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".
The `Adrenergic and cAMP-Dependent Triggering` node was added under issue #11949 and is the module's only node that conforms to another module. It exists because the variant alone does not produce the arrhythmia in several of these syndromes; the cAMP/PKA signalling that converts a primed channel into a beat is curated once in `cardiac_camp_pka_calcium_handling` and pointed at from here, because the same signalling arm can be entered pharmacologically by a phosphodiesterase inhibitor with no variant anywhere. Its adrenergic dependence is genotype-specific and the node carries the counter-evidence: in LQT2 and LQT3 most events occur at rest, so those subtypes should not conform to it on the strength of the LQT1 pattern.
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.
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.
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.
Downstream
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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.
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Sinoatrial Node Pacemaker Dysfunction
The same channel/pacemaker machinery, when loss-of-function, depresses sinoatrial automaticity and conduction.
Show evidence (2 references)
"Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval."
Supports the ion-channel-variant trigger that perturbs cardiac currents and action potential duration, generalized here beyond the long QT example.
"Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced cardiac channelopathy that has a high mortality in untreated patients."
Confirms the channelopathy framing for the calcium-handling arm (RYR2-CPVT) of the module, where the variant is in a calcium-release protein rather than a surface ion channel.
Adrenergic and cAMP-Dependent Triggering
trigger
A variant is not by itself an arrhythmia. In several of the syndromes this module covers, the events cluster around exertion or sudden emotion, and the resting heart is electrically unremarkable. The step that converts the latent defect into a beat is a catecholamine surge acting on beta-adrenergic receptors, raising cardiomyocyte cyclic AMP and activating protein kinase A, which phosphorylates the calcium-handling apparatus and loads the sarcoplasmic reticulum. That signalling arm is curated once, in `cardiac_camp_pka_calcium_handling`, and referenced from here rather than duplicated; the same arm can be entered pharmacologically by a phosphodiesterase inhibitor, which is why it is a module of its own. The dependence is genotype-specific, not universal: it is strongest in the calcium-handling syndromes (CPVT) and in LQT1, where most events occur on exertion, and weakest in LQT2 and LQT3, where most occur at rest. A conforming disorder entry should carry its own trigger evidence rather than inheriting this one.
Downstream
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Altered Action Potential and Calcium Handling
Protein kinase A loads the sarcoplasmic reticulum and phosphorylates the release machinery, so the variant-primed calcium handling departs from normal only once the adrenergic signal arrives.
Show evidence (3 references)
"the current understanding of cellular CPVT pathophysiology is that catecholamines released during stress or exercise activate β-adrenergic receptor signalling, leading to a cellular chain reaction that culminates in pathological calcium release during diastole and calcium-triggered action potentials"
States the whole arm this node stands for, from the catecholamine surge to the triggered beat, in a review that is explicit that the account rests mostly on mouse CPVT models.
"LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep."
670 genotyped long QT patients with symptoms, classified by the circumstances of the event. Indirect support for this node: exercise is a proxy for adrenergic drive rather than a measurement of it, but the clustering is what a required adrenergic trigger would produce.
"These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%)."
The same cohort, curated here as the limit of this node rather than as support for it: the adrenergic trigger is genotype-specific, and in LQT2 and LQT3 most events happen at rest. A conforming entry for those subtypes should not declare conformance on the strength of the LQT1 pattern.
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.
Used by disorders
CASQ2 CPVT
as Diastolic Sarcoplasmic Reticulum Calcium Leak
RYR2 CPVT
as Diastolic Sarcoplasmic Reticulum Calcium Leak
Timothy Syndrome
as Delayed cardiomyocyte repolarization and ventricular arrhythmia substrate
Downstream
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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.
Show evidence (2 references)
"A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD)."
Supports altered action potential duration as the central electrophysiologic consequence of the channel variant, with the QT interval as its surface surrogate.
"The most common cellular phenotype in CPVT is higher than normal cytoplasmic Ca2+ concentrations during diastole due to Ca2+ leak from the SR through mutant RyR2."
Supports the calcium-handling arm: pathological sarcoplasmic-reticulum calcium leak elevates diastolic cytosolic calcium.
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.
Downstream
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Ventricular Tachyarrhythmia
Triggered beats arising on a dispersed-repolarization substrate initiate reentrant and polymorphic ventricular tachyarrhythmia.
Show evidence (2 references)
"The Na+ influx leads to delayed after depolarizations (DADs) which trigger arrhythmia when reaching action potential threshold."
Supports delayed-afterdepolarization-driven triggered activity from the calcium-leak arm of the substrate node.
"The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD."
Supports dispersion of repolarization as the tissue-level arrhythmogenic substrate from the prolonged-APD arm.
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.
Used by disorders
CASQ2 CPVT
as Bidirectional and Polymorphic Ventricular Tachycardia
RYR2 CPVT
as Triggered Ventricular Arrhythmia
Downstream
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Syncope and Sudden Cardiac Death
Sustained ventricular tachyarrhythmia compromises cardiac output, causing syncope and, if unresolved, sudden cardiac death.
Show evidence (1 reference)
"It is now established that the deadly arrhythmias are caused by unregulated 'pathological' calcium release from the sarcoplasmic reticulum (SR), the major calcium storage organelle in striated muscle."
Supports the link from disordered calcium handling to the lethal ventricular arrhythmias of the calcium-handling arm.
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.
Downstream
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Syncope and Sudden Cardiac Death
Severe bradyarrhythmia, sinus pauses, or asystole reduce cerebral perfusion, causing syncope and risk of sudden death.
Show evidence (2 references)
"The sinoatrial node (SAN) is the primary pacemaker of the mammalian heart, initiating its electrical activation and ensuring that the heart's functional cardiac output meets physiological demand."
Establishes the sinoatrial node as the pacemaker whose ion-channel-driven automaticity fails in this branch.
"SAN dysfunction (SND) can cause complex cardiac arrhythmias that can manifest as severe sinus bradycardia, sinus arrest, chronotropic incompetence and increased susceptibility to atrial fibrillation, among other cardiac conditions."
Supports the bradyarrhythmic phenotypes (sinus bradycardia, sinus arrest, chronotropic incompetence) produced by sinoatrial node dysfunction.
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.
Show evidence (2 references)
"Background Short QT syndrome ( SQTS ) is a rare inheritable disease associated with sudden cardiac death."
Human clinical evidence tying an inherited channelopathy (short QT syndrome) to sudden cardiac death as the module endpoint.
"Symptoms range from palpitations to cardiac arrest, with mortality rates between 30 and 50% in untreated individuals by age 40"
Supports the high lethality of the arrhythmia endpoint in the calcium-handling arm (CPVT) when untreated.