• QT interval: the beginning of the QRS complex to the end of the T wave ^[1]
• It represents the total time for ventricular depolarisation and repolarisation.
• The QT interval is rate-dependent — it shortens at faster heart rates and lengthens at slower heart rates. Therefore, we must correct for heart rate.
• Correct QT for HR e.g. the Bazett equation: QTc = QT / √RR ^[1]
• If patient's heart rate is 60, no need to correct (because at 60 bpm, the R-R interval = 1 second, so √1 = 1) ^[1]

• ≥ 460 ms (before puberty) ^[2]
• ≥ 470 ms (adult males) ^[2]
• ≥ 480 ms (adult females) ^[2]
• The GC lecture slide uses generally > 0.45/0.46 seconds as a rough clinical cutoff ^[1]

Why is the female cutoff higher? After puberty, testosterone shortens the QT interval in males via effects on potassium channel expression, so males have shorter baseline QTc than females. This is why LQT2 usually presents in puberty / early adulthood ^[1] — the hormonal changes unmask the phenotype.

• Family history of LQTS, unexplained syncope, seizures, or sudden cardiac death (especially < 45 years)
• Specific gene mutations (see Aetiology)
• Autosomal dominant inheritance pattern (Romano-Ward syndrome, the most common form) ^[1]
• Autosomal recessive (Jervell and Lange-Nielsen syndrome — comes with sensorineural deafness) ^[1]

• Drugs (the 5A mnemonic): Antiarrhythmic (class Ia/III), Antipsychotic, Antidepressant, Antihistamine, Antimicrobial (macrolides, fluoroquinolones, azole antifungals) ^[2]
• Metabolic: hypo-Ca / hypo-K / hypo-Mg, hypothyroidism ^[2]
• Structural heart disease: hypertension, LVH ^[2]
• Female sex
• Bradycardia (longer diastolic period allows more prolongation of repolarisation)
• Pre-existing cardiac disease (heart failure, ischaemia)
• Polypharmacy (drug–drug interactions enhancing QT-prolonging effects)
• Hepatic/renal impairment (reduced drug clearance → higher drug levels)
• Electrolyte abnormalities, especially hypokalaemia (ECG changes: large U wave, loss of T wave, prolonged QT interval) ^[3]

• QRS = Phase 0 (depolarisation)
• ST segment = Phase 2 (plateau)
• T wave = Phase 3 (repolarisation)
• QT interval = Phase 0 through Phase 3 (total depolarisation + repolarisation time)

Key insight: The QT interval reflects the duration of the ventricular action potential. Anything that prolongs Phase 2 or Phase 3 will prolong the QT interval.

When repolarisation is prolonged, some ion channels (particularly L-type Ca²⁺ channels and the Na⁺/Ca²⁺ exchanger) can reactivate during the prolonged Phase 2/3, generating inward depolarising currents called early afterdepolarisations (EADs). If an EAD reaches the threshold for a new action potential, it triggers a premature ventricular beat. Because different regions of the ventricle repolarise at different rates (spatial dispersion of repolarisation), this premature beat can find some tissue still refractory and some already recovered — creating a re-entrant circuit that manifests as Torsades de Pointes.

The two main causes of long QT syndrome are: ^[1]

1. Congenital (ion channel gene mutations)
2. Acquired (drugs, metabolic, structural)

See the table above (LQT1 through LQT8+ and JLNS). The clinically most important are LQT1, LQT2, and LQT3, which together account for ~75–80% of genotype-positive cases.

Many patients can remain asymptomatic ^[1] — the QT prolongation is an ECG finding discovered incidentally or through family screening.

Usual presentations of LQTS: ^[1]

Trigger-Specific Symptom Patterns (Genotype-Phenotype Correlation)

Physical examination in LQTS is often entirely normal between events. However:

ECG Signs (The Most Important "Sign")

Long QTC syndrome, NOTCHED T WAVES → clinical diagnosis ^[7]

"Calibration normal; R-R interval normal; P-P interval normal; QRS normal; QTc prolonged; … Long QTC syndrome, NOTCHED T WAVES → clinical diagnosis. Patient scores 6.5" ^[7] — This describes using the Schwartz scoring system for LQTS diagnosis (the score of 6.5 indicates high probability; ≥ 3.5 = high probability).

Syncope: survival dependent on whether it's cardiovascular or not ^[5]

This is one of the most important differentials in clinical medicine and forensic pathology:

This is the most widely used clinical diagnostic scoring system. It was developed precisely because a single QTc measurement is insufficient — some patients with pathogenic mutations have borderline or even normal QTc at rest, while some healthy individuals have mildly prolonged QTc.

Schwartz score for diagnosis of LQTS: ECG findings, clinical Hx (e.g. syncope), family Hx ^[2][9]

^[9]

Interpretation: ^[9]

"Long QTC syndrome, NOTCHED T WAVES → clinical diagnosis. Patient scores 6.5" ^[7] — In the data interpretation case, the patient scored 6.5, placing them firmly in the high probability category.

These are the formal diagnostic criteria used in current practice. A diagnosis of LQTS can be established when any one of the following is present:

1. Schwartz score ≥ 3.5 in the absence of a secondary cause of QT prolongation
2. QTc ≥ 500 ms (using Bazett formula) on repeated 12-lead ECGs in the absence of a secondary cause
3. Confirmed pathogenic LQTS mutation regardless of QTc duration

Additionally, LQTS can be diagnosed with: 4. QTc 480–499 ms on repeated ECGs in a patient with unexplained syncope, in the absence of secondary causes and a pathogenic mutation is identified

The key principle: you can diagnose LQTS on clinical grounds alone (Schwartz ≥ 3.5 or QTc ≥ 500), on genetic grounds alone (pathogenic mutation), or by combining borderline clinical findings with positive genetics.

This is the cornerstone investigation. Every patient with suspected LQTS must have a 12-lead ECG.

Systematic ECG interpretation approach (as taught in the 10-step method ^[11]):

Key T-wave morphology patterns by subtype:

"Have to look for evidence for arrhythmia → patient will not have arrhythmia → so you have to find accessory signs" ^[6] — Just as you look for delta waves as a sign of WPW without catching the actual arrhythmia, in LQTS you look for prolonged QTc and notched T waves as "accessory signs" of arrhythmia risk.

Choice is dependent on how often patient gets symptoms → you want to catch those events ^[6]

Indications for ambulatory cardiac monitoring in LQTS: ^[8]

• Long QT syndrome: polymorphic VT — you're trying to document the arrhythmia
• Uncertain diagnostic value of dynamic QTc change in long QT syndromes ^[8] — meaning Holter is better for catching arrhythmias than for dynamic QTc measurement

What to look for on ambulatory monitoring:

• Non-sustained or sustained TdP (polymorphic VT with "twisting of the points")
• Ventricular ectopy (PVCs, couplets)
• T-wave alternans (beat-to-beat alternation of T-wave morphology — a marker of repolarisation instability)
• QTc variability — though as noted, uncertain diagnostic value of dynamic QTc change ^[8]
• Pause-dependent arrhythmia initiation — the classic "short-long-short" sequence preceding TdP

Some indications are for diagnosis → you need the cardiac monitoring data as part of the diagnostic criteria ^[6]

This is a key diagnostic tool in LQTS, especially when resting QTc is borderline or normal.

Provocative testing: exercise stress testing — epinephrine / isoproterenol ^[1][10]

Protocol:

1. Standard treadmill (Bruce protocol) or bicycle ergometer
2. Continuous 12-lead ECG monitoring
3. Measure QTc at rest, peak exercise, and critically during recovery (minutes 1–5)

What you're looking for:

Maladaptation of the QT interval to the changing heart rate, with evident QTc prolongation ± VT ^[1][10]

"You would think that bradycardia [causes] short QT, tachycardia long QT — so why exercise?" ^[1] "In some patients exercise will cause lengthening of the QT, allow provocation" ^[1]

Why does this happen? In normal physiology, as heart rate increases, the IKs current is augmented (via β-adrenergic stimulation → PKA phosphorylation of KCNQ1) to shorten the action potential and allow adequate diastolic filling at faster rates. In LQT1 (mutant IKs), this augmentation fails → the QT interval cannot shorten adequately → QTc paradoxically rises. In LQT2, recovery phase is most revealing because IKr normally handles the "tail-end" of repolarisation adaptation. In LQT3, exercise may actually normalise QTc (because faster rates reduce the time available for late INa current).

Epinephrine / Isoproterenol infusion test:

• Alternative to treadmill exercise, used when patient cannot exercise
• Low-dose epinephrine infusion (Shimizu protocol: 0.025–0.2 μg/kg/min) while monitoring QTc
• Positive result: paradoxical QTc prolongation ≥ 30 ms or absolute QTc ≥ 500 ms during infusion
• Particularly useful for unmasking LQT1

Genetic identification: identification of an LQTS gene mutation confirms the diagnosis ^[10]

Cascade family screening: Once a pathogenic mutation is identified in the proband, all first-degree relatives should be tested for the same specific mutation. This is:

• Efficient — you're testing for one known variant, not an entire panel
• Definitive — mutation-positive relatives carry the diagnosis (even if asymptomatic with normal QTc)
• Reassuring — mutation-negative relatives can be discharged from surveillance

Exclusion of reversible causes: electrolyte, thyroid function tests ^[1][10]

• Purpose: Exclude structural heart disease: hypertension, LVH ^[2] and other structural causes of arrhythmia (HCM, ARVC, dilated cardiomyopathy)
• Expected finding in congenital LQTS: Structurally normal heart — LQTS is a primary electrical disease
• If structural abnormalities are found, consider alternative diagnoses (HCM, ARVC) or coexisting conditions

• Not a first-line investigation for LQTS
• Indicated when echocardiography is inconclusive and you need to rule out ARVC (fibrofatty RV replacement), myocarditis, or HCM
• In LQTS: cardiac structure and function should be normal

Torsades de pointes: defibrillation ^[2]

• Immediate unsynchronised defibrillation (not synchronised cardioversion — TdP is polymorphic, and the defibrillator may not reliably identify QRS complexes for synchronisation)
• Follow standard ACLS cardiac arrest algorithm
• Energy: biphasic 120–200 J (or monophasic 360 J)

Why defibrillation and not synchronised cardioversion? Synchronised cardioversion delivers the shock timed to the R wave to avoid the vulnerable T-wave period. In polymorphic VT / TdP, the QRS morphology is constantly changing and the machine may misidentify R waves or fail to synchronise. Unsynchronised defibrillation bypasses this problem entirely.

Torsades de pointes: defibrillation, IV MgSO4, isoprenaline (β-agonist), transvenous ventricular pacing ^[2]

Beta-blockers (adrenergic blockade): prevent cardiac events in 70% of patients ^[1]

Beta-blockers (e.g. propranolol): given to ALL patients, ↓syncope and ↓sudden cardiac death ^[2]

"So if bradycardia is a trigger for LQTS, why are BB used? Since BB [cause bradycardia]" ^[1] — This is a critical conceptual question. The answer: beta-blockers are most effective in LQT1 and LQT2 where events are triggered by sympathetic surges (exercise, emotion, startle). The anti-adrenergic effect outweighs the bradycardia-inducing effect. In LQT3, where events are bradycardia-dependent, beta-blockers are less effective and must be used cautiously — often combined with an ICD or with a pacemaker to prevent excessive bradycardia.

Contraindications / Cautions:

• Severe asthma (non-selective BB may trigger bronchospasm — propranolol blocks β2)
• Symptomatic bradycardia / advanced AV block (unless pacemaker in situ)
• Decompensated heart failure (start only when stable)
• LQT3 subtype — use with caution; consider ICD backup or gene-specific therapy

Lifestyle advice: ^[1]

• Reduce exercise intensity with worse disease symptoms — In LQT1, competitive swimming and intense aerobic exercise should be avoided (the classic drowning trigger). In milder cases, moderate exercise with beta-blocker coverage may be permitted
• Medication avoidance → diphenhydramine antihistamine OTC ^[1] — Patients must be educated to check all medications (including over-the-counter drugs) for QT-prolonging potential before use. CredibleMeds.org is a useful reference. Antihistamines, decongestants, and some herbal remedies can prolong QT
• Avoid electrolyte imbalance, heatstroke ^[1] — Dehydration (from exercise, illness, or heatstroke) causes electrolyte depletion (K⁺, Mg²⁺) → worsens QT prolongation
• Use of AED ^[1] — All LQTS patients (and their families) should be trained in cardiopulmonary resuscitation, and an automated external defibrillator (AED) should be accessible where possible

Subtype-specific lifestyle modifications:

ICD: if sudden cardiac arrest or symptomatic (palpitation, syncope) despite beta-blockers ^[1]

Implantable cardioverter-defibrillator (ICD) if initially present with cardiac arrest without reversible cause ^[2]

ICD with pacemaking function: most effective Tx for high-risk patients, e.g. previous arrest, recurrent syncope failing BB + LCSD ^[9]

How the ICD works in LQTS:

• The ICD continuously monitors the heart rhythm
• If it detects VT/VF, it delivers a defibrillation shock to terminate the arrhythmia
• Modern ICDs also have pacemaker function — this is crucial in LQT3 where bradycardia triggers events. The pacemaker prevents the heart rate from dropping below a set threshold (e.g., 60 bpm), thereby eliminating pause-dependent TdP initiation
• ICDs can also deliver anti-tachycardia pacing (ATP) for monomorphic VT, though this is less relevant in LQTS where the arrhythmia is polymorphic

Complications of ICD:

• Inappropriate shocks (e.g., for sinus tachycardia misidentified as VT, or T-wave oversensing in LQTS patients with tall T waves)
• Device infection, lead malfunction, pneumothorax from implantation
• Psychological impact (anxiety about shocks, especially in young patients)

Left cardiac sympathetic denervation (LCSD): removal of cervicothoracic sympathetic ganglia (anti-adrenergic) ^[9]

Used in patients with recurrence of cardiac events despite BB ^[9]

One of the most elegant aspects of LQTS management is that knowing the genetic subtype allows targeted therapy:

Compare with Brugada syndrome management: BB not useful in Brugada ^[1] — In Brugada, the problem is SCN5A loss-of-function (reduced Na⁺ current), and beta-blockers can worsen the already reduced depolarisation. Conversely, isoproterenol / epinephrine / quinidine are useful for recurrent ventricular arrhythmias in Brugada ^[1], because increasing heart rate and enhancing Ito (via quinidine blockade) can suppress Brugada-related arrhythmias. This is the opposite approach to LQTS.

• LQTS patients (especially LQT2) have increased risk in the postpartum period (first 9 months after delivery) due to hormonal changes and sleep deprivation
• Continue beta-blockers throughout pregnancy (propranolol and nadolol are acceptable; benefit outweighs fetal risk)
• Plan delivery in a setting with cardiac monitoring and defibrillator access

• ICD implantation is technically challenging in small children → LCSD is an important alternative
• Beta-blocker dosing needs frequent adjustment with growth
• JLNS patients require cochlear implants for hearing + aggressive cardiac management

If a prolonged QTc is found incidentally (e.g., pre-operative ECG):

1. Repeat ECG to confirm
2. Check electrolytes, TFTs, drug history
3. If QTc ≥ 500 ms without reversible cause → manage as LQTS
4. If borderline (460–499 ms) → Schwartz score, consider cardiology referral
5. Anaesthetic implications: avoid sevoflurane (prolongs QT), droperidol, ondansetron at high doses; ensure normokalaemia and normomagnesaemia perioperatively

This is the signature arrhythmia of LQTS and the proximate cause of nearly all other cardiac complications.

• "Torsades de Pointes" → French for "twisting of the points" — the QRS axis rotates progressively around the isoelectric baseline, giving the ECG trace its characteristic spindle-shaped appearance
• TdP episodes usually self-terminating with ~4–5% of events being fatal ^[9]
• Mechanism recap: Prolonged action potential → EADs → triggered PVC landing on the vulnerable period → re-entry in a substrate with heterogeneous repolarisation → polymorphic VT

Why does TdP usually self-terminate? The chaotic ventricular activation during TdP often causes functional conduction block that interrupts the re-entrant circuit. Also, the brief period of very rapid rate may "reset" the repolarisation heterogeneity. However, in ~4–5% of episodes, the circus movement sustains itself and degenerates into VF.

Sudden cardiac death is the most devastating complication of LQTS ^[1].

• LQTS is listed among the causes of cardiac arrest: Others (5%): LQTS, Brugada syndrome, WPWS, drug-induced TdP, severe electrolyte imbalance ^[15]
• SCD can be the first and only manifestation of LQTS — in approximately 10% of patients, there are no preceding symptoms
• Risk factors for SCD in LQTS:
  • QTc ≥ 500 ms (risk increases markedly above this threshold)
  • Prior cardiac arrest or syncope
  • LQT3 genotype (events less frequent but more often lethal — occurs at rest, less likely to be witnessed)
  • Male sex before puberty; female sex after puberty
  • Family history of SCD
  • Jervell and Lange-Nielsen syndrome (homozygous, more severe phenotype)
  • Unrecognised / untreated LQTS

Why is LQT3 more lethal per event? LQT3 events occur during sleep/rest, meaning (a) they are less likely to be witnessed and treated promptly, and (b) bradycardia during sleep provides a longer diastolic interval for EADs to develop, creating a more sustained arrhythmia substrate. In contrast, LQT1 events during exercise are more likely to be witnessed by bystanders who can initiate CPR.

• Each syncopal episode represents a self-terminating TdP event
• Recurrent syncope significantly impairs quality of life
• Danger of misdiagnosis: syncope in LQTS is frequently attributed to vasovagal syncope or epilepsy, delaying diagnosis and appropriate treatment

• If TdP is prolonged but eventually self-terminates, the sustained period of cerebral hypoperfusion can cause hypoxic-ischaemic brain injury
• This manifests as cognitive impairment, memory deficits, or in severe cases, persistent vegetative state
• Hypoxic brain seizure ^[6] — the seizure-like activity during TdP is itself a manifestation of hypoxia, but prolonged episodes can cause permanent neurological damage

• Rare in LQTS but theoretically possible with very frequent non-sustained VT/TdP episodes
• Repeated bouts of tachycardia can lead to progressive LV dysfunction over time
• More relevant in patients with frequent ICD shocks for recurrent TdP

ICD with pacemaker function: most effective Tx for high-risk patients ^[9], but it comes with its own set of complications:

Electrical storm management: IV MgSO4, isoprenaline/overdrive pacing (to suppress pause-dependent TdP), deep sedation (to reduce catecholamine levels), and LCSD if refractory.