RARE DISEASE
Catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia
Catecholaminergic polymorphic ventricular tachycardia
Synonyms: Bidirectional ventricular tachycardia induced by catecholamine, CPVT, Malignant paroxysmal ventricular tachycardia, Polymorphic ventricular tachycardia induced by catecholamines
Synonyms: Bidirectional ventricular tachycardia induced by catecholamine, CPVT, Malignant paroxysmal ventricular tachycardia, Polymorphic ventricular tachycardia induced by catecholamines
Synonyms: Bidirectional ventricular tachycardia induced by catecholamine, CPVT, Malignant paroxysmal ventricular tachycardia, Polymorphic ventricular tachycardia induced by catecholamines
Drug discovery
5
drugs
With orphan designations
Overview
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome caused by dysregulated intracellular calcium handling (typically RYR2 or CASQ2 mutations). It manifests as bidirectional or polymorphic ventricular tachycardia triggered by exercise/emotional stress in structurally normal hearts. Untreated, it carries a 30–50% mortality by age 35. Diagnosis relies on exercise testing, clinical history, and genetic screening [1][2][6][14].
Therapies
First-line: Maximum-tolerated β-blockers (nadolol preferred) [3][14][19].
Add-on: Flecainide (2–3 mg/kg/day) for refractory arrhythmias [1][3][13].
Advanced: Left cardiac sympathetic denervation or ICD (cautiously, due to shock-induced storm risk) [1][3][14].
- Lifestyle: Avoid competitive sports/stress [1][3].
Categories: rare cardiac diseases, rare genetic diseases
Research Papers
779 drug discovery papers about Catecholaminergic polymorphic ventricular tachycardia, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
779 drug discovery papers about Catecholaminergic polymorphic ventricular tachycardia, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Gain-of-function mutation of type 2 ryanodine receptor attenuates dopaminergic neuron development associated with Ca2+ overload-triggered oxidative damage in mitochondria.
Type 2 ryanodine receptor (RyR2), a Ca2+ release channel located in the endoplasmic reticulum (ER) membrane, expresses catecholamine-induced polymorphic ventricular tachycardia (CPVT), and is a potential risk factor of autism spectrum disorder (ASD). However, the pathological relationship between RyR2 mutation-induced Ca2+ dysregulation and ASD pathology remains unclear. This study examined the association between CPVT-related RyR2 mutations and ASD pathology to determine its dopaminergic pathological role in ASD. Patient-derived stem cells from human exfoliated deciduous teeth were obtained from a boy with comorbid CPVT and ASD, and differentiated to dopaminergic neurons (RyR2-DNs). Two heterozygous missense mutations were identified in RyR2: c.9910C > G, p.Q3304E in exon 69 and c.14222C > T, p.A4741V in exon 99 (RyR269/99). RyR2-DNs showed cytosolic and mitochondrial Ca2+ accumulation, and impaired neurite outgrowth, suggesting that RyR269/99 is a gain-of-function mutation that promotes Ca2+ release from the ER and attenuates neurite development. RyR2-DNs also exhibited increased mitochondrial reactive oxygen species along with impaired mitochondrial oxidative phosphorylation. These mitochondrial abnormalities and neurite outgrowth were managed by pharmacological intervention of mitochondrial Ca2+ accumulation. Thus, RyR2 hyper-activation-induced mitochondrial Ca2+ overload may cause oxidative stress-related mitochondrial dysfunction, impairing DN development and dopaminergic dysregulation in ASD.
2026-08-06 | Case Report: Overlap of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia in two Chinese children with CALM2-related calmodulinopathy.
Calmodulinopathy is a rare CALM-related hereditary channelopathy presenting with long QT syndrome (LQTS), less commonly with catecholaminergic polymorphic ventricular tachycardia (CPVT) or LQTS/CPVT overlap. It carries high mortality and limited data from Chinese population. We reviewed two Chinese children with CALM2 mutation-related LQTS/CPVT overlap. Clinical data, genetic findings, and treatments were collected; outcomes were obtained via telephone follow-up. A systematic literature review was also performed. Case 1 was a 13-year-old girl with seven exercise-induced syncopal episodes. Sinus rhythm QTc 0.55 s, with bidirectional/polymorphic premature ventricular contractions, and ventricular tachycardia during exercise. A de novo CALM2 p.E140Q mutation was found. She remained event-free on propranolol and propafenone for two years. Case 2 was a 15-year-old boy with onset at 4 years. He experienced > 10 syncopal episodes triggered by recurrent exercise or emotional stress. Initial Holter monitoring revealed sinus bradycardia with a mean heart rate of 70 bpm and a maximum QTc of 0.51 s. A de novo CALM2 p.N98S mutation was found. Despite treatment with propranolol plus mexiletine, syncopal episodes continued, with the QTc interval further prolonged to 0.62 s. The p.E140Q variant is novel, whereas p.N98S has been previously reported. Literature suggests that β-blockers combined with Class Ic drugs may be more effective, and implantable cardioverter defibrillator (ICD) implantation should be considered in cases who respond poorly to medical therapy or survivors of aborted cardiac arrest. Patients who experience recurrent syncope coexisting with significant sinus bradycardia may have more severe phenotypes with higher risk of malignant arrhythmias, warranting earlier or more aggressive evaluation for device therapy. Genetic testing is recommended for suspected pediatric channelopathies with phenotype-guided individualized treatment.
2026-07-27 | Targeting the heart: CRISPR/Cas9-VPR mediated concurrent knockout and activation to treat cardiac diseases, exemplified by a gene therapy strategy for CPVT
Background: Cardiovascular diseases are the leading cause of death worldwide. Lifelong restrictions and often inadequate pharmacotherapeutic treatment put a heavy burden on patients and healthcare systems and leave many patients at constant risk of fatal cardiac events. In contrast, gene therapy offers potential cures for inherited or acquired cardiac diseases with currently nonexistent or limited treatment options, including heart failure, cardiomyopathies, and channelopathies, via a single application. Recombinant adeno-associated-virus (AAV) mediated in vivo transgene delivery is currently the gold standard for gene therapy. Yet, insufficient cardiac vector delivery, the small packaging capacity of 4.7 kb, and a lack of therapeutic approaches for diseases caused by gain-of-function mutations limit clinical applications. Thus, to date, no gene therapy for cardiac diseases has been approved, which illustrates the unmet need for further development of current approaches. Aims and methods: 1) AAV capsid engineering can be used to optimize cardiac transduction efficiency and specificity. Here, the tropism of four novel AAV9-based capsid variants carrying small peptide insertions was investigated in mice. 2) By initially implementing the recently developed dual rAAV-vector approach utilizing reconstitution via mRNA trans-splicing (REVeRT) in a heart context, we aimed to enable an efficient cardiac delivery of large transgenes. 3) Moreover, CRISPR/Cas9-VPR-mediated concurrent knockdown and activation (CONNACT) by single guide RNA multiplexing was evaluated as an innovative mutation-independent strategy to treat cardiac diseases with gain-of-function mutation origin. As such, catecholaminergic polymorphic ventricular tachycardia 1 (CPVT1), which is caused by gain-of-function mutations in the RYR2 gene, was addressed via a heart-specific knockout of Ryr2 and transactivation of Ryr1 via CONNACT as a novel gene therapeutical approach. Results: 1) The cardiac transduction efficacy of the novel AAV9 variants was comparable or inferior to that of the parental AAV9 capsid when administered intraperitoneally. 2) The dual REVeRT vector technology, combined with a cardiac-specific promoter, resulted in exceptional rates of up to 76% successfully targeted cardiomyocytes. 3) In the therapeutical approach, dual REVeRT vector-mediated delivery of CIRSPR/Cas9-VPR demonstrated a proof-of-concept for CONNACT in cardiac tissue. Ryr2 knockout could be linked to ER stress and SR disruption in mature cardiomyocytes, while Ryr1 activation showed no adverse effect. However, RYR1 could not functionally compensate for RYR2. Conclusion: This study demonstrates the power of REVeRT and CONNACT as valuable technologies for the development of cardiac gene therapies but indicates that the choice of analog proteins for functional compensation requires extensive preclinical work. Furthermore, our findings shed light on the impact of RYR2 depletion and RYR1 expression in mature cardiomyocytes.
2026-07-12 | Catecholaminergic Polymorphic Ventricular Tachycardia Type 2 Presenting as Seizure in a Child: Diagnostic Pitfalls.
Catecholaminergic polymorphic ventricular tachycardia is a rare inherited arrhythmogenic disorder. In children, it is often misdiagnosed as epilepsy due to convulsive syncope triggered by exercise. A 6-year-old boy presented with exercise-induced seizure-like episodes despite normal neuroimaging. Resting electrocardiogram and Holter were unremarkable, but exercise stress testing revealed bidirectional ventricular tachycardia. Genetic testing confirmed a homozygous CASQ2 mutation, consistent with catecholaminergic polymorphic ventricular tachycardia type 2. The patient was successfully managed with propranolol and flecainide, avoiding implantable cardioverter-defibrillator placement. Catecholaminergic polymorphic ventricular tachycardia type 2 often presents earlier and more severely than type 1. This case highlights the importance of exercise testing in pediatric syncope with normal baseline findings and emphasizes genotype-phenotype correlation when managing incidental findings. Catecholaminergic polymorphic ventricular tachycardia type 2 should be considered in any child with exertional seizures despite normal baseline evaluations. Combination therapy provides an effective alternative to early implantable cardioverter-defibrillator implantation.
2026-07-03 | Cardiomyocytes possess an intrinsic catecholaminergic machinery that regulates cellular homeostasis and electrophysiological stability
Abstract Background Catecholamines play a central role in cardiac performance, coordinating myocardial contractility, conduction, metabolism, and electrophysiological stability. In the heart, their actions have been attributed primarily to sympathetic nerve terminals and circulating adrenal catecholamines. The discovery of an intrinsic non-neuronal cholinergic system within cardiomyocytes challenges this neurocentric paradigm and raises the possibility that cardiomyocytes also possess an intrinsic catecholaminergic programme. Here, we investigated whether cardiomyocytes possess an intrinsic catecholaminergic programme and its contribution to cardiomyocyte homeostasis and stress responses. Methods We investigated catecholamine biosynthesis and handling in human induced pluripotent stem cell-derived cardiomyocytes, adult mouse cardiomyocytes, H9C2 cells, rat ventricular tissue, and Langendorff-perfused mouse hearts. Protein expression of catecholamine biosynthetic enzymes and vesicular monoamine transporters was assessed by immunoblotting and immunohistochemistry, while vesicular monoamine uptake was evaluated using fluorescent false neurotransmitters. Functional consequences of catecholamine biosynthesis inhibition were examined using pharmacological approaches, assessing cell viability, apoptosis, organelle homeostasis, metabolic signalling, and cardiac electrophysiology. Results Tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine β-hydroxylase, and vesicular monoamine transporters were detected in cardiomyocytes across models. Expression of catecholamine biosynthetic enzymes increased following ischaemia–reperfusion injury in rat heart tissue (TH p=0.008, AADC p=0.031, DBH p=0.008). Pharmacological inhibition of catecholamine biosynthesis caused dose-dependent reductions in cardiomyocyte viability (p<0.0001), increased apoptosis, organelle stress, and mitochondrial dysfunction, with greater effects under oxidative stress. Mechanistically, catecholamine depletion suppressed mTORC1 signalling and activated LKB1–AMPK–ULK1 pathways. In Langendorff-perfused hearts, tyrosine hydroxylase inhibition induced ventricular arrhythmias in 5 of 6 hearts, including sustained ventricular tachycardia, polymorphic ventricular tachycardia, and ventricular fibrillation. Conclusions These findings identify cardiomyocytes as previously unrecognised catecholamine-competent cells expressing intrinsic machinery for catecholamine biosynthesis and vesicular handling. Disruption of this pathway compromises metabolic and organelle homeostasis, activates energy-stress and autophagy-related signalling, and promotes malignant ventricular arrhythmias. Intrinsic cardiomyocyte catecholamine biology therefore represents a non-neuronal regulatory axis essential for myocardial resilience and electrical stability, with potential relevance to ischaemic injury and stress-induced dysfunction.
2026-08-11 | Gain-of-function mutation of type 2 ryanodine receptor attenuates dopaminergic neuron development associated with Ca2+ overload-triggered oxidative damage in mitochondria.
Type 2 ryanodine receptor (RyR2), a Ca2+ release channel located in the endoplasmic reticulum (ER) membrane, expresses catecholamine-induced polymorphic ventricular tachycardia (CPVT), and is a potential risk factor of autism spectrum disorder (ASD). However, the pathological relationship between RyR2 mutation-induced Ca2+ dysregulation and ASD pathology remains unclear. This study examined the association between CPVT-related RyR2 mutations and ASD pathology to determine its dopaminergic pathological role in ASD. Patient-derived stem cells from human exfoliated deciduous teeth were obtained from a boy with comorbid CPVT and ASD, and differentiated to dopaminergic neurons (RyR2-DNs). Two heterozygous missense mutations were identified in RyR2: c.9910C > G, p.Q3304E in exon 69 and c.14222C > T, p.A4741V in exon 99 (RyR269/99). RyR2-DNs showed cytosolic and mitochondrial Ca2+ accumulation, and impaired neurite outgrowth, suggesting that RyR269/99 is a gain-of-function mutation that promotes Ca2+ release from the ER and attenuates neurite development. RyR2-DNs also exhibited increased mitochondrial reactive oxygen species along with impaired mitochondrial oxidative phosphorylation. These mitochondrial abnormalities and neurite outgrowth were managed by pharmacological intervention of mitochondrial Ca2+ accumulation. Thus, RyR2 hyper-activation-induced mitochondrial Ca2+ overload may cause oxidative stress-related mitochondrial dysfunction, impairing DN development and dopaminergic dysregulation in ASD.
2026-08-06 | Case Report: Overlap of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia in two Chinese children with CALM2-related calmodulinopathy.
Calmodulinopathy is a rare CALM-related hereditary channelopathy presenting with long QT syndrome (LQTS), less commonly with catecholaminergic polymorphic ventricular tachycardia (CPVT) or LQTS/CPVT overlap. It carries high mortality and limited data from Chinese population. We reviewed two Chinese children with CALM2 mutation-related LQTS/CPVT overlap. Clinical data, genetic findings, and treatments were collected; outcomes were obtained via telephone follow-up. A systematic literature review was also performed. Case 1 was a 13-year-old girl with seven exercise-induced syncopal episodes. Sinus rhythm QTc 0.55 s, with bidirectional/polymorphic premature ventricular contractions, and ventricular tachycardia during exercise. A de novo CALM2 p.E140Q mutation was found. She remained event-free on propranolol and propafenone for two years. Case 2 was a 15-year-old boy with onset at 4 years. He experienced > 10 syncopal episodes triggered by recurrent exercise or emotional stress. Initial Holter monitoring revealed sinus bradycardia with a mean heart rate of 70 bpm and a maximum QTc of 0.51 s. A de novo CALM2 p.N98S mutation was found. Despite treatment with propranolol plus mexiletine, syncopal episodes continued, with the QTc interval further prolonged to 0.62 s. The p.E140Q variant is novel, whereas p.N98S has been previously reported. Literature suggests that β-blockers combined with Class Ic drugs may be more effective, and implantable cardioverter defibrillator (ICD) implantation should be considered in cases who respond poorly to medical therapy or survivors of aborted cardiac arrest. Patients who experience recurrent syncope coexisting with significant sinus bradycardia may have more severe phenotypes with higher risk of malignant arrhythmias, warranting earlier or more aggressive evaluation for device therapy. Genetic testing is recommended for suspected pediatric channelopathies with phenotype-guided individualized treatment.
2026-07-27 | Targeting the heart: CRISPR/Cas9-VPR mediated concurrent knockout and activation to treat cardiac diseases, exemplified by a gene therapy strategy for CPVT
Background: Cardiovascular diseases are the leading cause of death worldwide. Lifelong restrictions and often inadequate pharmacotherapeutic treatment put a heavy burden on patients and healthcare systems and leave many patients at constant risk of fatal cardiac events. In contrast, gene therapy offers potential cures for inherited or acquired cardiac diseases with currently nonexistent or limited treatment options, including heart failure, cardiomyopathies, and channelopathies, via a single application. Recombinant adeno-associated-virus (AAV) mediated in vivo transgene delivery is currently the gold standard for gene therapy. Yet, insufficient cardiac vector delivery, the small packaging capacity of 4.7 kb, and a lack of therapeutic approaches for diseases caused by gain-of-function mutations limit clinical applications. Thus, to date, no gene therapy for cardiac diseases has been approved, which illustrates the unmet need for further development of current approaches. Aims and methods: 1) AAV capsid engineering can be used to optimize cardiac transduction efficiency and specificity. Here, the tropism of four novel AAV9-based capsid variants carrying small peptide insertions was investigated in mice. 2) By initially implementing the recently developed dual rAAV-vector approach utilizing reconstitution via mRNA trans-splicing (REVeRT) in a heart context, we aimed to enable an efficient cardiac delivery of large transgenes. 3) Moreover, CRISPR/Cas9-VPR-mediated concurrent knockdown and activation (CONNACT) by single guide RNA multiplexing was evaluated as an innovative mutation-independent strategy to treat cardiac diseases with gain-of-function mutation origin. As such, catecholaminergic polymorphic ventricular tachycardia 1 (CPVT1), which is caused by gain-of-function mutations in the RYR2 gene, was addressed via a heart-specific knockout of Ryr2 and transactivation of Ryr1 via CONNACT as a novel gene therapeutical approach. Results: 1) The cardiac transduction efficacy of the novel AAV9 variants was comparable or inferior to that of the parental AAV9 capsid when administered intraperitoneally. 2) The dual REVeRT vector technology, combined with a cardiac-specific promoter, resulted in exceptional rates of up to 76% successfully targeted cardiomyocytes. 3) In the therapeutical approach, dual REVeRT vector-mediated delivery of CIRSPR/Cas9-VPR demonstrated a proof-of-concept for CONNACT in cardiac tissue. Ryr2 knockout could be linked to ER stress and SR disruption in mature cardiomyocytes, while Ryr1 activation showed no adverse effect. However, RYR1 could not functionally compensate for RYR2. Conclusion: This study demonstrates the power of REVeRT and CONNACT as valuable technologies for the development of cardiac gene therapies but indicates that the choice of analog proteins for functional compensation requires extensive preclinical work. Furthermore, our findings shed light on the impact of RYR2 depletion and RYR1 expression in mature cardiomyocytes.
2026-07-12 | Catecholaminergic Polymorphic Ventricular Tachycardia Type 2 Presenting as Seizure in a Child: Diagnostic Pitfalls.
Catecholaminergic polymorphic ventricular tachycardia is a rare inherited arrhythmogenic disorder. In children, it is often misdiagnosed as epilepsy due to convulsive syncope triggered by exercise. A 6-year-old boy presented with exercise-induced seizure-like episodes despite normal neuroimaging. Resting electrocardiogram and Holter were unremarkable, but exercise stress testing revealed bidirectional ventricular tachycardia. Genetic testing confirmed a homozygous CASQ2 mutation, consistent with catecholaminergic polymorphic ventricular tachycardia type 2. The patient was successfully managed with propranolol and flecainide, avoiding implantable cardioverter-defibrillator placement. Catecholaminergic polymorphic ventricular tachycardia type 2 often presents earlier and more severely than type 1. This case highlights the importance of exercise testing in pediatric syncope with normal baseline findings and emphasizes genotype-phenotype correlation when managing incidental findings. Catecholaminergic polymorphic ventricular tachycardia type 2 should be considered in any child with exertional seizures despite normal baseline evaluations. Combination therapy provides an effective alternative to early implantable cardioverter-defibrillator implantation.
2026-07-03 | Cardiomyocytes possess an intrinsic catecholaminergic machinery that regulates cellular homeostasis and electrophysiological stability
Abstract Background Catecholamines play a central role in cardiac performance, coordinating myocardial contractility, conduction, metabolism, and electrophysiological stability. In the heart, their actions have been attributed primarily to sympathetic nerve terminals and circulating adrenal catecholamines. The discovery of an intrinsic non-neuronal cholinergic system within cardiomyocytes challenges this neurocentric paradigm and raises the possibility that cardiomyocytes also possess an intrinsic catecholaminergic programme. Here, we investigated whether cardiomyocytes possess an intrinsic catecholaminergic programme and its contribution to cardiomyocyte homeostasis and stress responses. Methods We investigated catecholamine biosynthesis and handling in human induced pluripotent stem cell-derived cardiomyocytes, adult mouse cardiomyocytes, H9C2 cells, rat ventricular tissue, and Langendorff-perfused mouse hearts. Protein expression of catecholamine biosynthetic enzymes and vesicular monoamine transporters was assessed by immunoblotting and immunohistochemistry, while vesicular monoamine uptake was evaluated using fluorescent false neurotransmitters. Functional consequences of catecholamine biosynthesis inhibition were examined using pharmacological approaches, assessing cell viability, apoptosis, organelle homeostasis, metabolic signalling, and cardiac electrophysiology. Results Tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine β-hydroxylase, and vesicular monoamine transporters were detected in cardiomyocytes across models. Expression of catecholamine biosynthetic enzymes increased following ischaemia–reperfusion injury in rat heart tissue (TH p=0.008, AADC p=0.031, DBH p=0.008). Pharmacological inhibition of catecholamine biosynthesis caused dose-dependent reductions in cardiomyocyte viability (p<0.0001), increased apoptosis, organelle stress, and mitochondrial dysfunction, with greater effects under oxidative stress. Mechanistically, catecholamine depletion suppressed mTORC1 signalling and activated LKB1–AMPK–ULK1 pathways. In Langendorff-perfused hearts, tyrosine hydroxylase inhibition induced ventricular arrhythmias in 5 of 6 hearts, including sustained ventricular tachycardia, polymorphic ventricular tachycardia, and ventricular fibrillation. Conclusions These findings identify cardiomyocytes as previously unrecognised catecholamine-competent cells expressing intrinsic machinery for catecholamine biosynthesis and vesicular handling. Disruption of this pathway compromises metabolic and organelle homeostasis, activates energy-stress and autophagy-related signalling, and promotes malignant ventricular arrhythmias. Intrinsic cardiomyocyte catecholamine biology therefore represents a non-neuronal regulatory axis essential for myocardial resilience and electrical stability, with potential relevance to ischaemic injury and stress-induced dysfunction.
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Drug Discovery Landscape
5 orphan drug designations for Catecholaminergic polymorphic ventricular tachycardia.
5 orphan drug designations for Catecholaminergic polymorphic ventricular tachycardia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated viral vector serotype 8 containing the human CASQ2 gene | gene therapies | EMA | 2026-06-19 | — | Voisin Consulting Life Sciences |
(S)-(3-bromo-4-(trifluoromethyl)phenyl)(2-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)morpholino)methan-one | small molecules | FDA | 2026-03-30 | — | Agiana Pharmaceuticals |
4-[(7-Methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid, hemifumarate | small molecules | FDA | 2020-05-05 | — | RyCarma Therapeutics, Inc. |
adeno-associated viral vector serotype 8 containing the human cardiac calsequestrin gene | gene therapies | FDA | 2014-10-02 | — | Solid Biosciences Inc. |
Adeno-associated viral vector serotype 9 containing the human cardiac calsequestrin gene | gene therapies | EMA | 2014-07-29 | — | Voisin Consulting Life Sciences |
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