1. Introduction
The heart’s rhythmic contraction depends on the precise function of ion channels that regulate the flow of sodium (Na⁺), potassium (K⁺), and calcium (Ca²⁺) across the cardiac cell membrane. These channels govern the action potential in pacemaker and contractile cells, enabling excitation–contraction coupling and synchrony.
Ion channelopathies are inherited or acquired disorders caused by mutations in these channels, leading to abnormal cardiac electrical activity. These conditions increase the risk of arrhythmias and, in severe cases, sudden cardiac death (SCD).
Two of the most clinically significant inherited channelopathies are Long QT Syndrome (LQTS) and Brugada Syndrome (BrS). Understanding these syndromes requires knowledge of the underlying ionic currents, molecular mechanisms, and clinical manifestations.
2. Cardiac Ion Channels: Overview
Cardiac action potentials depend on coordinated function of:
- Sodium channels (Nav1.5): Fast inward Na⁺ current (INa) responsible for Phase 0 upstroke in ventricular myocytes.
- Potassium channels (IKr, IKs, IK1, Ito): Outward K⁺ currents that repolarize the membrane during Phases 1–3.
- Calcium channels (Cav1.2, Cav3.1): L-type (ICa,L) and T-type (ICa,T) channels that allow Ca²⁺ influx, critical for contraction and Phase 2 plateau.
Mutations affecting these channels can alter the duration, shape, or conduction of the action potential, predisposing to arrhythmias.
3. Long QT Syndrome (LQTS)
3.1 Definition
- LQTS is characterized by prolonged ventricular repolarization, evident as QT interval prolongation on ECG.
- Prolonged QT increases risk of torsades de pointes, a potentially fatal ventricular tachycardia.
3.2 Genetic Subtypes
LQTS is caused by mutations in genes encoding ion channels or their regulatory proteins. Major subtypes include:
| LQTS Type | Affected Channel | Molecular Defect | Effect |
|---|---|---|---|
| LQT1 | IKs (KCNQ1) | Loss-of-function | Reduced slow delayed rectifier K⁺ current → prolonged repolarization |
| LQT2 | IKr (KCNH2, HERG) | Loss-of-function | Reduced rapid delayed rectifier K⁺ current → prolonged repolarization |
| LQT3 | INa (SCN5A) | Gain-of-function | Persistent late sodium current → delayed repolarization |
| Others (LQT4–LQT15) | Ankyrin-B, CACNA1C, KCNE variants | Mixed mechanisms | Altered K⁺, Na⁺, Ca²⁺ currents |
3.3 Pathophysiology
- Prolonged repolarization increases action potential duration and predisposes to early afterdepolarizations (EADs).
- EADs can trigger torsades de pointes, especially during sympathetic activation.
3.4 Clinical Manifestations
- Syncope, palpitations, seizures
- Exercise- or stress-induced arrhythmias (particularly LQT1)
- Sudden cardiac death in severe cases
3.5 Triggers and Modifiers
- Medications that block K⁺ channels (e.g., antiarrhythmics, macrolides) exacerbate LQTS.
- Electrolyte disturbances (hypokalemia, hypomagnesemia) increase risk.
- Fever is a common trigger in some genotypes.
4. Brugada Syndrome (BrS)
4.1 Definition
- BrS is characterized by ST-segment elevation in right precordial leads (V1–V3) and sudden cardiac death due to ventricular fibrillation.
- Often occurs in structurally normal hearts.
4.2 Genetic Basis
- Most commonly caused by loss-of-function mutations in SCN5A, encoding the Nav1.5 sodium channel.
- Other genes (SCN1B, SCN10A, CACNA1C, CACNB2) also implicated.
4.3 Electrophysiological Mechanism
- Reduced INa during Phase 0 → slowed conduction, particularly in right ventricular outflow tract (RVOT).
- Unopposed Ito K⁺ current accentuates early repolarization → ST-segment elevation.
- Predisposes to reentrant ventricular arrhythmias.
4.4 Clinical Features
- Syncope, often nocturnal or at rest
- Ventricular fibrillation, SCD in young adults
- Family history of sudden cardiac death
4.5 Triggers
- Fever, certain medications (sodium channel blockers)
- Autonomic changes (vagal predominance at night)
5. Sodium Channelopathies
- SCN5A mutations can lead to:
- LQT3 (persistent late INa)
- Brugada syndrome (loss-of-function INa)
- Progressive cardiac conduction disease (PR/QRS prolongation)
- Mechanisms:
- Gain-of-function → delayed repolarization (LQT3)
- Loss-of-function → slowed conduction → arrhythmogenic substrate (BrS)
- Clinical relevance:
- Genetic testing can guide therapy (e.g., mexiletine for LQT3)
- Risk stratification for SCD
6. Potassium Channelopathies
- KCNQ1, KCNH2, KCNE1/2 mutations → LQT1 and LQT2
- IKr and IKs are critical for ventricular repolarization
- Loss-of-function prolongs action potential → torsades de pointes risk
- Other conditions:
- Short QT syndrome (gain-of-function K⁺ mutations) → increased arrhythmia risk
- Andersen-Tawil syndrome (KCNJ2 mutations) → QT prolongation, periodic paralysis
7. Calcium Channelopathies
- Mutations in CACNA1C (L-type Ca²⁺ channels) → Timothy syndrome
- Mechanism: delayed inactivation of ICa,L → prolonged QT
- Associated with multisystem features: syndactyly, autism, structural heart defects
- Impaired calcium handling increases risk of torsades de pointes and SCD
8. Sudden Cardiac Death Risk
- Ion channelopathies can precipitate fatal ventricular arrhythmias in structurally normal hearts.
- Risk factors include:
- Genetic mutation type (e.g., LQT2 > LQT1 for cardiac events)
- QT interval length (QTc > 500 ms)
- History of syncope or prior arrhythmias
- Male sex in Brugada syndrome
- Preventive strategies:
- β-blockers for LQTS (reduce sympathetic triggers)
- Implantable cardioverter-defibrillators (ICDs) for high-risk patients
- Avoidance of QT-prolonging drugs and fever management in BrS
9. Diagnostic Evaluation
- Electrocardiography (ECG): Prolonged QT, ST elevation patterns
- Genetic testing: Confirms mutations in SCN5A, KCNH2, KCNQ1, CACNA1C, etc.
- Provocation tests: Ajmaline or flecainide for Brugada pattern unmasking
- Family screening: Important due to autosomal dominant inheritance
10. Therapeutic Approaches
- β-blockers: LQTS, particularly LQT1
- Mexiletine: LQT3, reduces late INa
- ICD implantation: High-risk patients with history of SCD or syncope
- Lifestyle modifications: Avoid QT-prolonging drugs, control fever in BrS, manage electrolyte disturbances
- Research directions: Gene therapy, pharmacological stabilization of ion channels
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