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
776 drug discovery papers related to Catecholaminergic polymorphic ventricular tachycardia, with 5 first-in-class and 3 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
776 drug discovery papers related to Catecholaminergic polymorphic ventricular tachycardia, with 5 first-in-class and 3 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-06-30 | Long-Term Serial Exercise Stress Testing in Catecholaminergic Polymorphic Ventricular Tachycardia on Beta-Blocker and Flecainide Therapy.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially life-threatening arrhythmic disorder typically treated with beta-blockers and, occasionally, with flecainide. All patients underwent genetic testing, electrocardiogram, echocardiogram, and exercise testing. Ventricular arrhythmias were assessed using qualitative and quantitative scoring systems. Flecainide dosing was progressively titrated, and follow-up extended from 2007 to 2024. Among 235 genetically confirmed carriers of the RyR2 (ryanodine receptor 2) p.Gly357Ser mutation, 32 required combination therapy with beta-blockers and flecainide (age at diagnosis 18 [1-55] years; age at flecainide initiation 32 [15-66] years; 50% male). Forty-seven percent had an implantable cardioverter defibrillator (ICD). Flecainide was indicated for exercise-induced ventricular arrhythmias despite beta-blocker therapy, and the median treatment duration was 7.3 years. All patients received propranolol (median dose 65 mg/day). Flecainide (median dose 100 mg/day) was well tolerated, with no syncope or stress-induced symptoms. Before flecainide, five patients (16%) experienced ventricular arrhythmic events recorded by the ICD, including two requiring appropriate shocks; no events occurred after treatment initiation. Both qualitative (2.07 ± 0.77 vs. 1.22 ± 1.08, p < 0.001) and quantitative (69.78 ± 83.17 vs. 15.29 ± 5.53, p < 0.001) arrhythmic scores improved significantly. Additionally, maximum heart rate and the percentage of age-predicted maximum heart rate were significantly reduced, while metabolic equivalents increased significantly (12.3 ± 3.8 vs. 14.7 ± 7.5; p = 0.010). In CPVT patients, the addition of flecainide to beta-blocker therapy was associated with a significant reduction in arrhythmic burden and improvement in exercise-related parameters during long-term follow-up.
2026-06-19 | Selective Use of Nonselective Beta-Blockers: A Tailored Antiarrhythmic Approach.
Beta-blockers (BBs) are a cornerstone of antiarrhythmic therapy, yet assuming a uniform "class effect" oversimplifies their diverse pharmacological properties and might compromise efficacy. This review synthesizes evidence comparing the antiarrhythmic effects of different BBs in various clinical settings. While cardioselective agents offer improved tolerability, they often fail to blunt the broad adrenergic surge driving specific arrhythmias. Nonselective BBs (eg, nadolol, propranolol) provide superior efficacy in inherited channelopathies, such as catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, and life-threatening electrical storms. Furthermore, carvedilol is superior to metoprolol for preventing postoperative atrial fibrillation and reducing inappropriate shocks in patients with implantable cardioverter-defibrillators. Conversely, for managing chronic supraventricular tachycardia, cardioselective agents remain preferred. By leveraging distinct BB properties, clinicians can overcome the "one-size-fits-all" approach and tailor therapy to optimize antiarrhythmic efficacy. More research is needed to resolve uncertainties and assist clinicians in adopting a personalized approach to BBs therapy.
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.
2026-06-30 | Long-Term Serial Exercise Stress Testing in Catecholaminergic Polymorphic Ventricular Tachycardia on Beta-Blocker and Flecainide Therapy.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially life-threatening arrhythmic disorder typically treated with beta-blockers and, occasionally, with flecainide. All patients underwent genetic testing, electrocardiogram, echocardiogram, and exercise testing. Ventricular arrhythmias were assessed using qualitative and quantitative scoring systems. Flecainide dosing was progressively titrated, and follow-up extended from 2007 to 2024. Among 235 genetically confirmed carriers of the RyR2 (ryanodine receptor 2) p.Gly357Ser mutation, 32 required combination therapy with beta-blockers and flecainide (age at diagnosis 18 [1-55] years; age at flecainide initiation 32 [15-66] years; 50% male). Forty-seven percent had an implantable cardioverter defibrillator (ICD). Flecainide was indicated for exercise-induced ventricular arrhythmias despite beta-blocker therapy, and the median treatment duration was 7.3 years. All patients received propranolol (median dose 65 mg/day). Flecainide (median dose 100 mg/day) was well tolerated, with no syncope or stress-induced symptoms. Before flecainide, five patients (16%) experienced ventricular arrhythmic events recorded by the ICD, including two requiring appropriate shocks; no events occurred after treatment initiation. Both qualitative (2.07 ± 0.77 vs. 1.22 ± 1.08, p < 0.001) and quantitative (69.78 ± 83.17 vs. 15.29 ± 5.53, p < 0.001) arrhythmic scores improved significantly. Additionally, maximum heart rate and the percentage of age-predicted maximum heart rate were significantly reduced, while metabolic equivalents increased significantly (12.3 ± 3.8 vs. 14.7 ± 7.5; p = 0.010). In CPVT patients, the addition of flecainide to beta-blocker therapy was associated with a significant reduction in arrhythmic burden and improvement in exercise-related parameters during long-term follow-up.
2026-06-19 | Selective Use of Nonselective Beta-Blockers: A Tailored Antiarrhythmic Approach.
Beta-blockers (BBs) are a cornerstone of antiarrhythmic therapy, yet assuming a uniform "class effect" oversimplifies their diverse pharmacological properties and might compromise efficacy. This review synthesizes evidence comparing the antiarrhythmic effects of different BBs in various clinical settings. While cardioselective agents offer improved tolerability, they often fail to blunt the broad adrenergic surge driving specific arrhythmias. Nonselective BBs (eg, nadolol, propranolol) provide superior efficacy in inherited channelopathies, such as catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, and life-threatening electrical storms. Furthermore, carvedilol is superior to metoprolol for preventing postoperative atrial fibrillation and reducing inappropriate shocks in patients with implantable cardioverter-defibrillators. Conversely, for managing chronic supraventricular tachycardia, cardioselective agents remain preferred. By leveraging distinct BB properties, clinicians can overcome the "one-size-fits-all" approach and tailor therapy to optimize antiarrhythmic efficacy. More research is needed to resolve uncertainties and assist clinicians in adopting a personalized approach to BBs therapy.
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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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