Cardiac Ion-Channel Repolarization and Arrhythmogenesis Module

Module cardiac_ion_channel_repolarization 17 disorders Pathograph 6

A conserved cardiac electrophysiology mechanism module for inherited arrhythmia syndromes (channelopathies) in structurally normal hearts. Pathogenic variants in cardiac ion channels or calcium-handling proteins shift the balance of depolarizing and repolarizing currents and disturb sarcoplasmic-reticulum calcium handling. This alters cardiomyocyte action potential duration (APD) and/or diastolic calcium, generating afterdepolarization-driven triggered activity (early afterdepolarizations from prolonged APD; delayed afterdepolarizations from calcium leak). Regional heterogeneity of repolarization and conduction creates an arrhythmogenic substrate that supports reentrant and triggered ventricular tachyarrhythmia (torsade de pointes, polymorphic ventricular tachycardia, ventricular fibrillation), clinically manifesting as syncope and sudden cardiac death. A parallel branch captures the same ion-channel and pacemaker machinery acting in the sinoatrial node, where loss of function produces bradyarrhythmia and sinus arrest rather than tachyarrhythmia.

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Pathophysiology Nodes

6 shared nodes are defined in this module.

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Cell Types

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Biological Processes

membrane repolarization during cardiac muscle cell action potential GO:0086013 DYSREGULATED calcium ion transport GO:0006816 DYSREGULATED cardiac muscle cell action potential GO:0086001 ABNORMAL cardiac conduction GO:0061337 DYSREGULATED cardiac conduction GO:0061337 ABNORMAL cardiac conduction GO:0061337 DECREASED

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (for example, "cardiac_ion_channel_repolarization#Altered Action Potential and Calcium Handling"). The module is intended for inherited cardiac channelopathies and calcium-handling arrhythmia syndromes including Long QT syndrome, Short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (RYR2-CPVT), Timothy syndrome, torsade de pointes / short-coupled ventricular fibrillation, and familial sick sinus syndrome. Conforming nodes substitute the specific variant gene and current (e.g. KCNQ1/IKs or KCNH2/IKr loss of function in LQT1/LQT2, SCN5A late sodium current in LQT3, CACNA1C gain of function in Timothy syndrome, RYR2 calcium leak in CPVT, HCN4/SCN5A loss of function in sinus node dysfunction) while preserving the shared causal architecture. Key conformance target: "cardiac_ion_channel_repolarization#Arrhythmogenic Substrate and Triggered Activity".

Mechanistic Hypotheses

Repolarization-Reserve and Triggered-Activity Arrhythmia Model

repolarization_reserve_arrhythmia_model CANONICAL Evidence: 1

Evidence balance 1 support

Loss or gain of repolarizing/depolarizing current, or pathological sarcoplasmic-reticulum calcium leak, alters cardiomyocyte action potential duration and diastolic calcium. The resulting early or delayed afterdepolarizations, amplified by regional dispersion of repolarization, produce triggered and reentrant ventricular tachyarrhythmia and sudden cardiac death.

Sinoatrial Pacemaker Automaticity Failure Model

sinoatrial_automaticity_failure_model CANONICAL Evidence: 1

Evidence balance 1 support

The same ion-channel and pacemaker-current machinery governs sinoatrial node automaticity. Loss-of-function variants (for example in HCN4 or SCN5A) depress the pacemaker/funny current or sinoatrial conduction, producing bradyarrhythmia, sinus arrest, and chronotropic incompetence rather than ventricular tachyarrhythmia, with syncope and sudden death from hypoperfusion or asystole.

Discussions and Knowledge Gaps

For phenotypes such as Brugada syndrome, is the arrhythmogenic substrate driven primarily by abnormal repolarization (transmural dispersion from heterogeneous transient-outward current) or by depolarization/conduction slowing in the right ventricular outflow tract, and how do these models apply across the channelopathy spectrum?

KNOWLEDGE GAP OPEN gap_repolarization_vs_depolarization_substrate

Attached to: Arrhythmogenic Substrate and Triggered Activity

The module compresses several biophysical routes (afterdepolarization-driven triggered activity, repolarization dispersion, and depolarization/conduction slowing) into a single arrhythmogenic-substrate node. Disorder entries will need phenotype-specific evidence to decide which biophysical mechanism dominates, since the competing repolarization and depolarization hypotheses have different implications for risk stratification and therapy.

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Used By Disorder Entries

Andersen-Tawil Syndrome via KCNJ2 Loss-of-Function Variant → Cardiac Ion-Channel or Calcium-Handling Variant , Reduced Cardiac Inward Rectifier Current → Altered Action Potential and Calcium Handling , Delayed Terminal Repolarization and Triggered Activity → Arrhythmogenic Substrate and Triggered Activity , Bidirectional and Polymorphic Ventricular Tachycardia → Ventricular Tachyarrhythmia , Arrhythmic Loss of Cardiac Output → Syncope and Sudden Cardiac Death

Brugada syndrome via Reduced Depolarization Reserve → Cardiac Ion-Channel or Calcium-Handling Variant , RVOT Conduction Slowing → Arrhythmogenic Substrate and Triggered Activity , Current-Load Mismatch at RVOT Substrate → Arrhythmogenic Substrate and Triggered Activity , Malignant Ventricular Tachyarrhythmia → Ventricular Tachyarrhythmia , Syncope and Sudden Cardiac Death

CASQ2 CPVT via CASQ2 Loss of Function → Cardiac Ion-Channel or Calcium-Handling Variant , Diastolic Sarcoplasmic Reticulum Calcium Leak → Altered Action Potential and Calcium Handling , Delayed Afterdepolarizations and Triggered Activity → Arrhythmogenic Substrate and Triggered Activity , Bidirectional and Polymorphic Ventricular Tachycardia → Ventricular Tachyarrhythmia , Syncope and Sudden Cardiac Death

Familial Atrial Fibrillation via Atrial Ion-Channel or Coupling Variant → Cardiac Ion-Channel or Calcium-Handling Variant , Shortened Atrial Action Potential and Refractoriness → Altered Action Potential and Calcium Handling , Atrial Arrhythmogenic Substrate → Arrhythmogenic Substrate and Triggered Activity

Familial Long QT Syndrome via Reduced Repolarizing Potassium Current → Cardiac Ion-Channel or Calcium-Handling Variant , Persistent Late Sodium Current in LQT3 → Cardiac Ion-Channel or Calcium-Handling Variant , Prolonged Ventricular Action Potential Duration → Altered Action Potential and Calcium Handling , Early Afterdepolarizations → Arrhythmogenic Substrate and Triggered Activity , Torsades de Pointes → Ventricular Tachyarrhythmia , Syncope and Sudden Cardiac Death

Familial Sick Sinus Syndrome via Heritable Sinoatrial Node Pacemaker Dysfunction → Sinoatrial Node Pacemaker Dysfunction , HCN4 Pacemaker Current Loss of Function → Cardiac Ion-Channel or Calcium-Handling Variant , SCN5A Sodium Current Loss of Function → Cardiac Ion-Channel or Calcium-Handling Variant , Syncope and Sudden Cardiac Death

Jervell and Lange-Nielsen Syndrome 1 via Biallelic KCNQ1 Loss-of-Function Variants → Cardiac Ion-Channel or Calcium-Handling Variant , Near-Complete Loss of Cardiac I_Ks Repolarizing Current → Altered Action Potential and Calcium Handling , Markedly Prolonged QTc and Arrhythmogenic Substrate → Arrhythmogenic Substrate and Triggered Activity , Torsades de Pointes and Ventricular Fibrillation → Ventricular Tachyarrhythmia , Syncope, Cardiac Arrest, and Sudden Cardiac Death → Syncope and Sudden Cardiac Death

Jervell and Lange-Nielsen Syndrome 2 via Biallelic KCNE1 Loss of Function → Cardiac Ion-Channel or Calcium-Handling Variant , Loss of IKs Current in Cardiac Myocytes → Altered Action Potential and Calcium Handling , Arrhythmogenic Substrate and Ventricular Tachyarrhythmia → Ventricular Tachyarrhythmia , Syncope and Sudden Cardiac Death

Paroxysmal Familial Ventricular Fibrillation via Cardiac Ion-Channel Variant → Cardiac Ion-Channel or Calcium-Handling Variant , Accelerated Purkinje Repolarization and Altered Excitability → Altered Action Potential and Calcium Handling , Arrhythmogenic Substrate and Triggered Activity , Ventricular Fibrillation → Ventricular Tachyarrhythmia , Syncope and Sudden Cardiac Death

Progressive Cardiac Conduction Disease via SCN5A Loss-of-Function Variant in the Cardiac Sodium Channel → Cardiac Ion-Channel or Calcium-Handling Variant

RYR2 CPVT via RYR2 Gain-of-Function Variant → Cardiac Ion-Channel or Calcium-Handling Variant , CASQ2 Loss-of-Function → Cardiac Ion-Channel or Calcium-Handling Variant , Calmodulin Dysfunction → Cardiac Ion-Channel or Calcium-Handling Variant , Triadin Deficiency → Cardiac Ion-Channel or Calcium-Handling Variant , TECRL Deficiency → Cardiac Ion-Channel or Calcium-Handling Variant , Diastolic Sarcoplasmic Reticulum Calcium Leak → Altered Action Potential and Calcium Handling , Delayed After-Depolarizations → Arrhythmogenic Substrate and Triggered Activity , Triggered Ventricular Arrhythmia → Ventricular Tachyarrhythmia , Sinoatrial Node Dysfunction → Sinoatrial Node Pacemaker Dysfunction , Syncope and Sudden Cardiac Death

Short QT Syndrome via Ion-channel gain- and loss-of-function variants → Cardiac Ion-Channel or Calcium-Handling Variant , Accelerated myocardial repolarization → Altered Action Potential and Calcium Handling , Re-entry-prone arrhythmia substrate → Arrhythmogenic Substrate and Triggered Activity , Atrial and ventricular fibrillation susceptibility → Ventricular Tachyarrhythmia , Syncope and Sudden Cardiac Death

Sick Sinus Syndrome 2, Autosomal Dominant via HCN4 Loss-of-Function Variant → Cardiac Ion-Channel or Calcium-Handling Variant , Sinoatrial Node Automaticity Failure → Sinoatrial Node Pacemaker Dysfunction , Syncope and Sudden Cardiac Death

Sinoatrial Node Dysfunction and Deafness via Biallelic CACNA1D Loss of Function → Cardiac Ion-Channel or Calcium-Handling Variant , Sinoatrial Node Pacemaker Dysfunction , Exertion- and Stress-Triggered Syncope → Syncope and Sudden Cardiac Death

TANGO2 Deficiency Disorder via Cardiomyocyte ATP Depletion and Repolarization Instability → Altered Action Potential and Calcium Handling , Arrhythmogenic Substrate and Triggered Activity , Ventricular Tachyarrhythmia and Cardiac Arrest → Ventricular Tachyarrhythmia

Timothy Syndrome via CACNA1C gain-of-function with impaired Cav1.2 inactivation → Cardiac Ion-Channel or Calcium-Handling Variant , Delayed cardiomyocyte repolarization and ventricular arrhythmia substrate → Altered Action Potential and Calcium Handling , Early afterdepolarizations and arrhythmogenic substrate → Arrhythmogenic Substrate and Triggered Activity , Ventricular tachyarrhythmia (torsade de pointes) → Ventricular Tachyarrhythmia , Long QT interval and sudden cardiac death susceptibility → Syncope and Sudden Cardiac Death

Torsade de Pointes Syndrome With Short Coupling Interval via RYR2-mediated calcium release susceptibility → Altered Action Potential and Calcium Handling , SCN5A sodium-channel susceptibility → Cardiac Ion-Channel or Calcium-Handling Variant , Short-coupled premature ventricular trigger → Arrhythmogenic Substrate and Triggered Activity , Polymorphic ventricular tachyarrhythmia → Ventricular Tachyarrhythmia , Ventricular fibrillation and cardiac arrest → Syncope and Sudden Cardiac Death

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Pathograph

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Pathophysiology

Cardiac Ion-Channel or Calcium-Handling Variant

trigger

A pathogenic germline variant alters a cardiac ion channel or calcium-handling protein, changing the magnitude, kinetics, or gating of a depolarizing or repolarizing current, or destabilizing sarcoplasmic-reticulum calcium release. Representative genes include the potassium channels KCNQ1 (IKs) and KCNH2 (IKr), the cardiac sodium channel SCN5A, the L-type calcium channel CACNA1C, the ryanodine receptor RYR2, and the pacemaker channel HCN4. The variant is the upstream trigger common to inherited arrhythmia syndromes in structurally normal hearts.

cardiomyocyte CL:0000746

Used by disorders

Andersen-Tawil Syndrome as KCNJ2 Loss-of-Function Variant

Brugada syndrome as Reduced Depolarization Reserve

CASQ2 CPVT as CASQ2 Loss of Function

Familial Atrial Fibrillation as Atrial Ion-Channel or Coupling Variant

Familial Long QT Syndrome as Persistent Late Sodium Current in LQT3

Familial Long QT Syndrome as Reduced Repolarizing Potassium Current

Familial Sick Sinus Syndrome as HCN4 Pacemaker Current Loss of Function

Familial Sick Sinus Syndrome as SCN5A Sodium Current Loss of Function

Jervell and Lange-Nielsen Syndrome 1 as Biallelic KCNQ1 Loss-of-Function Variants

Jervell and Lange-Nielsen Syndrome 2 as Biallelic KCNE1 Loss of Function

Paroxysmal Familial Ventricular Fibrillation as Cardiac Ion-Channel Variant

Progressive Cardiac Conduction Disease as SCN5A Loss-of-Function Variant in the Cardiac Sodium Channel

RYR2 CPVT as Calmodulin Dysfunction

RYR2 CPVT as CASQ2 Loss-of-Function

RYR2 CPVT as RYR2 Gain-of-Function Variant

RYR2 CPVT as TECRL Deficiency

RYR2 CPVT as Triadin Deficiency

Short QT Syndrome as Ion-channel gain- and loss-of-function variants

Sick Sinus Syndrome 2, Autosomal Dominant as HCN4 Loss-of-Function Variant

Sinoatrial Node Dysfunction and Deafness as Biallelic CACNA1D Loss of Function

Timothy Syndrome as CACNA1C gain-of-function with impaired Cav1.2 inactivation

Torsade de Pointes Syndrome With Short Coupling Interval as SCN5A sodium-channel susceptibility

Downstream

Altered Action Potential and Calcium Handling The variant shifts net depolarizing/repolarizing current or sarcoplasmic-reticulum calcium release, changing action potential duration and diastolic calcium in working myocardium.
Sinoatrial Node Pacemaker Dysfunction The same channel/pacemaker machinery, when loss-of-function, depresses sinoatrial automaticity and conduction.

Altered Action Potential and Calcium Handling

central effector

The variant shifts the balance of cardiomyocyte membrane currents and calcium handling. Reduced repolarizing potassium current or persistent late sodium current prolongs action potential duration (long QT physiology); enhanced repolarizing current or reduced inward calcium current shortens it (short QT physiology); ryanodine-receptor calcium leak raises diastolic cytosolic calcium. Each disturbs the action potential and intracellular calcium that couple excitation to contraction.

cardiomyocyte CL:0000746

membrane repolarization during cardiac muscle cell action potential GO:0086013 DYSREGULATED calcium ion transport GO:0006816 DYSREGULATED

Used by disorders

Andersen-Tawil Syndrome as Reduced Cardiac Inward Rectifier Current

CASQ2 CPVT as Diastolic Sarcoplasmic Reticulum Calcium Leak

Familial Atrial Fibrillation as Shortened Atrial Action Potential and Refractoriness

Familial Long QT Syndrome as Prolonged Ventricular Action Potential Duration

Jervell and Lange-Nielsen Syndrome 1 as Near-Complete Loss of Cardiac I_Ks Repolarizing Current

Jervell and Lange-Nielsen Syndrome 2 as Loss of IKs Current in Cardiac Myocytes

Paroxysmal Familial Ventricular Fibrillation as Accelerated Purkinje Repolarization and Altered Excitability

RYR2 CPVT as Diastolic Sarcoplasmic Reticulum Calcium Leak

Short QT Syndrome as Accelerated myocardial repolarization

TANGO2 Deficiency Disorder as Cardiomyocyte ATP Depletion and Repolarization Instability

Timothy Syndrome as Delayed cardiomyocyte repolarization and ventricular arrhythmia substrate

Torsade de Pointes Syndrome With Short Coupling Interval as RYR2-mediated calcium release susceptibility

Downstream

Arrhythmogenic Substrate and Triggered Activity Prolonged action potential favors early afterdepolarizations; diastolic calcium leak drives delayed afterdepolarizations via sodium-calcium exchange, both producing triggered beats.

Arrhythmogenic Substrate and Triggered Activity

amplifier

Disturbed repolarization and calcium handling generate afterdepolarizations: early afterdepolarizations (EADs) arise from oscillations during prolonged plateau, and delayed afterdepolarizations (DADs) arise when sodium-calcium-exchanger current responds to diastolic calcium release. Regional heterogeneity of action potential duration and conduction produces dispersion of repolarization, the tissue-level substrate that allows triggered beats to initiate and sustain reentrant ventricular arrhythmia.

cardiomyocyte CL:0000746

cardiac muscle cell action potential GO:0086001 ABNORMAL cardiac conduction GO:0061337 DYSREGULATED

Used by disorders

Andersen-Tawil Syndrome as Delayed Terminal Repolarization and Triggered Activity

Brugada syndrome as Current-Load Mismatch at RVOT Substrate

Brugada syndrome as RVOT Conduction Slowing

CASQ2 CPVT as Delayed Afterdepolarizations and Triggered Activity

Familial Atrial Fibrillation as Atrial Arrhythmogenic Substrate

Familial Long QT Syndrome as Early Afterdepolarizations

Jervell and Lange-Nielsen Syndrome 1 as Markedly Prolonged QTc and Arrhythmogenic Substrate

Paroxysmal Familial Ventricular Fibrillation

RYR2 CPVT as Delayed After-Depolarizations

Short QT Syndrome as Re-entry-prone arrhythmia substrate

TANGO2 Deficiency Disorder

Timothy Syndrome as Early afterdepolarizations and arrhythmogenic substrate

Torsade de Pointes Syndrome With Short Coupling Interval as Short-coupled premature ventricular trigger

Downstream

Ventricular Tachyarrhythmia Triggered beats arising on a dispersed-repolarization substrate initiate reentrant and polymorphic ventricular tachyarrhythmia.

Ventricular Tachyarrhythmia

effector

Triggered activity and reentry on the arrhythmogenic substrate produce malignant ventricular tachyarrhythmia: torsade de pointes in long QT physiology, polymorphic or bidirectional ventricular tachycardia in catecholaminergic calcium-leak disorders, and ventricular fibrillation in short QT and Brugada physiology. These rhythms abolish effective cardiac output.

cardiomyocyte CL:0000746

cardiac conduction GO:0061337 ABNORMAL

Used by disorders

Andersen-Tawil Syndrome as Bidirectional and Polymorphic Ventricular Tachycardia

Brugada syndrome as Malignant Ventricular Tachyarrhythmia

CASQ2 CPVT as Bidirectional and Polymorphic Ventricular Tachycardia

Familial Long QT Syndrome as Torsades de Pointes

Jervell and Lange-Nielsen Syndrome 1 as Torsades de Pointes and Ventricular Fibrillation

Jervell and Lange-Nielsen Syndrome 2 as Arrhythmogenic Substrate and Ventricular Tachyarrhythmia

Paroxysmal Familial Ventricular Fibrillation as Ventricular Fibrillation

RYR2 CPVT as Triggered Ventricular Arrhythmia

Short QT Syndrome as Atrial and ventricular fibrillation susceptibility

TANGO2 Deficiency Disorder as Ventricular Tachyarrhythmia and Cardiac Arrest

Timothy Syndrome as Ventricular tachyarrhythmia (torsade de pointes)

Torsade de Pointes Syndrome With Short Coupling Interval as Polymorphic ventricular tachyarrhythmia

Downstream

Syncope and Sudden Cardiac Death Sustained ventricular tachyarrhythmia compromises cardiac output, causing syncope and, if unresolved, sudden cardiac death.

Sinoatrial Node Pacemaker Dysfunction

effector

When the variant causes loss of function in pacemaker or conduction currents, the sinoatrial node fails to generate or propagate impulses normally. Reduced funny current (HCN4) or depressed sodium current (SCN5A) in pacemaker and conduction tissue produces sinus bradycardia, sinus pauses/arrest, sinoatrial exit block, and chronotropic incompetence — the bradyarrhythmic counterpart to the ventricular-tachyarrhythmia branch.

cardiac pacemaker cell of sinoatrial node CL:1000477

cardiac conduction GO:0061337 DECREASED

Used by disorders

Familial Sick Sinus Syndrome as Heritable Sinoatrial Node Pacemaker Dysfunction

RYR2 CPVT as Sinoatrial Node Dysfunction

Sick Sinus Syndrome 2, Autosomal Dominant as Sinoatrial Node Automaticity Failure

Sinoatrial Node Dysfunction and Deafness

Downstream

Syncope and Sudden Cardiac Death Severe bradyarrhythmia, sinus pauses, or asystole reduce cerebral perfusion, causing syncope and risk of sudden death.

Syncope and Sudden Cardiac Death

outcome

Loss of effective cardiac output — from ventricular tachyarrhythmia or from severe bradyarrhythmia/asystole — causes transient cerebral hypoperfusion (syncope) and, when the rhythm does not terminate, sudden cardiac death. These are the shared clinical endpoints of the inherited arrhythmia syndromes, often the presenting or sentinel event.

Used by disorders

Andersen-Tawil Syndrome as Arrhythmic Loss of Cardiac Output

Brugada syndrome

CASQ2 CPVT

Familial Long QT Syndrome

Familial Sick Sinus Syndrome

Jervell and Lange-Nielsen Syndrome 1 as Syncope, Cardiac Arrest, and Sudden Cardiac Death

Jervell and Lange-Nielsen Syndrome 2

Paroxysmal Familial Ventricular Fibrillation

RYR2 CPVT

Short QT Syndrome

Sick Sinus Syndrome 2, Autosomal Dominant

Sinoatrial Node Dysfunction and Deafness as Exertion- and Stress-Triggered Syncope

Timothy Syndrome as Long QT interval and sudden cardiac death susceptibility

Torsade de Pointes Syndrome With Short Coupling Interval as Ventricular fibrillation and cardiac arrest