Residency · Residency · Medical Genetics Genomics
Inherited Arrhythmia Syndromes: Long QT, Brugada, and CPVT
Introduction
Inherited arrhythmia syndromes are a group of genetically determined cardiac ion channel disorders (channelopathies) that predispose to life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in the setting of a structurally normal heart. The three major syndromes -- long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) -- exemplify how genetic diagnosis enables precision management and family risk stratification.
Long QT Syndrome (LQTS)
Overview
LQTS has a prevalence of approximately 1 in 2,000 and is characterized by a prolonged QTc interval (greater than 470 ms in males, greater than 480 ms in females) with risk of torsades de pointes. Triggers include exercise, emotional stress, sleep, and auditory stimuli, with the relevant trigger depending on the specific genotype.
Major Genetic Subtypes
LQT1, caused by KCNQ1 mutations, accounts for approximately 35% of LQTS and involves loss-of-function of the IKs potassium current, with events typically triggered by exercise, especially swimming. LQT2, caused by KCNH2 (HERG) mutations, accounts for approximately 30% and involves loss-of-function of the IKr potassium current, with triggers including auditory stimuli, emotional stress, and the postpartum period. LQT3, caused by SCN5A gain-of-function variants in the sodium current, accounts for approximately 10%, with events occurring predominantly during rest or sleep. Over 15 additional subtypes have been described, though most are rare.
Diagnosis
The Schwartz score is a clinical scoring system incorporating QTc duration, T-wave morphology, symptoms, and family history. A QTc above 500 ms indicates high risk for cardiac events. Provocative testing with epinephrine QT stress testing can unmask concealed LQTS. Genetic testing is recommended for all clinically diagnosed patients and at-risk relatives.
Management
Beta-blockers (nadolol or propranolol preferred) are first-line for all LQTS and are most effective in LQT1. QT-prolonging drugs must be avoided, with comprehensive lists available at CredibleMeds.org. ICD implantation is indicated for cardiac arrest survivors, syncope on beta-blockers, or QTc above 500 ms with additional risk factors. Left cardiac sympathetic denervation (LCSD) is reserved for refractory cases or ICD-intolerant patients. Mexiletine, a sodium channel blocker, serves as adjunctive therapy for LQT3. Genotype-specific lifestyle modifications include avoiding competitive swimming for LQT1 and loud alarms for LQT2.
| Syndrome | Gene(s) | Channel/Current | Frequency | Trigger | ECG Features | Genotype-Specific Therapy |
|---|---|---|---|---|---|---|
| LQT1 | KCNQ1 | IKs (K+ loss-of-function) | ~35% of LQTS | Exercise, swimming | Broad-based T waves | Beta-blockers (most effective); avoid swimming |
| LQT2 | KCNH2 (HERG) | IKr (K+ loss-of-function) | ~30% of LQTS | Auditory stimuli, emotion, postpartum | Low-amplitude notched T waves | Beta-blockers; avoid sudden loud noise |
| LQT3 | SCN5A | INa (Na+ gain-of-function) | ~10% of LQTS | Rest, sleep | Late-onset peaked T waves; long ST segment | Mexiletine; ICD consideration |
| Brugada | SCN5A (~25%) | INa (Na+ loss-of-function) | 1 in 2,000–5,000 | Rest, sleep, fever | Coved ST in V1-V3 | Avoid fever; quinidine; ICD for high-risk |
| CPVT | RYR2 (AD), CASQ2 (AR) | Calcium handling | ~1 in 10,000 | Exercise, emotion | Normal resting ECG; bidirectional VT | Flecainide + beta-blockers; avoid exercise |
Brugada Syndrome (BrS)
Overview
Brugada syndrome has a prevalence of approximately 1 in 2,000-5,000 and is more common in Southeast Asian populations. It is characterized by a coved ST-segment elevation in right precordial leads (V1-V3) and predominantly affects males at an 8:1 ratio, with a testosterone-related mechanism proposed. Events occur during rest, sleep, fever, and vagal states.
Genetics
SCN5A is the only well-established gene, with loss-of-function variants found in approximately 20-30% of cases. The majority of Brugada syndrome is genotype-negative with current testing. Oligogenic and polygenic contributions are increasingly recognized. Inheritance is autosomal dominant with reduced penetrance.
Diagnosis
Diagnosis requires a spontaneous type 1 Brugada ECG pattern (coved ST elevation of 2 mm or greater with negative T wave in V1-V2). A sodium channel blocker challenge with ajmaline or procainamide serves as a provocation test for suspected cases. Clinical diagnosis requires the type 1 pattern plus either symptoms, family history of SCD, or documented ventricular arrhythmia.
Management
ICD is recommended for survivors of cardiac arrest or documented sustained VT. Drugs that unmask the Brugada pattern must be avoided (listed at BrugadaDrugs.org). Aggressive antipyretic use is essential, as fever is a common trigger. Quinidine, an Ito channel blocker, may be used prophylactically. Epicardial ablation targeting the arrhythmogenic substrate in the right ventricular outflow tract is an emerging therapy. Risk stratification of asymptomatic patients with type 1 pattern remains controversial.
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
Overview
CPVT has a prevalence of approximately 1 in 10,000 and presents with exercise- or emotion-triggered bidirectional or polymorphic VT in structurally normal hearts. The resting ECG is typically normal, unlike LQTS and BrS. Onset is usually in childhood, with mortality up to 30-50% by age 40 without treatment.
Genetics
RYR2 (ryanodine receptor 2) accounts for approximately 60% of CPVT through autosomal dominant gain-of-function variants causing abnormal calcium release from the sarcoplasmic reticulum. CASQ2 (calsequestrin 2) accounts for approximately 5% through autosomal recessive inheritance. TRDN, CALM1/2/3, and TECRL represent rare subtypes.
Diagnosis
Exercise stress testing is essential and reveals progressive ventricular ectopy with increasing heart rate; bidirectional VT is pathognomonic. Epinephrine provocation is an alternative when exercise testing is not feasible. Holter monitoring during physical activity provides additional data. Genetic testing confirms the diagnosis and enables cascade testing.
Management
High-dose beta-blockers (nadolol preferred) are first-line and must achieve adequate heart rate suppression. Flecainide is added as adjunctive therapy, as it directly inhibits RyR2-mediated calcium release. Competitive sports and strenuous exercise must be avoided. ICD is indicated for cardiac arrest survivors but must be used with caution, as ICD shocks can trigger catecholamine surges and electrical storm; it should always be combined with beta-blocker plus flecainide. LCSD serves as adjunctive therapy for refractory cases.
Genetic Testing Considerations
Testing Strategy
Cardiac channelopathy gene panels with targeted scope (5-20 genes) are preferred over broad panels to limit VUS burden. For LQTS, KCNQ1, KCNH2, and SCN5A account for approximately 75% of genotype-positive cases. For BrS, SCN5A is the only gene with strong clinical actionability. For CPVT, RYR2 and CASQ2 account for approximately 65% of cases.
Cascade Testing
Predictive testing of first-degree relatives is essential. Genotype-positive, phenotype-negative individuals still require clinical surveillance and lifestyle precautions. Genotype-negative relatives in a family with a known mutation can be released from surveillance.
Challenges
A high rate of variants of uncertain significance occurs, particularly in RYR2 (a large gene) and SCN5A. Reduced penetrance means genotype-positive individuals may have a normal ECG and never develop symptoms. Functional studies may be needed to clarify variant pathogenicity.
Clinical Pearls
Genotype-specific management is critical in LQTS, as triggers, treatment response, and prognosis differ significantly between LQT1, LQT2, and LQT3. In Brugada syndrome, fever is a modifiable trigger, and all patients and families should be educated about aggressive antipyretic therapy. CPVT is uniquely dangerous because the resting ECG is normal, making exercise stress testing the key diagnostic tool. All patients with inherited arrhythmia syndromes should receive a comprehensive medication list of drugs to avoid and carry this information at all times.
References
- Schwartz PJ, Ackerman MJ, Antzelevitch C, et al. Inherited cardiac arrhythmias. Nat Rev Dis Primers. 2020;6(1):58.
- Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10(12):1932-1963.
- Roston TM, Yuchi Z, Bhatikar R, et al. Catecholaminergic polymorphic ventricular tachycardia (CPVT): current management and future therapies. Heart Rhythm. 2017;14(12):e461.
- Brugada J, Campuzano O, Arbelo E, Sarquella-Brugada G, Brugada R. Present status of Brugada syndrome: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(9):1046-1059.