Genetic and Metabolic MedicineTier 1Disease (DEADMAN)

Inherited cardiac diseases - long QT syndrome

Description

Delayed ventricular repolarisation -> prolonged QTc -> risk of torsades de pointes and sudden death
Structurally normal heart
Congenital (channelopathy) vs acquired (drugs, electrolytes) - same final pathway, different management

Epidemiology

~1 in 2000
Commonest heritable arrhythmia syndrome
Presents childhood-young adulthood; F risk rises post-puberty and postpartum

Aetiopathogenesis

Congenital - three genes = ~75% of genotype-positive

Type	Gene	Current	Trigger
LQT1	KCNQ1	dec IKs	Exercise/swimming
LQT2	KCNH2 (hERG)	dec IKr	Emotion/auditory (alarm)
LQT3	SCN5A	inc late INa	Sleep/rest, bradycardia

Autosomal dominant (Romano-Ward) usual pattern
Jervell-Lange-Nielsen - AR, KCNQ1/KCNE1 biallelic + congenital sensorineural deafness, most severe phenotype

Acquired

Drugs: antiarrhythmics (Ia/III), macrolides, antipsychotics, methadone, ondansetron - many others (www.crediblemeds.org)
Electrolytes: hypoK, hypoMg, hypoCa
Bradycardia, complete heart block

Diagnosis

QTc prolonged: >=480ms (or >=460ms with syncope) strongly suggestive; borderline 460-480ms
- Bazett correction - overcorrects at high HR
Schwartz score - clinical + ECG + family history criteria
Exercise ECG - QTc fails to shorten/paradoxically prolongs in LQT1
Genetic testing - identifies gene in ~75% (guides risk + drug avoidance), cascade test relatives regardless of proband result

Management

All confirmed/probable congenital LQTS

Non-selective beta blocker (nadolol or propranolol preferred) - first-line, reduces events across genotypes
Avoid QT-prolonging drugs (crediblemeds.org) and correct electrolytes aggressively
LQT1: avoid competitive swimming unless treated; LQT2: avoid abrupt loud noise triggers/adequate sleep

Escalation

ICD if:
- Cardiac arrest survivor, OR
- Recurrent syncope/VT on adequate beta blockade
Left cardiac sympathetic denervation - beta blocker intolerant/refractory, adjunct to ICD in high-risk
Genotype-specific: Mexiletine adjunct in LQT3 (targets late INa)

Acquired

Stop offending drug, correct K+/Mg2+ (target high-normal), IV magnesium for torsades regardless of level, overdrive pacing/isoprenaline if bradycardia-dependent

Associations

Jervell-Lange-Nielsen - congenital deafness
Andersen-Tawil syndrome (LQT7, KCNJ2) - periodic paralysis, dysmorphism, QT prolongation
Timothy syndrome (LQT8, CACNA1C) - syndactyly, autism spectrum, very high-risk arrhythmia

Natural history & complications

Untreated symptomatic LQTS - significant mortality from recurrent torsades/VF
Beta blockade + trigger avoidance markedly reduces events across genotypes
Risk highest around adolescence/young adulthood; genotype determines trigger pattern lifelong
Family cascade screening prevents unrecognised sudden death in relatives

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