Long QT Syndrome — Congenital and Acquired

• Prolonged action potential duration: Mutations affecting cardiac potassium channels (IKs, IKr) cause loss-of-function, reducing outward repolarizing current, while mutations in sodium channels (INa) may cause gain-of-function with increased inward depolarizing current. This shifts the balance toward depolarization during phases 2-3 of the action potential, extending the QT interval.

• Early afterdepolarizations (EADs) and triggered activity: Prolonged repolarization creates a substrate for EADs—abnormal depolarizations occurring during phases 2-3 of the action potential when L-type calcium channels reopen. These EADs generate ectopic impulses that, under conditions of increased sympathetic tone or bradycardia-induced pause-dependent QT prolongation, trigger polymorphic ventricular tachycardia with the characteristic "torsades de pointes" (twisting of points) morphology where the QRS axis appears to rotate around the isoelectric line.

• Dispersion of repolarization: Heterogeneous spatial distribution of prolonged repolarization creates regions of different refractoriness, establishing substrate for reentrant arrhythmias. In congenital LQTS, the transmural, transseptal, and interventricular dispersion is exaggerated; acquired LQTS often demonstrates dispersion of repolarization particularly affecting the right precordial leads and the subepicardial layer.

• LQT1 (~40% of cases): Loss-of-function mutations in KCNQ1 gene encoding the slow delayed rectifier potassium channel (IKs); typically stress/exercise-triggered; associated with congenital deafness in recessive Jervell and Lange-Nielsen syndrome (~1-6% of congenital cases).

• LQT2 (~35% of cases): Loss-of-function mutations in KCNH2 gene encoding the rapid delayed rectifier potassium channel (IKr); often auditory-triggered (e.g., sudden loud noise); higher risk of SCD compared to LQT1.

• LQT3 (~10% of cases): Gain-of-function mutations in SCN5A gene encoding the cardiac sodium channel; sleep or rest-triggered arrhythmias; highest propensity for sudden death during sleep.

• LQT4-17: Rare variants (<5% collectively) involving ancillary proteins (ankyrin-B, connexin-43, calmodulin, caveolin-3).

Acquired LQTS

• Medications: Antiarrhythmics (Class IA: quinidine, procainamide, disopyramide; Class III: amiodarone, sotalol, dofetilide, ibutilide), antipsychotics (haloperidol, risperidone, clozapine), antiemetics (ondansetron, domperidone), antimicrobials (macrolides, fluoroquinolones, azoles), antiretrovirals (protease inhibitors), anticancer agents (tyrosine kinase inhibitors, arsenic trioxide), other agents (cisapride, pentamidine, ranolazine).

• Electrolyte abnormalities: Hypokalemia (most significant risk factor in acquired LQTS; increases QT dispersion and EAD susceptibility), hypomagnesemia (reduces potassium channel activity), hypocalcemia (prolongs phase 2 of action potential).

• Structural/systemic conditions: Bradycardia (pause-dependent QT prolongation), myocarditis, acute coronary syndromes, stroke/intracranial events (QT prolongation with catecholamine surge), hypothermia, hypothyroidism, sepsis, female sex (longer intrinsic QT interval), prolonged fasting/starvation.

• Drug interactions: Combination therapy or CYP3A4 inhibitors increasing drug levels (grapefruit juice, ketoconazole, verapamil) significantly increase risk.

Congenital LQTS

• Cardinal symptoms: Syncope or near-syncope (often recurrent, misattributed to vasovagal events), particularly with emotional distress, physical exertion, or sudden auditory stimuli depending on genotype (stress/exercise in LQT1, auditory in LQT2, sleep in LQT3); palpitations preceding syncope; abrupt loss of consciousness without prodrome (true seizure-like activity distinguishes cardiac syncope).

• Family history: Unexplained sudden death in young family members, family history of syncope, consanguinity (suggesting recessive inheritance in Jervell and Lange-Nielsen syndrome).

• Associated features: Congenital deafness (bilateral sensorineural) in Jervell and Lange-Nielsen (LQT1 recessive); normal baseline cardiovascular examination between events; patients often appear healthy, athletic, young.

Acquired LQTS

• Presentation context: Syncope or cardiac arrest in setting of recent medication initiation, electrolyte disturbance, or acute illness; often occurs at rest or during bradycardic periods rather than with exertion.

• Prodromal symptoms: Palpitations, presyncope; may lack warning signs with sudden collapse.

• Physical examination: Variable based on underlying etiology; bradycardia (if drug-induced or septic), signs of hypokalemia (muscle weakness, polyuria if concurrent diuretic use), signs of acute illness (fever, hemodynamic instability).

• Gender consideration: Women at higher risk for acquired LQTS, particularly postpartum or when exposed to QT-prolonging medications.

Electrocardiography (ECT) — Gold standard

• QT interval measurement: Measured from QRS onset to T-wave end; corrected for heart rate using Bazett formula (QTc = QT/√RR in seconds) or Fridericia formula (QTc = QT/∛RR) for more accurate correction at extreme heart rates. QTc >460 ms in males, >470 ms in females defines prolongation; however, diagnostic thresholds vary by age (children <50th percentile baseline QT by age/sex).

• T-wave morphology abnormalities: Bifid T-waves (two peaks separated by a notch, classic in LQT1), broad-based T-waves (LQT2), late-onset T-wave (LQT3 with prolonged ST segment); peaked, narrow T-waves may be seen in some genotypes.

• Secondary ECG findings: U-waves (when prominent may merge with T-wave, further obscuring true QT interval); ST segment depression or elevation; bradycardia (common in acquired LQTS, perpetuating condition); bifascicular blocks (suggesting alternate diagnosis or LQT4 with ankyrin-B dysfunction).

• Dynamic QT changes: Serial ECGs may reveal pause-dependent QT prolongation (QT lengthens following pause/premature beat, then gradually shortens) particularly characteristic in LQT3; stress testing may unmask LQTS in borderline cases (QT prolongation with exercise in LQT1, paradoxical minimal change in LQT3).

Laboratory evaluation

• Electrolyte panel: Serum potassium, magnesium, and calcium (even mild hypokalemia K <3.5 mEq/L increases risk in acquired LQTS and may unmask congenital forms); serum glucose (hypokalemia may coexist).

• Thyroid function: TSH, free T4 (hypothyroidism prolongs QT).

• Renal function: Creatinine, BUN (evaluates capacity to clear QT-prolonging drugs and electrolyte handling).

• Genetic testing: Indicated in congenital LQTS for definitive diagnosis and risk stratification; DNA sequencing of KCNQ1, KCNH2, SCN5A (covers ~70-75% of familial cases); may identify novel mutations. Genetic testing guides management and family screening.

Diagnostic imaging

• Echocardiography: Rules out structural heart disease (myocarditis, cardiomyopathy, valvular disease) that might cause secondary QT prolongation; generally normal in isolated congenital or acquired LQTS.

• Cardiac MRI: May be considered if myocarditis suspected clinically (recent viral prodrome, chest pain, elevated troponins).

Diagnostic criteria (Schwartz score for Congenital LQTS)

Specialized testing

• Epinephrine provocation challenge: In suspected congenital LQTS with borderline QTc, intravenous epinephrine infusion may unmask QT prolongation or trigger arrhythmias; particularly useful in LQT1 (stress-responsive).

• Auditory stimulation: Sudden loud noise may provoke arrhythmias in LQT2 (auditory-triggered).

• Ambulatory monitoring (Holter or event monitor): Documents spontaneous arrhythmias, frequency of premature beats, and any pause-dependent QT prolongation over 24-48 hours; may reveal polymorphic ventricular ectopy or torsades de pointes.

• Exercise stress testing: Can unmask LQTS or differentiate genotypes (QT prolongs with exercise in LQT1, minimally changes in LQT3).

Congenital LQTS

First-line pharmacotherapy

• Beta-blockers (e.g., propranolol 60-240 mg/day in divided doses, or nadolol 40-240 mg/day): Mechanism involves reduction of sympathetic-triggered EADs and decreased QT dispersion; reduces syncope risk by ~60% and SCD risk significantly. Highest efficacy in LQT1 (stress-responsive); less effective in LQT3 (rest/sleep-triggered).

• Selective sinus node inhibitor ivabradine (5-7.5 mg twice daily): Reduces heart rate via If channel inhibition without negative inotropic effects; useful adjunct to beta-blockers, particularly beneficial in LQT2 and those with inadequate beta-blocker response.

Second-line therapy

• Potassium supplementation: Elevates serum potassium to upper normal range (4.5-5.0 mEq/L) to maximize repolarizing current; especially useful in LQT2 and LQT3; requires monitoring to avoid hyperkalemia.

• Sodium channel blockers (e.g., mexiletine 1.2-1.8 g/day in divided doses): Reduces inward sodium current, beneficial in LQT3 (gain-of-function sodium channel mutations); less effective in other genotypes.

• Magnesium supplementation: May reduce torsades de pointes burden, though role is primarily in acquired LQTS; modest benefit in congenital forms.

Device therapy

• Implantable cardioverter-defibrillator (ICD): Indicated in patients with recurrent syncope despite medical therapy, those with previous cardiac arrest, high-risk genotypes (LQT2, LQT3), or evidence of QTc >500 ms. Provides secondary prevention; does not prevent triggering events.

• Left cardiac sympathetic denervation (LCSD): Surgical procedure removing sympathetic fibers to the left ventricle via thoracoscopic approach; considered in patients with recurrent syncope despite maximal medical therapy and ICD, particularly LQT1; mechanism involves reduction of sympathetic drive and QT dispersion. Increasingly used as bridge therapy before ICD placement in young patients.

Non-pharmacological measures (critical in all patients)

• Strict avoidance of QT-prolonging medications and electrolyte depletion; patient education regarding drug interactions essential.

• Electrolyte monitoring and supplementation: Maintain serum potassium >4.0 mEq/L, magnesium >2.0 mg/dL, calcium normal.

• Avoidance of triggers: Reduced strenuous exertion (particularly LQT1 and LQT2), avoidance of sudden emotional stress, avoiding cold exposure.

• Genetic counseling and family screening: Identify at-risk relatives; perform ECG and consider genetic testing in first-degree relatives.

Monitoring

• Serial ECGs: Baseline and annually; more frequently if medication changes; assess QTc trends.

• Electrolyte panel: At baseline and regularly (at least annually), more frequently if on diuretics or with intercurrent illness.

• Genetic testing and cascade screening: Once proband diagnosed, screen first-degree relatives.

• Compliance assessment: Ensure medication adherence; assess triggers and avoidance behaviors.

Acquired LQTS

• Withdrawal of offending agent: First-line definitive treatment; remove QT-prolonging medication if possible, substitute with alternative agents when indicated.

• Electrolyte repletion: Aggressive correction of hypokalemia (target K >4.0 mEq/L, ideally 4.5-5.0 mEq/L), hypomagnesemia (target >2.0 mg/dL, ideally 2.5 mg/dL), hypocalcemia; IV repletion for symptomatic or severe depletion.

• Heart rate management: Address bradycardia with temporary or permanent pacing if necessary (increases heart rate above critical threshold where QT is maximal).

• Magnesium sulfate: IV 1-2 g bolus over 5-20 minutes, then infusion for acute torsades de pointes; suppresses EADs and ventricular ectopy independent of serum magnesium level.

• ICD consideration: Temporary transvenous ICD in high-risk hospitalized patients; permanent ICD only if acquired LQTS develops chronically.

• Risk modification: Serial ECGs during hospitalization; avoid concurrent QT-prolonging medications; correct underlying illness (sepsis, stroke, myocarditis).

• Torsades de pointes: Polymorphic ventricular tachycardia characterized by QRS complexes that appear to rotate around the isoelectric line; may be self-limited (lasting seconds to minutes) or degenerate into ventricular fibrillation. Typically triggered by premature ectopic beat following a pause; can occur without warning in severe cases. Managed by magnesium sulfate IV, correction of underlying electrolytes, defibrillation if necessary, and removal of precipitants.

• Sudden cardiac death: The most feared complication; occurs in 1-3% of untreated congenital LQTS annually, with higher rates in high-risk genotypes (LQT

• Genotype–trigger pairing is the single most tested association: LQT1 → exertion, classically swimming/diving; LQT2 → sudden auditory startle (alarm clock, telephone) and the postpartum period; LQT3 → events during sleep or rest. A stem describing a young swimmer who nearly drowns is LQT1 until proven otherwise.

• Syncope misdiagnosed as epilepsy is the classic trap: convulsive activity from cerebral hypoperfusion in a child with exertional or startle-triggered collapse and a family history of drowning or crib death should prompt an ECG with QTc measurement, not an antiepileptic. A normal neurologic exam plus abrupt onset/rapid recovery favors arrhythmic syncope (2017 ACC/AHA/HRS syncope guideline).

• Best next step in hemodynamically stable torsades: IV magnesium sulfate (1–2 g), given regardless of the serum magnesium level, because it suppresses early afterdepolarizations directly. Pulseless torsades/ventricular fibrillation is a shockable rhythm → immediate unsynchronized defibrillation per AHA ACLS.

• Common distractor — antiarrhythmics that prolong QT: amiodarone, sotalol, procainamide, and ibutilide are wrong answers for torsades. So is class IA therapy. For recurrent pause-dependent (acquired, bradycardia-associated) torsades, the answer is rate acceleration — overdrive transvenous pacing or isoproterenol — but isoproterenol is avoided in congenital LQTS, where catecholamines provoke events.

• Beta blockers are first-line in congenital LQTS, including many asymptomatic patients (2017 AHA/ACC/HRS ventricular arrhythmia/SCD guideline). The board-preferred agents are non-selective, long-acting: nadolol or propranolol; ICD is reserved for survivors of cardiac arrest or breakthrough events on therapy.

• Deafness = Jervell and Lange-Nielsen (autosomal recessive, KCNQ1/KCNE1, severe phenotype); normal hearing with autosomal dominant transmission = Romano-Ward.

• Look for the reversible trigger in acquired LQTS: hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, and a newly added QT-prolonging drug or CYP3A4 inhibitor stacked on one. Withdrawal of the agent plus electrolyte repletion is the definitive move.

• Bazett overcorrects at tachycardia and undercorrects at bradycardia; a prominent U wave fused to the T wave can falsely lengthen the measured interval.