Fernández-Velasco et al.[62]
		Mice	CaMKII inhibitor counteracts the effects of adrenergic stimulation	Liu et al.[63]
I4587V	CT	hiPSC-CM	↑Diastolic [Ca2+]i and ↑DADs by ISO, can be reduced by S107	Sasaki et al.[64]
V4653F	CT	hiPSC-CM	↑Ca2+ abnormalities	Penttinen et al.[41]
		hiPSC-CM	↑Ca2+ abnormalities, can be reduced by carvedilol	Pölönen et al.[59]
R4790Ter	CT	hiPSC-CM	↑Calcium transient abnormalities, can be reduced by labetalol ↓SOICR threshold	Hopton et al.[65]
A4860G	CT	HL-1/HEK293	↓Response of RyR2 to activation by luminal Ca2+ ↓SOICR	Jiang et al.[66]
		Mice	↓RyR2 channel activity ↓Peak of Ca2+ release during systole ↑SR Ca2+ load ↑EADs	Zhao et al.[67]
S4938F	CT	hiPSC-CM	↑Frequency of spontaneous Ca2+ sparks and transients ↑SR Ca2+ content	Toth et al.[68]

AP, action potential; APD, action potential duration; CaMKII, Ca2+/calmodulin-dependent kinase II; CICR, calcium-induced calcium release; CT, C-terminal domain; Ctr, central domain; DADs, delayed afterdepolarizations; dV/dt, derivative of membrane voltage with respect to time; EADs, early after depolarizations; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocyte; ISO, isoproterenol; Loc, location; NT, N-terminal domain; PKA, protein kinase A; RyR2, ryanodine receptor type 2; SOICR, store overload-induced Ca²⁺ release; SR, sarcoplasmic reticulum.

1. Mutation types: Missense mutations predominate, accounting for approximately 86% to 92% of cases. Other types include frameshift mutations and splice site mutations^[69]. Most mutations result in gain-of-function alterations in the RyR2 channel, although a small number of loss-of-function mutations have been reported.

2. Mutation distribution: RyR2 mutations are predominantly concentrated in 3 regions. The C-terminal region (amino acids 3778–4201 and 4497–4959) contains the highest percentage of mutations at 44%. The central region (amino acids 2246–2534) accounts for approximately 19%, and the N-terminal region (amino acids 44–466) represents 18% of mutations^[70]. While early studies suggested mutations outside these 3 regions were rare, direct sequencing analysis has revealed that approximately 24% of RyR2 mutations are located outside these canonical domains^[70].

3. Functional impact: These mutations exert their pathogenic effects through multiple molecular mechanisms. Several mutation-specific mechanisms have been identified in mouse models, depending on their location within the RyR2 protein structure. In the C-terminal domain, the p.R4496C mutation is associated with increased Ca²⁺ sensitivity^[62], while the p.A4860G mutation within the pore results in loss of function^[67]. In the central domain, the p.R2474S mutation disrupts the zipping–unzipping interaction between the N-terminal and central domains^[48] and/or affects FKBP12.6 binding to RyR2, destabilizing it^[71]. N-terminal domain mutations such as p.R420Q interfere with interdomain interactions, particularly between the N-terminal and the core solenoid^[24], impairing RyR2 closing. Some CPVT variants have also been identified outside the hotspots, with distinct mechanisms, such as p.D3291V, which impair cyclic adenosine monophosphate (cAMP) response^[72].

3.1.2. Relationship between ryanodine receptor type 2 mutations and clinical phenotypes

Patients carrying RyR2 mutations demonstrate significant phenotypic heterogeneity. The age of onset varies widely, ranging from 2 to over 40 years, with a mean onset age of 7 to 12 years^[73]. The severity of ventricular arrhythmias varies from asymptomatic with ECG abnormalities to syncope, cardiac arrest, and sudden death^[73]. Additionally, individual responses to antiarrhythmic medications, such as β-blockers, show considerable variation^[73].

Although definitive genotype–phenotype correlations remain unclear, several studies have identified associations between specific RyR2 mutations and clinical features. Mutations in the C-terminal channel region are associated with longer QTc intervals, more severe ventricular arrhythmias, and poorer prognosis^[74,75]. RyR2 A1107M mutations are linked to CPVT with concurrent dilated cardiomyopathy phenotype^[76], while patients with RyR2 R169Q mutation frequently present with left ventricular noncompaction phenotype^[77]. Compound heterozygous patients carrying multiple RyR2 mutations typically exhibit more severe clinical manifestations^[77]. Furthermore, patients carrying multiple RyR2 variants show significantly increased risk of ventricular arrhythmias, even when some variants are considered “benign”^[78], emphasizing the importance of evaluating the composite effects of RyR2 variants.

3.2. Other pathogenic genes

3.2.1. Calsequestrin 2 gene

The CASQ2 gene is located on the short arm of chromosome 1 (1p13), contains 11 exons, and is primarily expressed in the heart^[79]. CASQ2 gene mutations are inherited in an autosomal recessive manner, accounting for approximately 2% to 5% of CPVT cases^[79].

1. Functional characteristics: CASQ2 encodes cardiac calsequestrin, a high-capacity, low-affinity calcium-binding protein in the SR, which plays a crucial role in maintaining calcium homeostasis in cardiomyocytes^[80]. As a regulatory protein of the RyR2 channel, CASQ2 forms a complex with RyR2, junctin, and triadin to regulate SR calcium release^[81]. At low calcium concentrations (<1 mM), CASQ2 binds tightly to RyR2 and inhibits its activity; at high calcium concentrations (>10 mM), CASQ2 dissociates from the complex, relieving the inhibition^[81,82]. Additionally, reduced CSQ2 levels and increased sarco/endoplasmic reticulum Ca²⁺-ATPase activity cause RyR2 hyperactivity without changing SR calcium content^[83].

2. Mutation impact: CASQ2 mutations primarily lead to deficient protein expression or severe functional defects^[84], resulting in decreased SR calcium storage^[85] and buffering capacity^[86], uncontrolled RyR2 activity, and disruption of intracellular calcium homeostasis^[86,87]. CPVT mouse model with the CASQ2 R33Q mutation exhibits reduced CASQ2 content, decreased SR calcium content, abnormal SR structure, and impaired protein clustering, replicating the stress-induced arrhythmias seen in human patients^[88]. Dysfunctional or decreased CASQ2 alters RyR2 channel sensitivity to luminal calcium concentration, lowering the threshold for store overload-induced Ca²⁺ release and exacerbating calcium leakage^[80,89]. Dominant-negative mutations (D307H, P308L) form heteropolymers that interfere with normal CASQ2 folding, leading to ectopic accumulation of aggregates and disrupted RyR2 coupling^{[84,87,90–96]}. CPVT-related mutations alter the secondary structure of CASQ2, causing abnormal aggregation in low calcium environments, with effects amplified during sympathetic stimulation^[95]. Additionally, CASQ2 gene polymorphisms are associated with susceptibility to other inherited arrhythmias such as idiopathic ventricular fibrillation^[97] and sudden cardiac arrest^[98], suggesting that CASQ2 dysfunction may be one of the common molecular foundations for various arrhythmias.

3.2.2. Calmodulin genes (calmodulin 1-3)

Calmodulin is a regulatory protein that binds to RyR2 and L-type calcium channels, modulating calcium signaling pathways in cardiac excitation–contraction coupling^[99]. CALM1-3 genes encode the same protein^[100], and mutations of calmodulin can cause arrhythmic syndromes with overlapping phenotypes including CPVT, idiopathic ventricular fibrillation, and long QT syndrome^[100–103]. Related mutations alter calmodulin interaction with RyR2, enhancing calcium release (gain-of-function) in CPVT, or impair calcium-dependent inactivation of L-type calcium channels, leading to prolonged repolarization and QT interval (long QT syndrome)^[104–110]. Patients carrying calmodulin mutations show diverse clinical presentations but often have a poor prognosis with a higher risk of sudden cardiac death^[102].

3.2.3. Triadin gene (triadin)

The TRDN gene encodes triadin, a scaffold protein located on the SR membrane and lumen of the SR that is part of the calcium release complex with RyR2, CASQ2, and junction^[111]. TRDN gene mutations cause triadin deficiency or instability, resulting in reduced T-tubule-SR junction area, decreased RyR2-LTCC (L-type calcium channel) coupling efficiency, and increased SR calcium leakage, leading to CPVT phenotype^[112–115]. In addition to arrhythmias, TRDN mutation patients may experience skeletal muscle symptoms such as mild to moderate muscle weakness^[116]. A new clinical phenotype called “triadin knockout syndrome” has been proposed, featuring dual characteristics of CPVT and long QT syndrome^[116–118].

3.2.4. TECRL gene

TECRL gene (chromosome 7) mutations are associated with a rare autosomal recessive subtype of CPVT (CPVT3)^[119]. Current understanding of TECRL protein function is limited, but it may be related to lipid metabolism^[120]. TECRL-deficient mouse and human induced pluripotent stem cell (iPSC)-derived cardiomyocyte models both exhibit mitochondrial dysfunction and lipid droplet accumulation^[121]. This type of CPVT often presents in infancy or early childhood, progresses rapidly, is difficult to control, and has a poor prognosis^{[119,122,123]}. Currently, there are no specific treatment approaches.

3.3. Genetic heterogeneity

3.3.1. Inheritance patterns

CPVT exhibits significant genetic heterogeneity, manifested in the diversity of inheritance patterns, gene expression profiles, and clinical phenotypes^[87,124,125]. CPVT1 carrying RyR2 gene mutations is predominantly inherited in an autosomal dominant manner, accounting for ~60% of CPVT cases^[126], while CPVT2 caused by CASQ2 gene mutations is mainly inherited in an autosomal recessive manner, comprising only 2% to 5%^[127]. Rare cases of autosomal dominant CASQ2 mutations have also been reported^[87,128,129]. CPVT associated with other genes such as TRDN, CALM1-3, and TECRL may follow more complex inheritance patterns, such as compound heterozygosity, though currently there are relatively few reported cases, warranting further research^{[115,119,130]}.

3.3.2. Expression profiles

Different CPVT-related genes show tissue-specific expression patterns^[131]. RyR2 and CASQ2 are highly expressed primarily in cardiac tissue^[132,133], while CALM genes are widely distributed across various tissues and organs^[134]. Different mutations within the same gene can have varying impacts on cardiac and skeletal muscle tissues^[135,136]. Patients carrying TRDN mutations may experience skeletal muscle symptoms such as mild to moderate muscle weakness in addition to cardiac arrhythmias^[136,137]. The phenotypic heterogeneity of CPVT suggests possible involvement of other modifier genes influencing disease development^[24,138,139], though current understanding of this aspect remains insufficient.

3.3.3. Phenotypic variations

Even within CPVT families carrying identical gene mutations, patients exhibit significant differences in clinical presentation^[74]. Variations in age of onset, concomitant atrial arrhythmias, exercise-induced arrhythmia thresholds, and drug efficacy commonly exist within families^[74,140]. CPVT clinical phenotypes show age-related characteristics, with children typically presenting with syncope, while the risk of ventricular arrhythmias and sudden death significantly increases in adulthood^[73]. Some genotypes may develop myocardial structural abnormalities^[141]. Environmental factors such as exercise load and emotional stress significantly impact CPVT phenotypes^[142,143].

4. Cellular and animal model studies

In order to understand the molecular mechanisms and pathogenesis of CPVT, different experimental models have been established. Current CPVT research models mainly include heterologous models, animal models, and human models.

4.1. Heterologous models

The earliest studies of RyR2 CPVT mutations utilized heterologous expression systems, particularly HEK293 cell lines. Jiang et al.^[27] expressed RyR2 channel mutations from multiple regions (including Q4201R, I4867M, S2246L, R2474S, R176Q, and L433P) in stable inducible HEK293 cell lines and found that all these mutants exhibited increased propensity for store overload-induced Ca²⁺ release (SOICR) and enhanced calcium sensitivity. Paavola et al.^[144] showed mutant RyR2 (P2328S and V4653F) in HEK293 cells exhibited spontaneous Ca²⁺ release at lower cAMP concentrations than wild type. Additionally, Eckey et al.^[145] expressed CASQ2 mutations (R33Q, F189L, and D307H) in Xenopus oocytes, revealing altered hERG channel function and Ca²⁺ buffer capacity. These heterologous expression systems offer significant advantages for CPVT research, including precise control of experimental conditions, isolation of specific protein interactions, and rapid assessment of multiple mutations, thereby providing fundamental mechanistic insights before proceeding to more complex animal models. However, they lack the cardiac context.

4.2. Animal models

Animal models, particularly zebrafish and mice, have been essential for CPVT research and understanding the disease mechanisms. Studies on zebrafish embryos showed that CPVT-associated calmodulin mutations (N53I and N97S) cause increased heart rates under β-adrenergic stimulation, suggesting cardiac contraction’s sensitivity to calmodulin integrity^[146]. Mouse models have been the most widely used animal models due to their genetic tractability and ease of manipulation. Our group found that cardiomyocytes from RyR2 R4496C knock-in mice exhibit normal basal Ca²⁺ transients but abnormal diastolic Ca²⁺ waves and delayed afterdepolarizations (DADs) during stress conditions. Recording of Ca²⁺ sparks in permeabilized cells exposed to different cytosolic [Ca²⁺]_i indicated that increased Ca²⁺ sensitivity is the primary arrhythmogenic mechanism of this mutation^[147]. Rabbits exhibit ion channel patterns more closely to those of humans than mice do^[147], making them potentially valuable for CPVT research. To date, one rabbit model with RyR2 mutation has been created, but the study is underway^[148]. To date, mouse models have provided critical insights into calcium handling abnormalities that underline CPVT pathophysiology, setting the foundation for translational studies in human models.

4.3. Induced pluripotent stem cell-cardiomyocyte models

In recent years, the emergence of iPSC technology has opened new avenues for CPVT mechanism research. Gao et al.¹⁴⁹ demonstrated through iPSC-cardiomyocyte models that the CALM2 p.E46K variant causes CPVT by enhancing CaM-RyR2 binding affinity, increasing SR Ca²⁺ leakage, and triggering arrhythmogenic Ca²⁺ waves. Compared with mature cardiomyocytes, iPSC-derived CPVT-specific cardiomyocytes retain the patients’ genetic background and can better simulate the human internal environment.

Engineered cardiac tissue models have also gained prominence in CPVT research. Park et al.¹⁵⁰ utilized engineered human cardiac tissue models and CRISPR/Cas9 gene editing to construct an optogenetically stimulated cardiac tissue model that simulates CPVT arrhythmias. Their research showed that CPVT tissues are prone to forming reentrant arrhythmias under high-frequency stimulation and catecholamine exposure. These engineered cardiac tissue models provide a powerful platform for studying CPVT mechanisms and evaluating potential treatment in a human-relevant context.

5. Pathogenesis of catecholaminergic polymorphic ventricular tachycardia

The pathogenesis of CPVT mainly involves calcium homeostasis imbalance and triggered activity, with abnormal calcium ion handling being the core pathological mechanism (Fig. 1). A deep understanding of these mechanisms is significant for developing new therapeutic strategies.

Figure 1.

Cardiac excitation–contraction coupling and arrhythmogenesis. During the cardiac action potential, Ca²⁺ enters the cytoplasm through L-type calcium channels (LTCCs), activating ryanodine receptors type 2 (RyR2) on the sarcoplasmic reticulum (SR) and triggering calcium-induced calcium release (CICR). This causes massive Ca²⁺ release from the SR, leading to myofilament activation and cellular contraction. During diastole, Ca²⁺ is primarily pumped back to the SR via the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, while a portion is extruded from the cell through the sodium-calcium exchanger (NCX) with a 3:1 stoichiometry (3Na⁺:1Ca²⁺). Under pathological conditions, abnormal RyR2 opening leads to spontaneous SR Ca²⁺ release, activating NCX to generate inward current and produce DADs. When DADs reach the action potential (AP) threshold, they can trigger abnormal spontaneous arrhythmias. This process involves regulation by calsequestrin 2 (CSQ2), FK506-binding protein 12 (FKBP12), calmodulin (CaM), and phosphorylation modifications by protein kinase A (PKA) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), which collectively modulate RyR2 function. Junctophilin-2 (JPH2) maintains the structural integrity of the junctional SR and T-tubule coupling essential for effective excitation–contraction coupling. Created in BioRender. Luo, S. (2025) https://BioRender.com/vws60tx. DADs, delayed afterdepolarizations.

5.1. Ryanodine receptor type 2 channel dysfunction

RyR2 channel dysfunction directly causes CPVT1, with any factors affecting RyR2 properties potentially contributing to disease pathogenesis. Several mechanisms proposed for CPVT1 include altered sensitivity to calcium, N-terminal domain unzipping, and FKBP12.6 dissociation, though these remain contentious and require further investigation.

5.1.1. Store overload-induced calcium release

SOICR was first described by Jiang et al. to characterize depolarization-independent calcium release triggered by SR calcium overload^[57]. Their hypothesis proposes that CPVT mutations lower the SOICR threshold by enhancing RyR2 sensitivity to luminal Ca²⁺, thereby increasing arrhythmia susceptibility. Chen’s team distinguished between physiological RyR2 activation by cytosolic Ca²⁺ (calcium-induced calcium release) and pathological activation by luminal Ca²⁺ during SR overload. However, this model faces significant challenges. Our studies demonstrated that permeabilized cells with RyR2 R4496C mutations exposed to elevated cytosolic Ca²⁺ show increased spark frequency, suggesting hypersensitivity to cytosolic calcium as well^[62]. Kashimura’s research on the RyR2 R4496C CPVT mouse model revealed that β-adrenergic stimulation triggers calcium waves by increasing SR content rather than by reducing the calcium wave threshold, indicating that enhanced luminal calcium sensitivity may not be universally present in CPVT pathophysiology^[151].

5.1.2. Increased Ca²⁺ sensitivity of ryanodine receptor type 2

RyR2 activates through calcium-induced calcium release when calcium enters through L-type channels. Calcium serves as a crucial RyR2 regulator with dual effects—activation at micromolar cytosolic concentrations and inhibition at millimolar levels, suggesting the presence of distinct binding sites with different affinities^[152]. CPVT1 research reveals altered calcium sensitivity in mutant channels, as demonstrated by the RyR2^R4496C mutation, which exhibits increased diastolic calcium spark frequency, indicating enhanced channel activity. Our study using permeabilized cells exposed to varying cytosolic calcium concentrations confirms dramatically increased sensitivity in mutated channels^[62]. ’Marx’s group also proposed that protein kinase A (PKA)-mediated hyperphosphorylation of RyR2 at S2809 increases Ca²⁺ sensitivity and causes FKBP12.6 to dissociate from RyR2, leading to abnormal channel activity^[153].

5.1.3. Alteration of intermolecular interactions

The first finding was instability of the interaction between N and central domains, which normally interact favoring the closed state, an interaction called “zipping.” The domain zipping–unzipping hypothesis proposed by Yamamoto et al.^[154] suggests that interactions between N-terminal (residues 1–600) and central (residues 2000–2500) domains regulate RyR2 function. Experimental models using DPc10 peptide demonstrate that domain unzipping causes calcium leak, enhances cAMP-dependent phosphorylation, and promotes FKBP12.6 dissociation^[155]. Studies in RyR2 R2474S knock-in mice show weakened interdomain interactions, with DPc10 treatment of wild-type cells reproducing mutant channel dysfunction^[48]. High-resolution crystallography reveals CPVT-linked mutations predominantly locate at domain interfaces, providing structural evidence supporting domain unzipping as a key mechanism underlying CPVT pathophysiology^[156,157]. More recently, it was shown that the R420Q mutations increase the interaction between the core solenoid and the N-terminal portion, interfering with proper closing of the channel^[24].

5.1.4. FK506-binding protein 12.6 (calstabin 2)-ryanodine receptor type 2 dissociation

FKBPs belong to the immunophilin family that binds immunosuppressive drugs like FK506 and rapamycin^[158]. FKBP12 (calstabin 1, 12 kDa, 108 amino acids) and its closest homolog FKBP12.6 (calstabin 2) interact with all RyR isoforms, stabilizing channels in closed states^[159]. Cryogenic electron microscopy analyses show both proteins bind at the junction between “clamp” and “handle” domains on the cytosolic cap^[160,161], with a study by Yuchi et al. identifying the SPRY1 loop as the precise binding location^[162]. Several CPVT1 mutations (L433P, S2246L, and R2474S) have been shown to reduce FKBP12.6 binding affinity to RyR2, suggesting defective binding as a pathological mechanism^[28,71]. Supporting this, FKBP12.6 overexpression reduces diastolic calcium leak associated with proarrhythmic DADs^[163], while Zhao et al.^[164] demonstrated that increased RyR sensitivity to calcium triggers when FKBP12.6 is absent or inhibited. However, contradictory evidence exists, Liu et al.^[61] found normal RyR2–FKBP12.6 interaction in RyR2 R4496C^+/− mice before and after adrenergic stimulation, with K201 (a compound promoting FKBP binding) failing to prevent arrhythmias, suggesting this mutation does not disrupt the RyR2/FKBP12.6 complex. Therefore, decreased FKBP affinity may not be a universal defect in CPVT1, requiring further investigation to clarify the role of FKBP in CPVT pathogenesis.

5.2. Calsequestrin 2 dysfunction

CASQ2 is the primary calcium buffering protein in the SR, playing a key role in maintaining calcium homeostasis in cardiac myocytes. CASQ2 dysfunction directly affects calcium ion storage and release in the SR^[86]. Under normal conditions, CASQ2 binds to calcium ions in a high-capacity, low-affinity manner, maintaining free calcium concentration at a relatively low level in the SR^[1]. Research has found that CASQ2 can regulate RyR2 open probability through interactions with proteins such as junctin and triadin while simultaneously maintaining a large reservoir of buffered Ca²⁺ near RyR2 that can be rapidly mobilized upon channel opening^[165,166]. When the CASQ2 function is impaired, its calcium-binding capacity decreases, resulting in reduced calcium storage capacity in the SR and significantly elevated free calcium concentration^[1,86].

5.3. The role of the autonomic nervous system

The autonomic nervous system, especially sympathetic activation, plays a key triggering and facilitating role in the pathogenesis of CPVT.

5.3.1. Sympathetic activation

As previously discussed, sympathetic activation leads to elevated catecholamine levels that activate β-adrenergic signaling pathways. This increases intracellular cAMP and PKA activity, which ultimately enhances RyR2 open probability and promotes spontaneous calcium release events that can trigger arrhythmias.

5.3.2. Vagal effects

Compared with the sympathetic nervous system, the role of the vagus nerve in CPVT has been less studied. Generally, it is believed that the vagus nerve activation may promote CPVT by inhibiting sinoatrial node automaticity, lowering heart rate, and prolonging diastole^[167], thus prolonging the time in which an ectopic beat can happen. Recent research indicates that chronic exercise training in CASQ2-deficient mice enhances vulnerability to ventricular arrhythmias through augmented vagal opposition during β-adrenergic stimulation. This parasympathetic predominance impedes heart rate acceleration and intensifies abnormal calcium leakage through RyR2 in ventricular cardiomyocytes of exercised CASQ2-knockout mice^[143]. In summary, sympathetic activation is an important triggering factor for CPVT by elevating intracellular cAMP levels, which activates PKA that phosphorylates the main actors of Ca²⁺ handling (LTCC, RyR2, and PLB), favoring spontaneous Ca²⁺ release. In contrast, the role of the vagus nerve may be more complex and requires further clinical and basic research to confirm. It might be that decreasing the heart rate gives more time for ventricular ectopic beats to happen. In-depth exploration of the mechanisms of autonomic regulation in CPVT pathogenesis has important implications for guiding the clinical application of therapeutic approaches such as β-blockers.

6. Diagnosis of catecholaminergic polymorphic ventricular tachycardia

The diagnosis of CPVT requires comprehensive consideration of clinical manifestations, physical examination, electrocardiography, imaging studies, and genetic testing. Patients with CPVT can be asymptomatic and only diagnosed as part of family screening^[168]. CPVT typically presents with exercise- or emotion-triggered syncope, palpitations, seizures, and sudden death, with most patients having normal resting ECGs^[168,169]. A significant subset of patients presents for the first time with cardiac arrest due to ventricular tachycardia or ventricular fibrillation. There are few differences based on sex, with a tendency towards earlier manifestation in boys compared with girls^[73]. The gold standard diagnostic tool is exercise stress testing, which can induce characteristic bidirectional or polymorphic ventricular tachycardia at heart rates of 110 to 130 beats/min^[170]. Supporting tests include 24-hour Holter monitoring, signal-averaged ECG, and cardiac imaging (echocardiography and magnetic resonance imaging) to exclude structural heart disease^[171–173]. Physical examination of patients with CPVT is typically unremarkable. Syncopal episodes are frequently misattributed to vasovagal events or neurological causes, with many patients incorrectly diagnosed with epilepsy due to seizure-like activity during syncope. This often results in a significant diagnostic delay, with an average of 2 years between first syncope and correct diagnosis^[73]. Genetic testing for mutations in RyR2 and CASQ2 genes provides definitive evidence, though negative results do not exclude CPVT^[174]. Early diagnosis is crucial as the disease typically begins in childhood (average onset 7–9 years) and carries a high risk of sudden death if untreated^[175].

7. Treatment of catecholaminergic polymorphic ventricular tachycardia

CPVT requires a comprehensive treatment strategy to prevent malignant arrhythmic events and sudden death, including lifestyle management, pharmacotherapy, left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillators (ICDs). The treatment plan for each CPVT patient should be individualized and strictly based on detailed risk stratification assessment results^{[127,176,177]}.

7.1. Lifestyle management

Lifestyle adjustments are crucial for CPVT patients. The most important is exercise restriction; patients should avoid strenuous activities, especially competitive sports^[178]. Exercise intensity should be maintained at low to moderate levels, with specific activities individually determined by healthcare providers. Additionally, emotional stress is a common trigger for CPVT events, requiring emotional management techniques and psychological support when necessary^[121,178]. CPVT patients should maintain regular living habits and avoid excessive fatigue^[178]. For environmental factors like extreme weather and high temperatures, patients need special caution, avoiding prolonged exposure to prevent dehydration and electrolyte disturbances. Proper daily routines, adequate sleep, and regular eating habits help maintain cardiac stability^[75,179].

7.2. Pharmacotherapy

7.2.1. β-adrenergic receptor blockers

β-blockers are the first-line medication for CPVT patients^[3,75]. Nonselective β-blockers such as nadolol (1–2 mg/kg per day) are preferred^[1], with propranolol as a common alternative^[180]. Selective β1-blockers appear less effective and should be avoided^[181].

For newly diagnosed patients, regular administration of β-blockers should begin promptly, gradually increasing to the maximum tolerated dose. Exercise tests should be performed regularly to evaluate drug efficacy and guide adjustments^[4]. Pediatric patients may require relatively higher doses compared with adults due to robust hepatic metabolism^[182]. Pregnant women should continue β-blockers if the benefits outweigh risks, with appropriate monitoring^[183]. For patients with comorbidities requiring other medications, drug interactions with β-blockers should be carefully evaluated^[183]. Genetically positive family members should receive β-blockers even if their exercise tests are negative. The presence of couplets or multiple successive ventricular premature beats during exercise testing significantly correlates with future arrhythmic events, indicating a need for treatment intensification^[75].

7.2.2. Flecainide

Flecainide is a class I antiarrhythmic drug that can further reduce ventricular arrhythmic events when combined with β-blockers for CPVT patients who remain symptomatic despite taking maximum tolerated doses of β-blockers^[184]. Research indicates that flecainide directly inhibits RyR2 channels and reduces triggered activity caused by DADs^[185,186].

Clinical studies have demonstrated the efficacy and safety of flecainide for refractory CPVT patients^[187,188]. Current guidelines recommend combining flecainide with β-blockers for CPVT patients with recurrent syncope, abnormal exercise tests despite β-blocker therapy, or those needing to reduce ICD discharge^[177]. However, evidence for flecainide monotherapy in CPVT is limited and not routinely recommended. The common dosage of flecainide is 100 to 300 mg/d, requiring individualized adjustment based on patient factors^[189]. Efficacy should focus on changes in exercise-induced arrhythmia burden, with the disappearance of serious arrhythmias such as ventricular tachycardia and fibrillation serving as markers of effectiveness^[187].

7.2.3. Verapamil

Although calcium channel blockers can reduce SR calcium release mediated by RyR2 channels, previous research evidence on the efficacy of verapamil for CPVT treatment is limited and somewhat controversial^[190–192]. One study suggested that β-blockers and calcium blockers could be better than β-blockers alone for preventing exercise-induced arrhythmias in CPVT^[193]. Verapamil may be more effective in CPVT patients carrying specific CASQ2 gene mutations^[192]. However, current international guidelines do not recommend verapamil as a routine first-line or second-line medication for CPVT patients^[177]. For individual patients with poor efficacy from β-blockers and flecainide, adding verapamil can be considered as an option, but requires careful monitoring of efficacy and safety^[194]. When using verapamil, attention should be paid to possible adverse reactions such as bradycardia and hypotension, especially when combined with β-blockers^[194].

7.3. Left cardiac sympathetic denervation

For refractory CPVT patients with inadequate response to pharmacotherapy and ICD, LCSD is an important nonpharmacological treatment option^[195]. LCSD blocks sympathetically mediated ventricular arrhythmias by removing part of the cardiac sympathetic nerves^[196]. Current clinical evidence indicates that LCSD can reduce arrhythmia burden in symptomatic, drug-resistant CPVT patients^[9–11]. A cohort study including 63 CPVT patients who underwent LCSD showed a significant reduction in ventricular arrhythmias and cardiac events postsurgery, with only 24% of patients experiencing recurrence within 5 years and only one death^[196]. Therefore, LCSD may be considered for patients with symptoms or ICD discharges who have an inadequate response to pharmacological interventions^[196]. Notably, LCSD is not a curative treatment; patients still need to continue regular medication postsurgery and undergo periodic follow-up to assess prognosis.

7.4. Implantable cardioverter-defibrillator therapy

ICD is recommended for cardiac arrest survivors and syncope patients unresponsive to drug therapy^[12]. For high-risk CPVT patients intolerant to medications or refusing LCSD, preventive ICD implantation can reduce sudden death risk^[11] and is recommended for pediatric patients with persistent syncope or ventricular tachycardia despite β-blocker therapy^[177]. To reduce complications, drug therapy should be optimized before implantation, LCSD necessity assessed, and psychological evaluations conducted^[127]. ICD programming should minimize unnecessary stimulation, extend monitoring intervals, and restrict shocks to only the most dangerous arrhythmias. During follow-up, recurrent arrhythmias should prompt evaluation of triggers, medication adherence, and potential therapy intensification^[127].

8. Limitations

This review has several limitations. First, the available evidence on CPVT is largely derived from studies with heterogeneous designs, including small patient cohorts, case reports, and experimental models, which may limit the generalizability of the conclusions. Second, some mechanistic insights are based on animal models or heterologous expression systems, which, although valuable, may not fully replicate human pathophysiology. Third, our literature search was limited to articles published in English and primarily retrieved from PubMed, which may have led to incomplete retrieval of relevant studies and potential publication bias. Finally, because CPVT is a rare condition, certain genotype–phenotype correlations and therapeutic effects are supported by limited datasets, and further large-scale, multicenter research is needed to strengthen the evidence base.

9. Conclusion

CPVT is a severe hereditary arrhythmic disorder with limited diagnostic and therapeutic options. Despite growing understanding of CPVT in recent years, challenges remain in accurate diagnosis, risk prediction, and effective treatment. Future research should focus on discovering new pathogenic genes through whole-genome sequencing, investigating regulatory networks and epigenetic modifications, and developing gene-specific therapies using CRISPR/Cas9 and RNA interference technologies. Novel drug development targeting molecules beyond RyR2 and the creation of myocardium-specific delivery systems also offer promising directions. With advances in modern medical technology and translational research, particularly in gene editing applications, CPVT diagnosis and treatment are expected to continuously improve, ultimately achieving precision medicine that enhances patient prognosis.

Acknowledgments

Nil.

Conflicts of interest

The authors declare that they have no conflicts of interest with regard to the content of this manuscript.

Funding source

This work was supported by the Agence nationale de la recherche (ANR-19-CE14-0031-01, ANR-23-CE14-0009-02), European Commission, Horizon 2020 Framework Programme, Research and Innovation Staff Exchange (RISE) Call Marie Skłodowska-Curie Research and Innovation Staff Exchange (H2020-MSCA-RISE-2016, Project number: 734931) (to AMG).

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the preparation of this manuscript.

Author contributions

SL performed the literature search and drafted the initial manuscript. AMG conceived the manuscript and critically revised the manuscript for important intellectual content. All authors read and approved the final version for publication.