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5
Pathophys.
7
Phenotypes
7
Pathograph
2
Genes
4
Treatments
1
Trials
11
References
1
Deep Research

Pathophysiology

5
RYR2-mediated calcium release susceptibility
Rare patient-linked RYR2 variants can alter RyR2-mediated calcium release, creating a susceptibility substrate for premature ventricular ectopy in structurally normal hearts.
cardiomyocyte link
RYR2 link
calcium ion transport link ↕ DYSREGULATED
heart link
Show evidence (1 reference)
"The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions."
Functional evidence links a patient-associated RYR2 variant to abnormal calcium release, a plausible trigger substrate for short-coupled ectopy.
SCN5A sodium-channel susceptibility
Rare patient-linked SCN5A variants can alter Nav1.5 recovery from inactivation, creating a candidate sodium-channel susceptibility substrate for short-coupled ventricular ectopy.
cardiomyocyte link
SCN5A link
sodium ion transmembrane transport link ⚠ ABNORMAL
monoatomic ion channel activity link ⚠ ABNORMAL
heart link
Show evidence (1 reference)
DOI:10.1111/pace.13924 PARTIAL In Vitro
"showed a significantly shortened recovery time from inactivation."
Supports altered sodium-channel kinetics as a candidate upstream mechanism in one reported case.
Short-coupled premature ventricular trigger
The defining electrophysiologic event is a premature ventricular contraction with an extremely short coupling interval, often arising from Purkinje or right ventricular endocavitary structures and initiating TdP, polymorphic ventricular tachycardia, or VF.
cardiomyocyte link Purkinje myocyte link
cardiac conduction link ↕ DYSREGULATED cardiac muscle cell action potential link ⚠ ABNORMAL membrane depolarization during cardiac muscle cell action potential link ⚠ ABNORMAL
heart link moderator band link
Show evidence (2 references)
DOI:10.1161/01.cir.89.1.206 SUPPORT Human Clinical
"the torsade had the unusual particularity of an extremely short coupling interval of the first beat or of the isolated premature beats (245 +/- 28 milliseconds)"
Defines the short-coupled initiating beat in the original clinical series.
DOI:10.1007/s00392-021-01840-z SUPPORT Human Clinical
"the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients."
Supports Purkinje/moderator-band ventricular trigger localization in a contemporary mapping and ablation cohort.
Polymorphic ventricular tachyarrhythmia
Short-coupled PVCs initiate torsade de pointes or polymorphic ventricular tachycardia and may degenerate into ventricular fibrillation.
cardiomyocyte link Purkinje myocyte link
cardiac conduction link ⚠ ABNORMAL
heart link
Show evidence (1 reference)
DOI:10.3389/fcvm.2022.922525 SUPPORT Human Clinical
"The short-coupled variant of torsade de pointes (scTdP) is characterized by a particular electrocardiogram (ECG) pattern that shows a short-coupling interval of the initial Tdp beat and that can degenerate into ventricular fibrillation without the presence of structural heart disease."
Systematic review evidence supports short-coupled initiation, malignant ventricular arrhythmia, and absence of structural heart disease as core disease features.
Ventricular fibrillation and cardiac arrest
Degeneration into ventricular fibrillation produces cardiac arrest or sudden cardiac death unless terminated by defibrillation or an implantable cardioverter-defibrillator.
cardiomyocyte link
cardiac conduction link ↕ DYSREGULATED
heart link
Show evidence (2 references)
DOI:10.1161/01.cir.89.1.206 SUPPORT Human Clinical
"In 10 cases they deteriorated into ventricular fibrillation."
Shows frequent degeneration from short-coupled TdP into ventricular fibrillation in the original clinical series.
DOI:10.1161/01.cir.89.1.206 SUPPORT Human Clinical
"During a mean follow-up of 7 years there were 5 deaths (4 sudden)."
Supports sudden death risk when malignant arrhythmias are not fully controlled.

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Torsade de Pointes Syndrome With Short Coupling Interval Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.

Phenotypes

7
Cardiovascular 4
Syncope Syncope (HP:0001279)
Show evidence (1 reference)
DOI:10.1007/s00392-021-01840-z SUPPORT Human Clinical
"Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope"
Documents syncope as a presenting manifestation in a recurrent short-coupled TdP ablation cohort.
Ventricular fibrillation Ventricular fibrillation (HP:0001663)
Show evidence (1 reference)
DOI:10.1161/01.cir.89.1.206 SUPPORT Human Clinical
"In 10 cases they deteriorated into ventricular fibrillation."
Supports VF as a frequent malignant outcome in the original series.
Cardiac arrest Cardiac arrest (HP:0001695)
Show evidence (2 references)
DOI:10.1007/s00392-021-01840-z SUPPORT Human Clinical
"Four patients initially presented with sudden cardiac arrest"
Supports cardiac arrest as a common severe presentation in the ablation cohort.
DOI:10.1002/joa3.12071 SUPPORT Human Clinical
"cardiac arrest caused by ventricular fibrillation (VF)."
Documents cardiac arrest from VF in an infant case, supporting the severity spectrum beyond adults.
Sudden cardiac death Sudden cardiac death (HP:0001645)
Show evidence (1 reference)
DOI:10.1161/01.cir.89.1.206 SUPPORT Human Clinical
"During a mean follow-up of 7 years there were 5 deaths (4 sudden)."
Supports sudden cardiac death as a major outcome risk.
Other 3
Short-coupled premature ventricular contraction Premature ventricular contraction (HP:0006682)
Show evidence (1 reference)
DOI:10.3389/fcvm.2022.922525 SUPPORT Human Clinical
"The ECGs of all selected patients showed a short first-coupling interval (302 ± 62 ms)"
Supports short first-coupling interval as a diagnostic ECG feature across a systematic review of reported cases.
Short-coupled torsade de pointes Torsade de pointes (HP:0001664)
Show evidence (1 reference)
DOI:10.1161/01.cir.89.1.206 SUPPORT Human Clinical
"syncope related to a typical ECG aspect of torsade de pointes"
Documents TdP as the characteristic presenting rhythm in the original syndrome description.
Polymorphic ventricular tachycardia Polymorphic ventricular tachycardia (HP:0031677)
Show evidence (1 reference)
clinicaltrials:NCT05593757 SUPPORT Human Clinical
"initiated by a short-coupled premature ventricular contraction (PVC)."
Clinical trial registry text defines the modern short-coupled idiopathic VF/PVT phenotype.
🧬

Genetic Associations

2
RYR2 calcium-release susceptibility (Susceptibility)
Show evidence (2 references)
"enhanced store overload-induced Ca2+ release in response to cytosolic Ca2+ was observed in RyR2-I784F cells."
Supports a functional RYR2 calcium-release mechanism in a patient-linked variant, while remaining limited to a rare case-based susceptibility model.
"The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions."
Directly supports abnormal diastolic RyR2 channel behavior as a plausible arrhythmogenic substrate.
SCN5A sodium-channel candidate susceptibility (Susceptibility)
Show evidence (2 references)
DOI:10.1111/pace.13924 PARTIAL Human Clinical
"We identified an SCN5A mutation R800H"
Documents a patient-level SCN5A variant in short-coupled TdP with malignant ventricular arrhythmia.
DOI:10.1111/pace.13924 PARTIAL In Vitro
"showed a significantly shortened recovery time from inactivation."
Supports altered sodium-channel gating as a candidate mechanism in a subset of short-coupled TdP.
💊

Treatments

4
Implantable cardioverter-defibrillator placement
Action: implantable cardioverter-defibrillator placement MAXO:0000474
ICD placement provides secondary prevention by terminating VF or sustained malignant ventricular arrhythmia, but recurrent shocks may require additional drug therapy or ablation.
Show evidence (2 references)
DOI:10.3389/fcvm.2022.922525 SUPPORT Human Clinical
"The Kaplan-Meier survival curve revealed increased survival in patients with implantable cardioverter defibrillator (ICD) implantation than in patients without ICD implantation"
Systematic-review evidence supports ICD implantation as protective secondary prevention.
clinicaltrials:NCT05593757 SUPPORT Human Clinical
"patients are protected from sudden cardiac death by an implantable cardioverter-defibrillator (ICD)"
Trial registry rationale recognizes ICDs as sudden-death protection in short-coupled idiopathic VF.
Verapamil therapy
Action: Pharmacotherapy NCIT:C15986
Agent: verapamil
Verapamil can suppress short-coupled ventricular triggers and recurrent TdP/VF in some patients, but it should not be modeled as complete sudden death prevention.
Show evidence (2 references)
DOI:10.1161/01.cir.89.1.206 PARTIAL Human Clinical
"verapamil is in our experience the only drug apparently active on the arrhythmias; however, it does not prevent sudden death."
Supports verapamil as arrhythmia-suppressive but incomplete protection.
DOI:10.1002/joa3.12071 SUPPORT Human Clinical
"which were controlled by verapamil."
Supports verapamil responsiveness of short-coupled PVC-triggered VT/VF in a pediatric case.
Quinidine therapy
Action: Pharmacotherapy NCIT:C15986
Agent: quinidine
Quinidine is being prospectively compared with verapamil for short-coupled idiopathic VF, but current registry evidence states that its event-reduction effect is unknown.
Show evidence (1 reference)
clinicaltrials:NCT05593757 PARTIAL Human Clinical
"Verapamil and quinidine have been suggested as effective antiarrhythmic drugs, but at present it is unknown whether these drugs reduce the incidence of arrhythmic events."
Supports quinidine as an actively studied antiarrhythmic option while preserving uncertainty about event reduction.
Catheter ablation of culprit PVC trigger
Action: ablation therapy MAXO:0000452
Catheter ablation can target a mapped short-coupled culprit PVC, especially a moderator-band or Purkinje-network trigger, in recurrent sc-TdP or electrical storm.
Show evidence (1 reference)
DOI:10.1007/s00392-021-01840-z SUPPORT Human Clinical
"eliminated sc-TdP in all patients"
Supports ablation as a disease-specific intervention when the culprit short-coupled trigger can be mapped.
🔬

Clinical Trials

1
NCT05593757 PHASE_II UNKNOWN
Open-label randomized crossover pilot trial comparing quinidine with verapamil in short-coupled idiopathic ventricular fibrillation.
Target Phenotypes: Ventricular fibrillation Polymorphic ventricular tachycardia
Show evidence (1 reference)
clinicaltrials:NCT05593757 SUPPORT Human Clinical
"This pilot study will provide insight into the advisability and feasibility of a randomized controlled trial (RCT) and provide data needed to determine the most appropriate design and the sample size."
ClinicalTrials.gov summary supports the existence and purpose of the quinidine-versus-verapamil pilot trial.
{ }

Source YAML

click to show
name: Torsade de Pointes Syndrome With Short Coupling Interval
creation_date: "2026-05-06T17:40:18Z"
updated_date: "2026-05-06T17:40:18Z"
description: >-
  Torsade-de-pointes syndrome with short coupling interval is a rare primary
  electrical heart disease in which very short-coupled premature ventricular
  contractions initiate torsade de pointes, polymorphic ventricular
  tachycardia, or ventricular fibrillation despite a normal QT interval and no
  overt structural heart disease. The disorder creates risk for syncope,
  electrical storm, cardiac arrest, and sudden cardiac death; genetic evidence
  supports heterogeneous susceptibility rather than a single uniform cause.
category: Genetic
disease_term:
  preferred_term: torsade-de-pointes syndrome with short coupling interval
  term:
    id: MONDO:0013317
    label: torsade-de-pointes syndrome with short coupling interval
parents:
- Cardiac Arrhythmia
- Channelopathy
synonyms:
- Short-coupled torsade de pointes
- Short-coupled variant torsade de pointes
- Short-coupled idiopathic ventricular fibrillation
- Short-coupled ventricular fibrillation
- Torsade de pointes with short coupling interval
- TdP with short coupling interval
notes: >-
  Scope is limited to the short-coupled TdP/short-coupled idiopathic
  ventricular fibrillation phenotype. This entry intentionally distinguishes
  the disorder from classic congenital or acquired long-QT torsade de pointes,
  catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and
  short-QT syndrome, which have separate diagnostic criteria and mechanisms.
genetic:
- name: RYR2 calcium-release susceptibility
  association: Susceptibility
  features: >-
    Rare RYR2 variants have been reported in individual short-coupled TdP or
    short-coupled idiopathic ventricular fibrillation cases. Functional
    evidence from RYR2-I784F supports abnormal calcium release as a plausible
    trigger substrate, but the evidence remains case-based and may be
    oligogenic in some patients.
  gene_term:
    preferred_term: RYR2
    term:
      id: hgnc:10484
      label: RYR2
  evidence:
  - reference: DOI:10.1038/s41598-021-84373-9
    reference_title: A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: enhanced store overload-induced Ca2+ release in response to cytosolic Ca2+ was observed in RyR2-I784F cells.
    explanation: >-
      Supports a functional RYR2 calcium-release mechanism in a patient-linked
      variant, while remaining limited to a rare case-based susceptibility
      model.
  - reference: DOI:10.1038/s41598-021-84373-9
    reference_title: A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions.
    explanation: >-
      Directly supports abnormal diastolic RyR2 channel behavior as a plausible
      arrhythmogenic substrate.
- name: SCN5A sodium-channel candidate susceptibility
  association: Susceptibility
  features: >-
    SCN5A-R800H has been reported in a patient with short-coupled TdP and
    functional testing showed altered recovery from inactivation. Current
    evidence supports SCN5A as a candidate susceptibility gene rather than a
    definitive monogenic explanation for all cases.
  gene_term:
    preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  evidence:
  - reference: DOI:10.1111/pace.13924
    reference_title: "<i>SCN5A</i> mutation identified in a patient with short-coupled variant of torsades de pointes"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: We identified an SCN5A mutation R800H
    explanation: >-
      Documents a patient-level SCN5A variant in short-coupled TdP with
      malignant ventricular arrhythmia.
  - reference: DOI:10.1111/pace.13924
    reference_title: "<i>SCN5A</i> mutation identified in a patient with short-coupled variant of torsades de pointes"
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: showed a significantly shortened recovery time from inactivation.
    explanation: >-
      Supports altered sodium-channel gating as a candidate mechanism in a
      subset of short-coupled TdP.
pathophysiology:
- name: RYR2-mediated calcium release susceptibility
  conforms_to: "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"
  role: central_effector
  description: >-
    Rare patient-linked RYR2 variants can alter RyR2-mediated calcium release,
    creating a susceptibility substrate for premature ventricular ectopy in
    structurally normal hearts.
  genes:
  - preferred_term: RYR2
    term:
      id: hgnc:10484
      label: RYR2
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: calcium ion transport
    term:
      id: GO:0006816
      label: calcium ion transport
    modifier: DYSREGULATED
  evidence:
  - reference: DOI:10.1038/s41598-021-84373-9
    reference_title: A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions.
    explanation: >-
      Functional evidence links a patient-associated RYR2 variant to abnormal
      calcium release, a plausible trigger substrate for short-coupled ectopy.
  downstream:
  - target: Short-coupled premature ventricular trigger
    description: >-
      RyR2-mediated calcium-release susceptibility can promote premature
      ventricular ectopy capable of triggering short-coupled TdP or VF.
- name: SCN5A sodium-channel susceptibility
  conforms_to: "cardiac_ion_channel_repolarization#Cardiac Ion-Channel or Calcium-Handling Variant"
  role: trigger
  description: >-
    Rare patient-linked SCN5A variants can alter Nav1.5 recovery from
    inactivation, creating a candidate sodium-channel susceptibility substrate
    for short-coupled ventricular ectopy.
  genes:
  - preferred_term: SCN5A
    term:
      id: hgnc:10593
      label: SCN5A
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  molecular_functions:
  - preferred_term: monoatomic ion channel activity
    term:
      id: GO:0005216
      label: monoatomic ion channel activity
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
    modifier: ABNORMAL
  evidence:
  - reference: DOI:10.1111/pace.13924
    reference_title: "<i>SCN5A</i> mutation identified in a patient with short-coupled variant of torsades de pointes"
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: showed a significantly shortened recovery time from inactivation.
    explanation: >-
      Supports altered sodium-channel kinetics as a candidate upstream
      mechanism in one reported case.
  downstream:
  - target: Short-coupled premature ventricular trigger
    description: >-
      Sodium-channel susceptibility can promote premature ventricular ectopy
      capable of triggering short-coupled TdP or VF.
- name: Short-coupled premature ventricular trigger
  conforms_to: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity"
  role: amplifier
  description: >-
    The defining electrophysiologic event is a premature ventricular
    contraction with an extremely short coupling interval, often arising from
    Purkinje or right ventricular endocavitary structures and initiating TdP,
    polymorphic ventricular tachycardia, or VF.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Purkinje myocyte
    term:
      id: CL:0002068
      label: Purkinje myocyte
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: moderator band
    term:
      id: UBERON:8470002
      label: moderator band
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DYSREGULATED
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: ABNORMAL
  - preferred_term: membrane depolarization during cardiac muscle cell action potential
    term:
      id: GO:0086012
      label: membrane depolarization during cardiac muscle cell action potential
    modifier: ABNORMAL
  evidence:
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the torsade had the unusual particularity of an extremely short coupling
      interval of the first beat or of the isolated premature beats (245 +/-
      28 milliseconds)
    explanation: >-
      Defines the short-coupled initiating beat in the original clinical
      series.
  - reference: DOI:10.1007/s00392-021-01840-z
    reference_title: Catheter ablation of short-coupled variant of torsade de pointes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients.
    explanation: >-
      Supports Purkinje/moderator-band ventricular trigger localization in a
      contemporary mapping and ablation cohort.
  downstream:
  - target: Polymorphic ventricular tachyarrhythmia
    description: >-
      The short-coupled ventricular trigger initiates TdP, polymorphic VT, or
      VF.
- name: Polymorphic ventricular tachyarrhythmia
  conforms_to: "cardiac_ion_channel_repolarization#Ventricular Tachyarrhythmia"
  role: effector
  description: >-
    Short-coupled PVCs initiate torsade de pointes or polymorphic ventricular
    tachycardia and may degenerate into ventricular fibrillation.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Purkinje myocyte
    term:
      id: CL:0002068
      label: Purkinje myocyte
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: DOI:10.3389/fcvm.2022.922525
    reference_title: "Short-coupled variant of torsade de pointes: A systematic review of case reports and case series"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The short-coupled variant of torsade de pointes (scTdP) is characterized
      by a particular electrocardiogram (ECG) pattern that shows a
      short-coupling interval of the initial Tdp beat and that can degenerate
      into ventricular fibrillation without the presence of structural heart
      disease.
    explanation: >-
      Systematic review evidence supports short-coupled initiation, malignant
      ventricular arrhythmia, and absence of structural heart disease as core
      disease features.
  downstream:
  - target: Ventricular fibrillation and cardiac arrest
    description: >-
      Sustained or recurrent polymorphic ventricular tachyarrhythmia can
      degenerate into VF, producing syncope, aborted sudden cardiac death, or
      fatal sudden cardiac death.
- name: Ventricular fibrillation and cardiac arrest
  conforms_to: "cardiac_ion_channel_repolarization#Syncope and Sudden Cardiac Death"
  role: outcome
  description: >-
    Degeneration into ventricular fibrillation produces cardiac arrest or
    sudden cardiac death unless terminated by defibrillation or an implantable
    cardioverter-defibrillator.
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: DYSREGULATED
  evidence:
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 10 cases they deteriorated into ventricular fibrillation.
    explanation: >-
      Shows frequent degeneration from short-coupled TdP into ventricular
      fibrillation in the original clinical series.
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During a mean follow-up of 7 years there were 5 deaths (4 sudden).
    explanation: >-
      Supports sudden death risk when malignant arrhythmias are not fully
      controlled.
phenotypes:
- category: Cardiovascular
  name: Short-coupled premature ventricular contraction
  diagnostic: true
  description: >-
    The diagnostic trigger is an extremely short-coupled premature ventricular
    contraction or ventricular extrasystole that initiates TdP, polymorphic VT,
    or VF.
  phenotype_term:
    preferred_term: Premature ventricular contraction
    term:
      id: HP:0006682
      label: Premature ventricular contraction
  evidence:
  - reference: DOI:10.3389/fcvm.2022.922525
    reference_title: "Short-coupled variant of torsade de pointes: A systematic review of case reports and case series"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The ECGs of all selected patients showed a short first-coupling interval (302 ± 62 ms)
    explanation: >-
      Supports short first-coupling interval as a diagnostic ECG feature across
      a systematic review of reported cases.
- category: Cardiovascular
  name: Short-coupled torsade de pointes
  diagnostic: true
  description: >-
    Torsade de pointes is initiated by a ventricular beat with a short coupling
    interval rather than the pause-dependent long-coupled trigger typical of
    long-QT torsade.
  phenotype_term:
    preferred_term: Torsade de pointes
    term:
      id: HP:0001664
      label: Torsade de pointes
  evidence:
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      syncope related to a typical ECG aspect of torsade de pointes
    explanation: >-
      Documents TdP as the characteristic presenting rhythm in the original
      syndrome description.
- category: Cardiovascular
  name: Polymorphic ventricular tachycardia
  diagnostic: true
  description: >-
    The ventricular tachyarrhythmia may be recorded as polymorphic ventricular
    tachycardia, especially in contemporary idiopathic VF diagnostic frameworks.
  phenotype_term:
    preferred_term: Polymorphic ventricular tachycardia
    term:
      id: HP:0031677
      label: Polymorphic ventricular tachycardia
  evidence:
  - reference: clinicaltrials:NCT05593757
    reference_title: "Quinidine Versus Verapamil in Short-coupled Idiopathic Ventricular Fibrillation: an Open-label, Randomized Crossover Pilot Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: initiated by a short-coupled premature ventricular contraction (PVC).
    explanation: >-
      Clinical trial registry text defines the modern short-coupled idiopathic
      VF/PVT phenotype.
- category: Neurological
  name: Syncope
  description: >-
    Transient loss of consciousness can be the first manifestation of
    self-terminating or resuscitated malignant ventricular arrhythmia.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: DOI:10.1007/s00392-021-01840-z
    reference_title: Catheter ablation of short-coupled variant of torsade de pointes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope
    explanation: >-
      Documents syncope as a presenting manifestation in a recurrent
      short-coupled TdP ablation cohort.
- category: Cardiovascular
  name: Ventricular fibrillation
  description: >-
    Short-coupled TdP or polymorphic VT can degenerate into ventricular
    fibrillation.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 10 cases they deteriorated into ventricular fibrillation.
    explanation: >-
      Supports VF as a frequent malignant outcome in the original series.
- category: Cardiovascular
  name: Cardiac arrest
  description: Sustained malignant ventricular arrhythmia can produce sudden cardiac arrest.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: DOI:10.1007/s00392-021-01840-z
    reference_title: Catheter ablation of short-coupled variant of torsade de pointes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four patients initially presented with sudden cardiac arrest
    explanation: Supports cardiac arrest as a common severe presentation in the ablation cohort.
  - reference: DOI:10.1002/joa3.12071
    reference_title: Electrical storm in an infant with short-coupled variant of torsade de pointes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: cardiac arrest caused by ventricular fibrillation (VF).
    explanation: >-
      Documents cardiac arrest from VF in an infant case, supporting the
      severity spectrum beyond adults.
- category: Cardiovascular
  name: Sudden cardiac death
  description: >-
    Fatal ventricular fibrillation or cardiac arrest can cause sudden cardiac
    death.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During a mean follow-up of 7 years there were 5 deaths (4 sudden).
    explanation: Supports sudden cardiac death as a major outcome risk.
diagnosis:
- name: Electrocardiographic short-coupled TdP or VF diagnosis
  description: >-
    Diagnosis depends on ECG or rhythm-device documentation of TdP,
    polymorphic VT, or VF initiated by a very short-coupled premature
    ventricular contraction, usually with normal baseline QT interval.
  results: >-
    A short-coupled PVC initiating TdP/PVT/VF supports the diagnosis, whereas
    long-QT, short-QT, pause-dependent TdP, CPVT, Brugada syndrome, early
    repolarization syndrome, and structural heart disease should be evaluated
    as alternatives when clinically indicated.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: MAXO:0000900
      label: electrocardiography
  evidence:
  - reference: DOI:10.1111/pace.13924
    reference_title: "<i>SCN5A</i> mutation identified in a patient with short-coupled variant of torsades de pointes"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: TdP without QT prolongation
    explanation: >-
      Supports normal QT interval plus extremely short-coupled ventricular
      extrasystoles as the diagnostic distinction from long-QT torsade.
  - reference: DOI:10.1002/joa3.12071
    reference_title: Electrical storm in an infant with short-coupled variant of torsade de pointes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His electrocardiogram (ECG) at rest was within the normal range.
    explanation: >-
      Supports that the baseline ECG can be normal despite malignant
      short-coupled ventricular arrhythmia.
- name: Structural heart disease exclusion
  description: >-
    Evaluation should exclude overt structural or ischemic heart disease before
    classifying the phenotype as short-coupled idiopathic TdP/VF.
  results: >-
    No structural heart disease with malignant short-coupled ventricular
    arrhythmia supports the short-coupled TdP diagnosis.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: MAXO:0010203
      label: echocardiography
  evidence:
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: no structural heart disease who presented with syncope related to a typical ECG aspect of torsade de pointes.
    explanation: >-
      The original series defined the phenotype in patients without structural
      heart disease.
- name: Arrhythmia genetic testing
  description: >-
    Inherited-arrhythmia genetic testing may identify candidate or
    patient-specific variants and can help exclude overlapping channelopathy
    diagnoses, but a negative or inconclusive result does not exclude the
    disorder.
  results: >-
    Candidate variants in genes such as RYR2 or SCN5A may support
    susceptibility assessment when interpreted with the ECG phenotype.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: DOI:10.1111/pace.13924
    reference_title: "<i>SCN5A</i> mutation identified in a patient with short-coupled variant of torsades de pointes"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: among seven consecutive scTdP patients.
    explanation: >-
      Supports use of inherited-arrhythmia panels in reported scTdP cases, but
      genetic testing is not yet a definitive diagnostic requirement.
treatments:
- name: Implantable cardioverter-defibrillator placement
  description: >-
    ICD placement provides secondary prevention by terminating VF or sustained
    malignant ventricular arrhythmia, but recurrent shocks may require
    additional drug therapy or ablation.
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: MAXO:0000474
      label: implantable cardioverter-defibrillator placement
  evidence:
  - reference: DOI:10.3389/fcvm.2022.922525
    reference_title: "Short-coupled variant of torsade de pointes: A systematic review of case reports and case series"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Kaplan-Meier survival curve revealed increased survival in patients
      with implantable cardioverter defibrillator (ICD) implantation than in
      patients without ICD implantation
    explanation: >-
      Systematic-review evidence supports ICD implantation as protective
      secondary prevention.
  - reference: clinicaltrials:NCT05593757
    reference_title: "Quinidine Versus Verapamil in Short-coupled Idiopathic Ventricular Fibrillation: an Open-label, Randomized Crossover Pilot Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: patients are protected from sudden cardiac death by an implantable cardioverter-defibrillator (ICD)
    explanation: >-
      Trial registry rationale recognizes ICDs as sudden-death protection in
      short-coupled idiopathic VF.
- name: Verapamil therapy
  description: >-
    Verapamil can suppress short-coupled ventricular triggers and recurrent
    TdP/VF in some patients, but it should not be modeled as complete sudden
    death prevention.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: verapamil
      term:
        id: CHEBI:9948
        label: verapamil
  evidence:
  - reference: DOI:10.1161/01.cir.89.1.206
    reference_title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      verapamil is in our experience the only drug apparently active on the
      arrhythmias; however, it does not prevent sudden death.
    explanation: >-
      Supports verapamil as arrhythmia-suppressive but incomplete protection.
  - reference: DOI:10.1002/joa3.12071
    reference_title: Electrical storm in an infant with short-coupled variant of torsade de pointes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which were controlled by verapamil.
    explanation: >-
      Supports verapamil responsiveness of short-coupled PVC-triggered VT/VF in
      a pediatric case.
- name: Quinidine therapy
  description: >-
    Quinidine is being prospectively compared with verapamil for
    short-coupled idiopathic VF, but current registry evidence states that its
    event-reduction effect is unknown.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: quinidine
      term:
        id: CHEBI:28593
        label: quinidine
  evidence:
  - reference: clinicaltrials:NCT05593757
    reference_title: "Quinidine Versus Verapamil in Short-coupled Idiopathic Ventricular Fibrillation: an Open-label, Randomized Crossover Pilot Trial"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Verapamil and quinidine have been suggested as effective antiarrhythmic
      drugs, but at present it is unknown whether these drugs reduce the
      incidence of arrhythmic events.
    explanation: >-
      Supports quinidine as an actively studied antiarrhythmic option while
      preserving uncertainty about event reduction.
- name: Catheter ablation of culprit PVC trigger
  description: >-
    Catheter ablation can target a mapped short-coupled culprit PVC, especially
    a moderator-band or Purkinje-network trigger, in recurrent sc-TdP or
    electrical storm.
  treatment_term:
    preferred_term: ablation therapy
    term:
      id: MAXO:0000452
      label: ablation therapy
  evidence:
  - reference: DOI:10.1007/s00392-021-01840-z
    reference_title: Catheter ablation of short-coupled variant of torsade de pointes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: eliminated sc-TdP in all patients
    explanation: >-
      Supports ablation as a disease-specific intervention when the culprit
      short-coupled trigger can be mapped.
clinical_trials:
- name: NCT05593757
  phase: PHASE_II
  status: UNKNOWN
  description: >-
    Open-label randomized crossover pilot trial comparing quinidine with
    verapamil in short-coupled idiopathic ventricular fibrillation.
  target_phenotypes:
  - preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  - preferred_term: Polymorphic ventricular tachycardia
    term:
      id: HP:0031677
      label: Polymorphic ventricular tachycardia
  evidence:
  - reference: clinicaltrials:NCT05593757
    reference_title: "Quinidine Versus Verapamil in Short-coupled Idiopathic Ventricular Fibrillation: an Open-label, Randomized Crossover Pilot Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This pilot study will provide insight into the advisability and
      feasibility of a randomized controlled trial (RCT) and provide data
      needed to determine the most appropriate design and the sample size.
    explanation: >-
      ClinicalTrials.gov summary supports the existence and purpose of the
      quinidine-versus-verapamil pilot trial.
references:
- reference: DOI:10.1002/joa3.12071
  title: Electrical storm in an infant with short‐coupled variant of torsade de pointes
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.1007/s00392-021-01840-z
  title: Catheter ablation of short-coupled variant of torsade de pointes
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.hrthm.2016.10.015
  title: A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.ijcard.2016.11.052
  title: An RyR2 mutation found in a family with a short-coupled variant of torsade de pointes
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.1038/s41598-021-84373-9
  title: A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.1111/pace.13924
  title: "<i>SCN5A</i> mutation identified in a patient with short‐coupled variant of torsades de pointes"
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.1161/01.cir.89.1.206
  title: Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.1186/s13287-024-04074-8
  title: An hiPSC-CM approach for electrophysiological phenotyping of a patient-specific case of short-coupled TdP
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.15420/aer.2025.34
  title: "Idiopathic Ventricular Fibrillation: Substrates, Mechanisms and Treatment"
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.3389/fcvm.2022.922525
  title: "Short-coupled variant of torsade de pointes: A systematic review of case reports and case series"
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
- reference: DOI:10.3389/fcvm.2024.1363848
  title: "Mechanisms of torsades de pointes: an update"
  found_in:
  - Torsade_De_Pointes_Syndrome_With_Short_Coupling_Interval-deep-research-falcon.md
  findings: []
📚

References & Deep Research

References

11
Electrical storm in an infant with short‐coupled variant of torsade de pointes
No top-level findings curated for this source.
Catheter ablation of short-coupled variant of torsade de pointes
No top-level findings curated for this source.
A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia
No top-level findings curated for this source.
An RyR2 mutation found in a family with a short-coupled variant of torsade de pointes
No top-level findings curated for this source.
A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes
No top-level findings curated for this source.
<i>SCN5A</i> mutation identified in a patient with short‐coupled variant of torsades de pointes
No top-level findings curated for this source.
Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias.
No top-level findings curated for this source.
An hiPSC-CM approach for electrophysiological phenotyping of a patient-specific case of short-coupled TdP
No top-level findings curated for this source.
Idiopathic Ventricular Fibrillation: Substrates, Mechanisms and Treatment
No top-level findings curated for this source.
Short-coupled variant of torsade de pointes: A systematic review of case reports and case series
No top-level findings curated for this source.
Mechanisms of torsades de pointes: an update
No top-level findings curated for this source.

Deep Research

1
Falcon
Torsade de Pointes Syndrome With Short Coupling Interval (Short‑Coupled TdP / Short‑Coupled Ventricular Fibrillation) — Comprehensive Research Report
Edison Scientific Literature 39 citations 2026-05-06T13:59:15.716076

Torsade de Pointes Syndrome With Short Coupling Interval (Short‑Coupled TdP / Short‑Coupled Ventricular Fibrillation) — Comprehensive Research Report

Executive summary

Short‑coupled torsades de pointes (scTdP), also called the short‑coupled variant of torsade de pointes and often discussed today under short‑coupled ventricular fibrillation (SCVF) / Purkinje‑triggered idiopathic ventricular fibrillation, is a malignant ventricular tachyarrhythmia syndrome characterized by polymorphic VT/TdP and/or VF initiated by an extremely short‑coupled PVC (classically ~200–300 ms) in patients without baseline QT prolongation and typically without overt structural heart disease. It carries high risk of syncope, electrical storm, and sudden cardiac death; ICD therapy is the only consistently supported sudden‑death preventive intervention, while verapamil can suppress episodes but is not fully protective. Increasing evidence implicates His‑Purkinje/right ventricular endocavitary triggers (e.g., moderator band insertion) and heterogeneous genetic contributions including RYR2, SCN5A, and Purkinje‑repolarization risk haplotypes (e.g., DPP6). (leenhardt1994shortcoupledvariantof pages 1-3, leenhardt1994shortcoupledvariantof pages 9-10, wang2022shortcoupledvariantof pages 1-2, steinfurt2022catheterablationof pages 1-3, steinfurt2022catheterablationof pages 3-7)


1. Disease information

1.1 Definition and current understanding

The original description (Leenhardt et al., 1994-01, Circulation) observed 14 patients with syncope and a typical TdP ECG pattern without long‑QT syndrome, in whom TdP had “the unusual particularity of an extremely short coupling interval of the first beat or of the isolated premature beats (245±28 milliseconds).” (leenhardt1994shortcoupledvariantof pages 1-3)

The diagnosis is now commonly framed as TdP/VF initiated by a short‑coupled PVC on a normal QT background, resembling an “R‑on‑T” phenomenon. A 2022 systematic review summarizes it as “TdP/VF triggered by a short‑coupled premature ventricular complex (PVC) on a normal QT interval.” (wang2022shortcoupledvariantof pages 1-2)

A 2024 TdP mechanistic update notes that although TdP classically refers to long‑QT polymorphic VT, the term has also been used for polymorphic arrhythmias without QT prolongation, including “short‑coupled variant of TdP currently known as short‑coupled ventricular fibrillation.” (tsuji2024mechanismsoftorsades pages 1-2)

1.2 Synonyms / alternative names

  • Short‑coupled variant of torsade de pointes (SCV‑TdP) (leenhardt1994shortcoupledvariantof pages 1-3)
  • Short‑coupled torsade de pointes (scTdP) (wang2022shortcoupledvariantof pages 1-2)
  • Short‑coupled ventricular fibrillation (SCVF) / short‑coupled idiopathic VF phenotype (tsuji2024mechanismsoftorsades pages 1-2, NCT05593757 chunk 1)
  • Purkinje‑triggered idiopathic ventricular fibrillation (conceptual phenotype) (wang2022shortcoupledvariantof pages 12-14, steinfurt2022catheterablationof pages 3-7)

1.3 Key identifiers (OMIM/Orphanet/ICD/MeSH/MONDO)

Within the retrieved evidence set, explicit cross‑references to OMIM, Orphanet, ICD‑10/ICD‑11, MeSH, or MONDO were not present, and an OpenTargets disease lookup for “short‑coupled torsades de pointes” did not resolve a disease ID during tool execution. Therefore, these identifiers cannot be provided from the current evidence corpus and would require targeted ontology/database queries beyond the retrieved texts. (wang2022shortcoupledvariantof pages 1-2)

1.4 Evidence source type

Most knowledge for this entity comes from case series, systematic reviews of case reports/series, and small retrospective ablation cohorts, rather than large prospective epidemiologic cohorts. (wang2022shortcoupledvariantof pages 1-2, steinfurt2022catheterablationof pages 1-3)


2. Etiology

2.1 Primary causal factors

Immediate trigger: A short‑coupled PVC initiating polymorphic VT/TdP that often degenerates into VF. (wang2022shortcoupledvariantof pages 1-2, leenhardt1994shortcoupledvariantof pages 1-3)

Substrate concept: Many cases appear “idiopathic” on standard testing, but convergent data point to His‑Purkinje/endocavitary trigger sites (Purkinje fibers, moderator band, RVOT) and to genetic/oligogenic susceptibility affecting calcium handling or conduction. (wang2022shortcoupledvariantof pages 12-14, touathamici2021aspry1domain pages 1-2, steinfurt2022catheterablationof pages 3-7)

2.2 Risk factors

Genetic risk factors / associations (examples with variant‑level detail): * RYR2 variants reported in familial and sporadic scTdP phenotypes, including p.M995V (c.2983A>G) (familial SCV‑TdP) (kimura2017anryr2mutation pages 2-3) and p.I784F (c.2350A>T) (sudden death case), with functional evidence of increased spontaneous Ca2+ release/SOICR and “leaky channel” behavior under non‑stress conditions. (touathamici2021aspry1domain pages 1-2, touathamici2021aspry1domain pages 2-3) * SCN5A p.R800H (c.2399G>A) identified in a scTdP patient within a 7‑patient cohort screened by a 45‑gene inherited‑arrhythmia panel; functional studies showed shortened recovery from inactivation. (sonoda2020scn5amutationidentified pages 1-2) * DPP6 risk haplotype: discussed as a Purkinje‑specific repolarization acceleration mechanism creating gradients that predispose to short‑coupled PVCs; DPP6 haplotype carrier status is a principal diagnostic criterion for the ongoing QUEEN‑IVF trial. (steinfurt2022catheterablationof pages 3-7, NCT05593757 chunk 1)

Family history: In the original 1994 series, 4/14 had familial sudden death history. (leenhardt1994shortcoupledvariantof pages 1-3)

Physiologic stressors: scTdP episodes may occur at rest and are often not related to adrenergic stress in some series, but individual cases suggest fever/hyperthermia can exacerbate triggers. (leenhardt1994shortcoupledvariantof pages 9-10, ham2024anhipsccmapproach pages 1-2)

2.3 Protective factors

No specific protective genetic variants or environmental protective factors were identified in the retrieved corpus.

2.4 Gene–environment interactions

A 2024 patient‑specific hiPSC‑CM model in a fever‑associated VF/scTdP case supports a temperature‑sensitive increase in abnormal calcium events, suggesting hyperthermia as a potential trigger interacting with an underlying susceptibility: “at 39 °C the incidence of [early after transients] further increased.” (ham2024anhipsccmapproach pages 1-2)


3. Phenotypes

3.1 Core clinical phenotypes (with suggested HPO terms)

  • Syncope (HPO suggestion: Syncope [HP:0001279]) — presenting symptom in original series and later reports. (leenhardt1994shortcoupledvariantof pages 1-3)
  • Ventricular fibrillation (HPO suggestion: Ventricular fibrillation [HP:0001663]) — common degeneration endpoint. (leenhardt1994shortcoupledvariantof pages 1-3)
  • Torsades de pointes / polymorphic VT (HPO suggestion: Torsade de pointes [HP:0001677]; Ventricular tachycardia [HP:0004756]) (leenhardt1994shortcoupledvariantof pages 1-3, wang2022shortcoupledvariantof pages 1-2)
  • Premature ventricular contractions (HPO suggestion: Premature ventricular contractions [HP:0006689]) — short‑coupled trigger PVCs. (wang2022shortcoupledvariantof pages 1-2)
  • Sudden cardiac arrest (HPO suggestion: Cardiac arrest [HP:0001695]) — frequent first presentation in modern cohorts. (steinfurt2022catheterablationof pages 1-3)
  • Electrical storm (clinical term; HPO suggestion: map to recurrent VT/VF) — frequent in malignant presentations. (steinfurt2022catheterablationof pages 1-3)

3.2 ECG phenotype (defining features)

Key ECG features across cohorts include: * Extremely short PVC coupling interval: mean 245±28 ms in the original series (leenhardt1994shortcoupledvariantof pages 1-3); pooled mean 302±62 ms in a systematic review (wang2022shortcoupledvariantof pages 1-2); ≤300 ms inclusion criterion used in several studies. (fujii2017atype2 pages 2-3) * Normal baseline QT/QTc: described as normal QT in the original series and systematic review framing. (leenhardt1994shortcoupledvariantof pages 9-10, wang2022shortcoupledvariantof pages 1-2)

3.3 Age of onset, severity, and progression

  • Adults: Leenhardt mean age 34.6±10 years; mean follow‑up 7 years. (leenhardt1994shortcoupledvariantof pages 1-3)
  • Pediatric: infant electrical storm case at 10 months, demonstrating possible very early onset. (kise2018electricalstormin pages 1-3)
  • Severity: high risk of VF degeneration (10/14 in original series). (leenhardt1994shortcoupledvariantof pages 1-3)
  • EP study: low inducibility by programmed stimulation in original series (2/14 inducible). (leenhardt1994shortcoupledvariantof pages 1-3)

3.4 Quality of life impact

While disease‑specific QoL instruments were not reported in the retrieved primary series, the need for ICD shocks and recurrent arrhythmias implies substantial QoL impact; the QUEEN‑IVF trial rationale notes recurrent shocks “can negatively affect quality of life.” (NCT05593757 chunk 1)


4. Genetic / molecular information

4.1 Causal genes and candidate genes

Evidence in the retrieved corpus supports a genetically heterogeneous architecture with candidate/causal roles for RYR2 and SCN5A in subsets, and a broader susceptibility framework including Purkinje‑specific repolarization modifiers (e.g., DPP6 haplotype) and possible oligogenic combinations. (sonoda2020scn5amutationidentified pages 1-2, touathamici2021aspry1domain pages 1-2, steinfurt2022catheterablationof pages 3-7, NCT05593757 chunk 1)

Gene Reported variant / finding Disease context Evidence type Mechanistic implication Allele frequency / prevalence notes Citations
RYR2 p.M995V, c.2983A>G Familial short-coupled variant of TdP (SCV-TdP) Family report / candidate causal variant Supports abnormal RyR2-mediated Ca2+ handling in scTdP; authors discuss prior RyR2-H29D evidence for diastolic Ca2+ leak under non-stress conditions, consistent with EAD/DAD-related triggering No population frequency reported in retrieved context (kimura2017anryr2mutation pages 2-3)
RYR2 p.H29D (previously reported) scTdP / short-coupled ventricular arrhythmia Prior case-based and functional literature summarized in later papers Leaky RyR2 channel at diastolic Ca2+ under non-stress conditions; implicates spontaneous Ca2+ release as trigger substrate No allele frequency reported in retrieved context (kimura2017anryr2mutation pages 2-3, fujii2017atype2 pages 2-3)
RYR2 p.I784F, c.2350A>T Patient with short-coupled premature ventricular beats/polymorphic VT, sudden death, normal QTc Exome sequencing + functional assay in HEK293 cells + structural biophysics Enhanced store-overload induced Ca2+ release (SOICR), conformational change in SPRY1 domain, increased propensity to spontaneous Ca2+ release, “leaky channel under non-stress conditions”; supports Ca2+ wave/NCX inward current/DAD-trigger mechanism Extremely rare; MAF 0.0008% in gnomAD exomes (touathamici2021aspry1domain pages 1-2, touathamici2021aspry1domain pages 2-3, touathamici2021aspry1domain pages 9-10, touathamici2021aspry1domain pages 10-11)
SCN5A p.R800H, c.2399G>A scTdP in a 38-year-old man; identified in a screen of 7 consecutive scTdP patients using a 45-gene inherited-arrhythmia panel Cohort sequencing + heterologous functional expression Shortened recovery time from inactivation of Nav1.5 channels; peak sodium current trend larger than WT; suggests altered sodium-channel kinetics can predispose to short-coupled triggering No allele frequency reported in retrieved context (sonoda2020scn5amutationidentified pages 1-2)
GJA5 (Cx40) p.A96S, c.286G>T Same scTdP/sudden death case carrying RYR2-I784F Exome sequencing; mechanistic interpretation based on known Purkinje expression and prior pathogenicity for atrial fibrillation May impair electrical coupling / reduce conduction velocity in Purkinje fibers, acting with RyR2-mediated Ca2+ dysregulation to facilitate reentry or triggered VF; supports possible oligogenic basis Reported as rare; MAF ~0.012–0.016% in population databases cited in paper (touathamici2021aspry1domain pages 1-2, touathamici2021aspry1domain pages 2-3, touathamici2021aspry1domain pages 9-10)
TNNI3K p.R244X (nonsense) Same scTdP/sudden death case carrying RYR2-I784F and GJA5-A96S Exome sequencing / candidate modifier Considered a possible susceptibility or modifier factor rather than clearly causal; hypothesized to contribute to conduction abnormalities in an oligogenic model No population frequency reported in retrieved context (touathamici2021aspry1domain pages 1-2, touathamici2021aspry1domain pages 9-10)
DPP6 Risk haplotype / mutation (not a single variant specified in retrieved context) Short-coupled idiopathic VF phenotype; included in current trial eligibility as DPP6 haplotype carriers Mechanistic cohort literature summarized in ablation paper; prospective trial stratification Selectively accelerated Purkinje fiber repolarization causing strong repolarization gradients with adjacent ventricular muscle, creating substrate for re-entry and short-coupled PVCs Prevalence not reported in retrieved context; carrier status explicitly used for enrollment in QUEEN-IVF (steinfurt2022catheterablationof pages 3-7, NCT05593757 chunk 1, NCT05593757 chunk 2)
RYR2 (gene-level association) Multiple rare variants reported across scTdP studies scTdP / short-coupled idiopathic VF Cohort subset sequencing and literature synthesis RyR2 dysfunction linked to intracellular Ca2+ release abnormalities; a plausible upstream mechanism for Purkinje-triggered PVCs and VF/TdP in patients without structural heart disease In Fujii et al., 7 scTdP cases were identified within an IVF cohort; no family history of SCD in that subset (fujii2017atype2 pages 2-3)
Oligogenic model RYR2-I784F + GJA5-A96S + TNNI3K-R244X Purkinje-fiber ectopy causing scTdP / sudden death Integrative genetic + functional interpretation Combined defects in Ca2+ sensitivity/release and conduction coupling may better explain Purkinje ectopy and VF than a single-gene model alone No combined genotype frequency reported (touathamici2021aspry1domain pages 1-2, touathamici2021aspry1domain pages 9-10)

Table: This table summarizes reported genetic associations for short-coupled torsade de pointes/short-coupled idiopathic ventricular fibrillation, including specific variants, evidence types, mechanistic interpretations, and frequency notes. It is useful for distinguishing stronger functionally supported findings from candidate or modifier associations.

4.2 Pathogenic variants (examples)

  • RYR2 p.I784F (c.2350A>T) is extremely rare (reported MAF 0.0008% in gnomAD exomes) and is functionally associated with increased spontaneous Ca2+ release/SOICR. (touathamici2021aspry1domain pages 2-3)
  • SCN5A p.R800H (c.2399G>A) functional data indicate altered sodium channel inactivation recovery. (sonoda2020scn5amutationidentified pages 1-2)

4.3 Modifier genes / oligogenicity

Touat‑Hamici et al. propose a possible oligogenic basis: RyR2‑I784F alongside GJA5 (Cx40) and TNNI3K variants may collectively affect Ca2+ handling and conduction in Purkinje tissue. (touathamici2021aspry1domain pages 1-2, touathamici2021aspry1domain pages 9-10)

4.4 Epigenetics / chromosomal abnormalities

No epigenetic or chromosomal abnormality evidence was found in the retrieved corpus.


5. Environmental information

5.1 Environmental and lifestyle factors

No consistent lifestyle, toxicologic, or occupational exposures were identified as causal in the retrieved evidence.

5.2 Infectious agents

Not established as a primary cause in the retrieved corpus; however, fever/hyperthermia coinciding with VF/scTdP in a 2024 patient‑specific study suggests systemic illness can be a trigger context even when a clear pathogen is not specified. (ham2024anhipsccmapproach pages 1-2)


6. Mechanism / pathophysiology

6.1 Causal chain (proposed)

  1. Upstream susceptibility (genetic and/or microstructural): variants affecting RyR2 Ca2+ release, sodium channel kinetics (SCN5A), conduction coupling (Cx40), or Purkinje repolarization gradients (DPP6 haplotype). (sonoda2020scn5amutationidentified pages 1-2, touathamici2021aspry1domain pages 1-2, steinfurt2022catheterablationof pages 3-7)
  2. Cellular trigger formation: abnormal intracellular Ca2+ handling can generate spontaneous Ca2+ release events (SOICR), activating NCX current and producing DADs that trigger ectopy. (touathamici2021aspry1domain pages 2-3)
  3. Tissue‑level trigger: a short‑coupled PVC from the Purkinje system/endocavitary structures (e.g., moderator band insertion) occurs during the vulnerable period (R‑on‑T‑like), initiating polymorphic VT/TdP. (wang2022shortcoupledvariantof pages 1-2, steinfurt2022catheterablationof pages 3-7)
  4. Clinical arrhythmia manifestation: polymorphic VT/TdP may degenerate to VF, causing syncope or sudden cardiac arrest. (leenhardt1994shortcoupledvariantof pages 1-3)

6.2 Purkinje vulnerability and modern mechanistic framing (2024 update)

A 2024 TdP mechanisms review (focused primarily on long‑QT TdP but discussing short‑coupled VF as a TdP‑spectrum label) reinforces the concept of triggered beats and substrate heterogeneity, and emphasizes Purkinje susceptibility to afterdepolarizations under IKr blockade, and the clinical role of Purkinje‑targeted ablation. (tsuji2024mechanismsoftorsades pages 1-2)

6.3 Patient‑specific cellular modeling (2024)

In a patient‑specific hiPSC‑CM study (2024-12, Stem Cell Research & Therapy), the abstract states: “Membrane potential data from the patient also revealed shorter action potentials that, combined with the EATs, indicate the premature release of calcium during diastole, which could be responsible for the extrasystoles in the patient.” (ham2024anhipsccmapproach pages 1-2)

6.4 Ontology term suggestions (mechanism‑linked)

GO biological processes (suggestions): * Regulation of cardiac conduction; regulation of heart rate; calcium ion transport; regulation of membrane depolarization; regulation of action potential; intracellular calcium ion homeostasis.

Cell Ontology (CL) cell types (suggestions): * Cardiac Purkinje cell; ventricular cardiomyocyte.

UBERON anatomical structures (suggestions): * Heart; right ventricle; His‑Purkinje system; moderator band.

(These mappings are ontology suggestions based on mechanistic descriptions in the retrieved literature rather than explicit ontology annotations in the source texts.) (steinfurt2022catheterablationof pages 3-7, touathamici2021aspry1domain pages 2-3)


7. Anatomical structures affected

7.1 Organ/system level

Primary affected system: cardiovascular system, specifically ventricular electrical rhythm. (leenhardt1994shortcoupledvariantof pages 1-3)

7.2 Tissue/cellular level and trigger sites

Evidence points to His‑Purkinje/endocavitary structures as frequent trigger sources.

A 2022 3D‑mapping ablation series reports: “In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients.” (steinfurt2022catheterablationof pages 1-3)


8. Temporal development

8.1 Onset

Often young adulthood (mean ~mid‑30s) but can present in infancy. (leenhardt1994shortcoupledvariantof pages 1-3, kise2018electricalstormin pages 1-3)

8.2 Course

Episodic, unpredictable; may present as recurrent syncope, aborted sudden cardiac arrest, or electrical storm. Long‑term arrhythmia behavior is described as unpredictable in the original series. (leenhardt1994shortcoupledvariantof pages 9-10, steinfurt2022catheterablationof pages 1-3)


9. Inheritance and population

9.1 Epidemiology

True population prevalence and incidence are not well quantified in the retrieved primary sources; much evidence is from case series and registries.

However, multiple sources emphasize rarity: * The systematic review aggregated 22 case reports and 103 case series patients (reflecting sparse case‑based literature). (wang2022shortcoupledvariantof pages 1-2)

9.2 Inheritance patterns

Both sporadic and familial presentations occur: * Familial sudden death history in 4/14 patients in the 1994 series. (leenhardt1994shortcoupledvariantof pages 1-3) * Familial RYR2‑associated SCV‑TdP supports heritable risk in some families. (kimura2017anryr2mutation pages 2-3)

Penetrance/expressivity are not quantifiable from the retrieved evidence.


10. Diagnostics

10.1 Clinical criteria and ECG criteria

Key diagnostic elements include: * Documented polymorphic VT/TdP or VF initiated by a short‑coupled PVC, typically <300 ms in classic descriptions (leenhardt1994shortcoupledvariantof pages 1-3, steinfurt2022catheterablationof pages 1-3) and <350 ms in the contemporary QUEEN‑IVF trial diagnostic criterion. (NCT05593757 chunk 1) * No baseline QT prolongation / normal QTc, distinguishing from classic pause‑dependent long‑QT TdP. (leenhardt1994shortcoupledvariantof pages 1-3, wang2022shortcoupledvariantof pages 1-2) * Exclusion of significant structural heart disease via echo/CMR/coronary assessment. (steinfurt2022catheterablationof pages 1-3, ham2024anhipsccmapproach pages 1-2)

Source / cohort Disease label / definition Coupling interval (PVC → TdP/VF) QT / QTc Typical PVC morphology / origin Key outcome statistics Citations
Leenhardt 1994 original series (n=14) New electrocardiographic entity: TdP in patients without structural heart disease or long-QT syndrome, triggered by an extremely short-coupled premature beat Mean 245 ± 28 ms; isolated VPBs also consistently <300 ms Normal QT interval; no evidence of long-QT syndrome Homogeneous initiating VPB morphology in 9/14; not yet anatomically mapped in this era 10/14 degenerated to VF; mean follow-up 7 years; 5 deaths total, 4 sudden; only 2/14 inducible on programmed stimulation; 9 alive at follow-up (3 ICD, 6 verapamil) (leenhardt1994shortcoupledvariantof pages 1-3, leenhardt1994shortcoupledvariantof pages 9-10)
Wang 2022 systematic review (22 case reports + 103 case-series patients) scTdP/scVF = TdP/VF triggered by short-coupled PVCs despite otherwise normal baseline ECG and no structural heart disease Mean first coupling interval 302 ± 62 ms overall; historical syndrome range 200–300 ms; Purkinje origin 274 ± 28 ms vs RVOT 380 ± 70 ms; cutoff >319 ms predicts RVOT origin Baseline QT normal; short QT syndrome marker discussed separately as QT ≤320 ms Trigger PVC QRS 135 ± 17 ms overall; Purkinje origin narrower than RVOT (131 ± 17 vs 147 ± 8 ms); common origins are Purkinje system and RVOT 58% received ICD; 22% arrhythmia recurrence; 92% alive during follow-up; ICD associated with better survival than no ICD (log-rank P=0.001) (wang2022shortcoupledvariantof pages 8-11, wang2022shortcoupledvariantof pages 1-2, wang2022shortcoupledvariantof pages 2-4, wang2022shortcoupledvariantof pages 12-14)
Fujii 2017 scTdP subset within IVF cohort (n=7) scTdP phenotype within idiopathic VF cohort Inclusion threshold ≤300 ms; mean 282 ± 13 ms Mean QTc 422 ± 21 ms (normal range overall) Triggering PVC QRS width 138 ± 16 ms; mechanistic focus on RyR2/Ca2+ handling rather than fixed site mapping All had arrhythmic syncope, documented VF, or TdP; mean EF 62%; no structural heart disease; no family history of sudden cardiac death in this cohort (fujii2017atype2 pages 2-3)
Kimura 2017 familial RYR2-associated case SCV-TdP described as rare syndrome in otherwise healthy young adults, often at rest and usually not inducible Usually <300 ms Distinct from long-QT, Brugada, and short-QT syndromes Not site-mapped here; literature discussion supports calcium-handling/Purkinje-related triggers Approx. 30% family history of sudden death in prior reports; typical onset 31–34 years; ICD recommended; RF ablation plus ICD/drugs useful (kimura2017anryr2mutation pages 2-3)
Steinfurt 2022 ablation cohort (n=5) Recurrent sc-TdP/VF with monomorphic short-coupled PVC trigger; authors argue this phenotype predominantly arises from moderator band free-wall insertion/Purkinje network All <300 ms; individual cases 240–280 ms Structural/ischemic heart disease excluded; syndrome defined by absence of QT prolongation in background literature Monomorphic PVC with late-transition LBBB pattern, superior axis; 4/5 mapped to moderator band free-wall insertion, 1 to inferoseptal RV/papillary muscle region; Purkinje potential preceded PVC in 2/5 4/5 presented with sudden cardiac arrest, 1/5 with recurrent syncope; ablation eliminated sc-TdP in all; no recurrence at mean 2.7 years (range 6 months–8 years); all received ICD (steinfurt2022catheterablationof pages 1-3, steinfurt2022catheterablationof pages 3-7)
Infant case 2018 First reported infant with ScTdP/electrical storm Extremely short 200–240 ms QTc 380 ms; resting 12-lead ECG otherwise normal PVC-triggered VF/VT; no structural heart disease on echo Out-of-hospital cardiac arrest with VF; ICD implanted; sustained VT/VF controlled with verapamil plus amiodarone, though nonsustained VT persisted (kise2018electricalstormin pages 1-3)
QUEEN-IVF trial (NCT05593757) diagnostic framework Short-coupled idiopathic VF/PVT defined for trial enrollment after exclusion of competing syndromes/structural disease Principal diagnostic criterion: documented PVT (≥3 beats) or VF initiated by PVC with coupling interval <350 ms; isolated PVC <350 ms after index arrest/syncope also eligible Excludes resting HR-corrected QT <350 ms or >480 ms Designed for short-coupled IVF phenotype; includes DPP6 haplotype carriers; excludes pathogenic/likely pathogenic RYR2 carriers and successful ablation without recurrence Phase 2 open-label randomized crossover pilot; estimated n=24; primary endpoint = sustained ventricular arrhythmia severity score over 3 years; compares oral quinidine 200 mg TID vs verapamil 320–480 mg/day (NCT05593757 chunk 1, NCT05593757 chunk 2)

Table: This table compiles the main diagnostic ECG features, coupling interval thresholds, QT/QTc characteristics, likely PVC origins, and outcome data for short-coupled torsades de pointes/short-coupled ventricular fibrillation. It is useful for comparing the original syndrome description, later systematic review data, mapping/ablation cohorts, and the current interventional trial framework.

10.2 Electrophysiology study

Inducibility is often low: in the original series, “Only 2 patients had a tachyarrhythmia inducible by programmed stimulation.” (leenhardt1994shortcoupledvariantof pages 1-3)

10.3 Differential diagnosis

Differential considerations include: * Classic torsades de pointes due to congenital/acquired long‑QT syndrome (long coupling interval trigger beat) (leenhardt1994shortcoupledvariantof pages 1-3) * Pause‑dependent TdP versus short‑coupled PVC‑initiated polymorphic VT (QUEEN‑IVF excludes pause‑dependent TdP by R‑R criteria). (NCT05593757 chunk 1) * Other heritable syndromes excluded in QUEEN‑IVF: Brugada syndrome, early repolarization syndrome, CPVT; also excludes baseline QTc <350 ms or >480 ms. (NCT05593757 chunk 1)

10.4 Genetic testing strategy

Evidence supports targeted inherited arrhythmia gene testing: * A 45‑gene inherited‑arrhythmia panel in scTdP identified SCN5A p.R800H in 1/7 patients, illustrating panel utility in selected cases. (sonoda2020scn5amutationidentified pages 1-2) * QUEEN‑IVF requires that “Genetic testing has been initiated” (results not required at inclusion), reflecting modern practice. (NCT05593757 chunk 1)


11. Outcome / prognosis

11.1 Mortality and sudden death

High risk is evident in early series: * In the original 1994 cohort: “During a mean follow-up of 7 years there were 5 deaths (4 sudden).” (leenhardt1994shortcoupledvariantof pages 1-3)

11.2 Prognostic effect of ICD

Systematic review data support ICD survival benefit: Kaplan–Meier analysis showed increased survival with ICD versus no ICD (log‑rank P=0.001). (wang2022shortcoupledvariantof pages 1-2)

11.3 Post‑ablation outcomes

In a 5‑patient multicenter ablation cohort, ablation eliminated sc‑TdP in all patients “with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up.” (steinfurt2022catheterablationof pages 1-3)


12. Treatment

12.1 Core management principles

  1. Prevent sudden death: ICD for secondary prevention is strongly supported, given residual sudden death risk despite drug suppression. (leenhardt1994shortcoupledvariantof pages 1-3, wang2022shortcoupledvariantof pages 1-2)
  2. Suppress short‑coupled triggers and reduce shocks: verapamil, and in selected cases other antiarrhythmics, plus ablation when a culprit PVC is identifiable. (steinfurt2022catheterablationof pages 1-3, NCT05593757 chunk 1)
Management domain Intervention / strategy Evidence / role in short-coupled TdP / short-coupled VF Reported outcomes / recurrence Suggested MAXO term(s) Citations
Acute resuscitation External defibrillation / cardioversion Used for VF, polymorphic VT, electrical storm, and sudden cardiac arrest presentations; original and later case series describe frequent degeneration to VF requiring emergency shock therapy In the original 14-patient series, 10/14 episodes deteriorated into VF; infant and adult case reports survived arrest with acute resuscitation MAXO: defibrillation; MAXO: cardioversion (kise2018electricalstormin pages 1-3, steinfurt2022catheterablationof pages 1-3, leenhardt1994shortcoupledvariantof pages 1-3)
Acute antiarrhythmic stabilization Verapamil (IV/oral transition) Most consistently reported drug for suppressing short-coupled PVC-triggered TdP/VF; considered first-line pharmacotherapy in many reports/reviews, though protection from sudden death is incomplete Leenhardt: arrhythmias appeared responsive but sudden death still occurred; infant case: sustained VT/VF controlled after verapamil addition; Steinfurt cohort: effective in 1 patient; current QUEEN-IVF trial formally compares verapamil vs quinidine MAXO: calcium channel blocker therapy; MAXO: antiarrhythmic agent therapy (wang2022shortcoupledvariantof pages 1-2, kise2018electricalstormin pages 1-3, kimura2017anryr2mutation pages 2-3, touathamici2021aspry1domain pages 1-2, steinfurt2022catheterablationof pages 1-3, NCT05593757 chunk 1)
Acute antiarrhythmic stabilization Ajmaline Not standard first-line therapy, but in one mapped ablation cohort patient, ajmaline suppressed short-coupled PVCs and terminated VF, supporting sodium-channel–sensitive trigger mechanisms in select cases In Steinfurt cohort patient #2, ajmaline suppressed PVCs and terminated VF before EP study MAXO: sodium channel blocker therapy; MAXO: antiarrhythmic agent therapy (steinfurt2022catheterablationof pages 3-7)
Acute adjunctive therapy Amiodarone Often ineffective or insufficient in scTdP/scVF, though sometimes required transiently in refractory electrical storm; not considered reliably protective Leenhardt: unlike verapamil, amiodarone not apparently active; infant case required amiodarone initially because VF/VT was refractory to defibrillation, but longer-term control improved only after verapamil MAXO: amiodarone therapy; MAXO: antiarrhythmic agent therapy (kise2018electricalstormin pages 1-3, leenhardt1994shortcoupledvariantof pages 1-3)
Acute adjunctive therapy Beta-blockers Frequently ineffective in this phenotype compared with long-QT or catecholaminergic syndromes; often reported as failed prior therapy Ineffective in original series and later case-based literature; specifically ineffective in patients from the ablation cohort MAXO: beta-adrenergic receptor antagonist therapy (kimura2017anryr2mutation pages 2-3, steinfurt2022catheterablationof pages 1-3, leenhardt1994shortcoupledvariantof pages 1-3)
Acute adjunctive therapy Magnesium, lidocaine, procainamide, cilostazol Mentioned in later cohort review as therapies that may fail; evidence for benefit in short-coupled TdP specifically is weak and inconsistent Steinfurt introduction notes pharmacologic treatment failure with Mg2+, lidocaine, procainamide, quinidine, cilostazol in prior experience/literature; one cohort patient had lidocaine ineffective MAXO: magnesium supplementation; MAXO: lidocaine therapy; MAXO: procainamide therapy (steinfurt2022catheterablationof pages 1-3, steinfurt2022catheterablationof pages 3-7)
Acute electrical storm care Isoproterenol / sympathetic modulation / deep sedation No direct disease-specific efficacy data were retrieved for scTdP itself; broader electrical storm reviews discuss these approaches, but available short-coupled-specific sources emphasize culprit-PVC suppression, ICD, and ablation instead Not established from disease-specific primary evidence retrieved here MAXO: adrenergic agonist therapy; MAXO: sedation (wang2022shortcoupledvariantof pages 1-2)
Chronic pharmacotherapy Verapamil Most consistently supported chronic suppressive drug; reduces ectopy/arrhythmia burden but does not reliably prevent sudden death, so should not replace definitive protection in high-risk patients Original series: 6 survivors on verapamil alone, but overall 5 deaths (4 sudden) across 7-year follow-up; systematic review states verapamil partially suppresses arrhythmias but does not prevent SCD MAXO: calcium channel blocker therapy; MAXO: sudden cardiac death prevention (wang2022shortcoupledvariantof pages 1-2, leenhardt1994shortcoupledvariantof pages 1-3, leenhardt1994shortcoupledvariantof pages 9-10)
Chronic pharmacotherapy Quinidine Evidence is mixed and evolving; some contemporary reviews and the ongoing QUEEN-IVF trial support active evaluation, but older scTdP reports often found it ineffective Included as comparator in randomized crossover pilot trial (quinidine 200 mg TID vs verapamil 320–480 mg/day); older familial review described quinidine as ineffective in SCV-TdP MAXO: quinidine therapy; MAXO: antiarrhythmic agent therapy (kimura2017anryr2mutation pages 2-3, NCT05593757 chunk 1, NCT05593757 chunk 2)
Chronic pharmacotherapy Flecainide Limited disease-specific evidence; used adjunctively in at least one ablated patient after procedure In Steinfurt cohort, 1 patient remained free from VF for 2.5 years on flecainide after ablation MAXO: flecainide therapy; MAXO: antiarrhythmic agent therapy (steinfurt2022catheterablationof pages 3-7)
Chronic pharmacotherapy Dantrolene / flecainide / verapamil screening in patient-specific hiPSC model 2024 disease-modeling work suggested these agents altered calcium-handling parameters but did not reduce early after-transient incidence in that patient-derived cellular model Supports mechanistic heterogeneity and need for individualized treatment; not yet clinical efficacy evidence MAXO: calcium release modulator therapy; MAXO: experimental therapy (ham2024anhipsccmapproach pages 1-2)
Device therapy Implantable cardioverter-defibrillator (ICD) Most important proven protection against sudden cardiac death; emphasized across original series, systematic review, and modern case series Wang review: ICD associated with increased survival vs no ICD; original series suggested ICD because verapamil did not prevent sudden death; ablation cohort implanted ICD in all 5 patients for secondary prevention MAXO: implantable cardioverter-defibrillator implantation; MAXO: sudden cardiac death prevention (wang2022shortcoupledvariantof pages 8-11, wang2022shortcoupledvariantof pages 1-2, steinfurt2022catheterablationof pages 1-3, leenhardt1994shortcoupledvariantof pages 1-3, leenhardt1994shortcoupledvariantof pages 9-10)
Device therapy Transvenous vs subcutaneous ICD Both have been used for secondary prevention; some reviews caution about subcutaneous ICD limitations such as T-wave oversensing in this phenotype Steinfurt cohort: 2 transvenous and 3 subcutaneous ICDs; systematic review notes subcutaneous ICDs may be problematic because of T-wave oversensing MAXO: transvenous ICD implantation; MAXO: subcutaneous ICD implantation (wang2022shortcoupledvariantof pages 12-14, steinfurt2022catheterablationof pages 3-7)
Catheter ablation Purkinje potential-guided ablation Key interventional strategy when a culprit short-coupled PVC is identifiable; especially relevant for Purkinje-origin triggers with preceding Purkinje potentials Systematic review and ablation series support high success in suppressing recurrent TdP/VF; ICD backup remains prudent because late recurrences and occult substrate may persist MAXO: catheter ablation; MAXO: electrophysiology study (wang2022shortcoupledvariantof pages 12-14, tsuji2024mechanismsoftorsades pages 1-2, steinfurt2022catheterablationof pages 3-7, arnaud2025idiopathicventricularfibrillation pages 5-6)
Catheter ablation target Moderator band free-wall insertion / moderator band complex Best-defined contemporary target in recurrent scTdP/scVF with characteristic late-transition LBBB, superior-axis PVC morphology and coupling interval <300 ms Steinfurt cohort: 4/5 culprit PVCs mapped to moderator band free-wall insertion; ablation eliminated sc-TdP in all 5 with no recurrence at mean 2.7 years (range 6 months to 8 years) MAXO: catheter ablation; MAXO: intracardiac echocardiography-guided procedure (steinfurt2022catheterablationof pages 1-3, steinfurt2022catheterablationof pages 3-7)
Catheter ablation target RVOT origin Less common but recognized malignant trigger source; longer coupling interval and wider PVC QRS than Purkinje-origin events Wang review: RVOT-origin scTdP had coupling interval 380 ± 70 ms vs 274 ± 28 ms for Purkinje; cutoff >319 ms predicted RVOT origin MAXO: catheter ablation; MAXO: right ventricular outflow tract ablation (wang2022shortcoupledvariantof pages 8-11, wang2022shortcoupledvariantof pages 1-2)
Catheter ablation target Papillary muscle / inferoseptal right ventricle Alternative right ventricular endocavitary trigger locations when moderator band anatomy is not dominant In Steinfurt cohort, 1/5 culprit PVCs arose from inferoseptal RV/papillary muscle region; all ablation procedures were acutely successful MAXO: catheter ablation (steinfurt2022catheterablationof pages 3-7)
Long-term strategy Combined therapy: ICD + antiarrhythmic drug +/− ablation Common real-world approach because drugs alone incompletely protect from SCD and ablation may eliminate the trigger but not all substrate Familial/case literature recommends ICD, with RF ablation and drugs used to suppress recurrent fatal arrhythmias; modern sources propose ablation in recurrent VF/electrical storm and sometimes first-line when trigger is clear MAXO: combination therapy; MAXO: implantable cardioverter-defibrillator implantation; MAXO: catheter ablation (kimura2017anryr2mutation pages 2-3, steinfurt2022catheterablationof pages 1-3, wang2022shortcoupledvariantof pages 1-2, arnaud2025idiopathicventricularfibrillation pages 5-6)

Table: This table summarizes acute and chronic management approaches reported for short-coupled torsades de pointes and short-coupled ventricular fibrillation, including drugs, ICD therapy, and catheter ablation targets. It highlights where evidence is strongest, especially for ICD implantation and moderator-band/Purkinje-trigger ablation.

12.2 Pharmacotherapy

Verapamil * The original series concluded: “verapamil is in our experience the only drug apparently active on the arrhythmias; however, it does not prevent sudden death.” (leenhardt1994shortcoupledvariantof pages 1-3) * Later synthesis similarly notes partial suppression without definitive sudden‑death protection. (wang2022shortcoupledvariantof pages 1-2)

Quinidine * Evidence is mixed across historical reports; it is being actively tested prospectively in the QUEEN‑IVF crossover trial against verapamil. (NCT05593757 chunk 1)

12.3 Catheter ablation

High‑resolution mapping identifies frequent moderator band/Purkinje targets: * The 2022 series concluded sc‑TdP “predominantly originates from the MB free wall insertion and its Purkinje network,” with excellent mid‑term outcomes. (steinfurt2022catheterablationof pages 1-3)

12.4 Device therapy

ICD is repeatedly emphasized: * “Therefore, we strongly suggest the use of ICD therapy” in the original series’ long‑term discussion. (leenhardt1994shortcoupledvariantof pages 9-10)

12.5 Experimental / clinical trials

QUEEN‑IVF (NCT05593757) * Title: Quinidine Versus Verapamil in Short-coupled Idiopathic Ventricular Fibrillation (QUEEN‑IVF), open‑label randomized crossover pilot (Phase 2), estimated n=24, start 2022-10-01, last update posted 2023-09-13. * Interventions: quinidine 200 mg TID vs verapamil 320–480 mg/day. * Primary endpoint: sustained ventricular arrhythmia severity score over 3 years. (NCT05593757 chunk 1)

ClinicalTrials.gov URL (registry): https://clinicaltrials.gov/study/NCT05593757 (NCT05593757 chunk 1)


13. Prevention

13.1 Primary prevention

No established population screening or primary prevention strategy exists due to rarity and uncertain penetrance.

13.2 Secondary/tertiary prevention

  • ICD implantation is the principal sudden‑death preventive measure after presentation. (leenhardt1994shortcoupledvariantof pages 1-3, wang2022shortcoupledvariantof pages 1-2)
  • Ablation can be considered to prevent recurrent VF/electrical storm and reduce ICD shocks when a culprit trigger PVC is mapped. (steinfurt2022catheterablationof pages 1-3)

14. Other species / natural disease

No naturally occurring non‑human disease analogs were identified in the retrieved corpus.


15. Model organisms / experimental models

15.1 Human cellular model (2024)

A notable recent development is patient‑specific hiPSC‑CM modeling of scTdP/idiopathic VF with fever‑associated recurrences, demonstrating early after‑calcium transients and shorter action potentials and enabling pharmacologic screening in vitro. (ham2024anhipsccmapproach pages 1-2, ham2024anhipsccmapproach pages 2-4)

15.2 Suggested model systems (based on mechanism)

  • hiPSC‑CMs with engineered RYR2 variants to study SOICR/DAD mechanisms.
  • Purkinje‑enriched in vitro preparations (where feasible) given Purkinje‑centric trigger hypotheses.

Notable statistics (recent and foundational)

  • Original series: 245±28 ms coupling interval; 10/14 degenerated to VF; 5 deaths (4 sudden) over mean 7 years. (leenhardt1994shortcoupledvariantof pages 1-3)
  • Systematic review (2022): pooled first coupling interval 302±62 ms; Purkinje vs RVOT coupling intervals 274±28 vs 380±70 ms; ICD associated with improved survival; 58% ICD implantation; 92% alive during follow‑up in aggregated cases. (wang2022shortcoupledvariantof pages 1-2, wang2022shortcoupledvariantof pages 8-11)
  • Ablation cohort (2022): 4/5 mapped to moderator band free‑wall insertion; no recurrence at mean 2.7 years follow‑up. (steinfurt2022catheterablationof pages 1-3)
  • hiPSC‑CM phenotyping (2024): early after‑transients in 8.14% of patient measurements vs 0% in controls under normothermia, increasing at 39°C. (ham2024anhipsccmapproach pages 2-4)

Key evidence excerpts (direct quotes from abstracts)

  • Leenhardt 1994 (Circulation; 1994-01): “there was no evidence of long QT syndrome, and the torsade had the unusual particularity of an extremely short coupling interval… (245±28 milliseconds).” (leenhardt1994shortcoupledvariantof pages 1-3)
  • Leenhardt 1994 (Circulation; 1994-01): “During a mean follow-up of 7 years there were 5 deaths (4 sudden).” (leenhardt1994shortcoupledvariantof pages 1-3)
  • van Ham 2024 (Stem Cell Research & Therapy; 2024-12): “Membrane potential data from the patient also revealed shorter action potentials that, combined with the EATs, indicate the premature release of calcium during diastole…” (ham2024anhipsccmapproach pages 1-2)
  • Steinfurt 2022 (Clinical Research in Cardiology; online 2021-03-26; print 2022): “Catheter ablation… eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years… of follow-up.” (steinfurt2022catheterablationof pages 1-3)

Evidence gaps / limitations in current report

  • Ontology identifiers (MONDO/OMIM/Orphanet/MeSH/ICD) were not available in the retrieved texts and thus are not asserted here.
  • Large-scale incidence/prevalence data remain limited in the retrieved corpus; most data are case series.
  • Some 2023–2024 guideline‑level statements and a 2023 pharmacology review were not obtainable through the current retrieval, so therapy recommendations are based on available primary series, systematic review, and trial registry evidence.

Appendix: URLs and publication dates for key sources (from retrieved metadata)

  • Leenhardt et al. Circulation1994-01 — https://doi.org/10.1161/01.cir.89.1.206 (leenhardt1994shortcoupledvariantof pages 1-3)
  • Wang et al. Frontiers in Cardiovascular Medicine2022-08 — https://doi.org/10.3389/fcvm.2022.922525 (wang2022shortcoupledvariantof pages 1-2)
  • Steinfurt et al. Clinical Research in Cardiology — online 2021-03-26, journal issue 2022 — https://doi.org/10.1007/s00392-021-01840-z (steinfurt2022catheterablationof pages 1-3)
  • Sonoda et al. Pacing and Clinical Electrophysiology2020-05 — https://doi.org/10.1111/pace.13924 (sonoda2020scn5amutationidentified pages 1-2)
  • Fujii et al. Heart Rhythm2017-01 — https://doi.org/10.1016/j.hrthm.2016.10.015 (fujii2017atype2 pages 2-3)
  • Touat‑Hamici et al. Scientific Reports2021-03 — https://doi.org/10.1038/s41598-021-84373-9 (touathamici2021aspry1domain pages 1-2)
  • Tsuji et al. Frontiers in Cardiovascular Medicine2024-03 — https://doi.org/10.3389/fcvm.2024.1363848 (tsuji2024mechanismsoftorsades pages 1-2)
  • QUEEN‑IVF trial (ClinicalTrials.gov NCT05593757) — first posted 2022-10-25, last update posted 2023-09-13 — https://clinicaltrials.gov/study/NCT05593757 (NCT05593757 chunk 1)

References

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