Long QT Syndrome

• Disrupted Potassium Channel Function (LQT1, LQT5): Loss-of-function mutations in genes encoding voltage-gated potassium channels (KCNQ1 and KCNE1) impair the slowly activating delayed rectifier potassium current (IKs). Since the IKs current is responsible for repolarization in the plateau phase of the action potential, its reduction prolongs the action potential duration (APD). This is the most common form of congenital LQTS. The prolonged APD creates a longer window during which the ventricle is partially replenished but still refractory, during which ectopic activity can trigger dangerous arrhythmias. IKs is particularly important during sympathetic stimulation, explaining why exercise and emotional stress trigger arrhythmias in these patients—beta-adrenergic activation normally increases IKs to shorten the QT interval during periods of increased heart rate, but this compensatory mechanism is absent in LQT1/5 patients.

• Impaired Potassium Channel Inactivation (LQT2): Mutations in KCNH2 (human ether-a-go-go-related gene, hERG) cause loss-of-function of the rapidly activating delayed rectifier potassium current (IKr). The hERG channel is particularly susceptible to drug-induced blockade and genetic mutations. The IKr current repolarizes the ventricle in the final phase of repolarization; its impairment results in APD prolongation. LQT2 patients typically present with arrhythmias triggered by auditory stimuli (phone ringing, alarm clocks) or sudden awakening, due to autonomic effects on IKr during these states. Interestingly, LQT2 arrhythmias are often preceded by a pause in heart rate, which allows further recovery and greater diastolic calcium accumulation in the sarcoplasmic reticulum, contributing to the arrhythmogenic substrate.

• Excessive Calcium Channel Function (LQT8): Gain-of-function mutations in CACNA1C (encoding the L-type calcium channel Cav1.2) result in increased inward calcium current (ICa-L), prolonging the plateau phase of the action potential and extending the APD. This form is associated with Timothy syndrome and multisystem manifestations including developmental delay, immune deficiency, and cardiac abnormalities beyond LQTS. The prolonged inward calcium current creates the substrate for early afterdepolarizations during repolarization, particularly when triggered by adrenergic stimulation or abnormal calcium handling.

• Abnormal Sodium Channel Function (LQT3): Gain-of-function mutations in SCN5A (encoding the cardiac sodium channel Nav1.5) result in persistence of the inward sodium current (INa) during the plateau and repolarization phases. This "late sodium current" (INa-L) delays repolarization and prolongs the APD. LQT3 arrhythmias characteristically occur during sleep or bradycardia when the heart rate is slow, as the prolonged action potential causes greater diastolic calcium load and afterdepolarizations. SCN5A mutations can also cause Brugada syndrome, familial atrial fibrillation, and dilated cardiomyopathy depending on the functional consequence.

• Early Afterdepolarizations and Torsades de Pointes Mechanism: The prolonged APD creates the electrophysiologic conditions for early afterdepolarizations (EADs)—spontaneous depolarizations that occur during the plateau or late repolarization phase (phases 2-3 of the action potential). EADs occur when the balance between inward and outward currents during repolarization is disrupted; the prolonged APD increases the likelihood that inward calcium and sodium currents will reactivate before complete repolarization is achieved. When an EAD reaches threshold, it triggers a premature action potential. When multiple cardiac myocytes have heterogeneous APDs (as occurs with QT prolongation), the resulting dispersion of repolarization creates regions with different electrical properties; a single ectopic beat arising from an EAD in one region may encounter tissue that is partially repolarized in an adjacent region, creating a reentrant circuit. This mechanism underlies torsades de pointes, the characteristic polymorphic ventricular tachycardia in LQTS, which appears as a rhythm that twists around an imaginary baseline axis.

• Altered Calcium Handling: Multiple genetic forms of LQTS involve abnormal intracellular calcium handling. Calcium overload in cardiac myocytes increases the likelihood of delayed afterdepolarizations and triggered activity. Furthermore, calcium-dependent protein kinases (CaMKII) are often activated in LQTS, phosphorylating calcium channels and ryanodine receptors, which further exacerbates calcium handling abnormalities and increases arrhythmia susceptibility.

• Sympathetic Nervous System Sensitivity: The QT interval normally shortens with increased heart rate (sympathetic stimulation), a process mediated by increased IKs current. In LQT1/LQT5, the blunted IKs response means the QT interval fails to shorten appropriately during exercise, resulting in paradoxical prolongation of the QTc (rate-corrected QT) during activity. In contrast, LQT3 patients have a relatively preserved ability to shorten the QT during tachycardia, explaining their characteristic arrhythmias during bradycardia or sleep.

Congenital LQTS (Primary Genetic Forms)

• LQT1 (KCNQ1 mutations, ~40% of congenital cases): Autosomal dominant inheritance with variable penetrance and expression. Clinical arrhythmias are typically triggered by physical exertion, swimming, or emotional stress in children and young adults. Homozygous forms (Jervell and Lange-Nielsen syndrome) are autosomal recessive and associated with congenital sensorineural deafness, representing a more severe phenotype with QT intervals often exceeding 500 ms.

• LQT2 (KCNH2/hERG mutations, ~35% of congenital cases): Autosomal dominant inheritance. Distinguished clinically by vulnerability to arrhythmias triggered by auditory stimuli (sudden loud noises, alarm clocks, phone ringing) and emotional stress. Arrhythmias often follow a pause in heart rate or occur during sleep. The hERG channel is particularly susceptible to acquired block by numerous drugs, such that LQT2 patients are at particular risk for drug-induced LQTS.

• LQT3 (SCN5A mutations, ~10% of congenital cases): Autosomal dominant inheritance. Characterized clinically by arrhythmias occurring during rest, sleep, or sudden bradycardia; exercise and emotional stress are less commonly triggers compared to LQT1. Patients with LQT3 often have a more benign clinical course, though the risk is not negligible. The late sodium current is inhibited by ranolazine, which is used therapeutically in LQT3.

• LQT4-LQT7 (Other genetic forms): LQT4 is associated with Ankyrin-B mutations and presents similarly to LQT1. LQT5 (KCNE1) and LQT6 (KCNE2) are rare, encoding potassium channel beta-subunits. LQT7 (Andersen-Tawil syndrome, KCNJ2 mutations) presents with QT prolongation, U waves, bidirectional ventricular tachycardia, and characteristic dysmorphic features.

• LQT8 (Timothy Syndrome, CACNA1C mutations): Rare but severe, presenting in infancy with syndromic features including immune deficiency, autism spectrum disorder, and multisystem developmental abnormalities alongside marked QT prolongation. Associated with high mortality risk in childhood.

• Other Genetic Forms: Mutations in genes encoding calmodulin (CALMODULIN, CALM1, CALM2, CALM3) cause calmodulinopathy-LQTS presenting with severe phenotypes and infantile-onset arrhythmias.

Acquired LQTS (Secondary)

• Drug-Induced QT Prolongation: The most common cause of acquired LQTS in clinical practice. Class IA antiarrhythmics (quinidine, procainamide, disopyramide), Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), and numerous non-cardiac drugs including macrolide antibiotics (azithromycin, erythromycin), fluoroquinolone antibiotics (levofloxacin, moxifloxacin), antipsychotics (haloperidol, chlorpromazine, clozapine), antiemetics (ondansetron, domperidone), and antiretrovirals (protease inhibitors) block the hERG potassium channel and prolong the QT interval. Risk increases with higher doses, polypharmacy, female sex, electrolyte abnormalities, bradycardia, and baseline QT prolongation.

• Electrolyte Abnormalities: Hypokalemia and hypomagnesemia impair cardiac repolarization and increase arrhythmia risk, often in combination with QT-prolonging drugs. Hypocalcemia also prolongs the QT interval through uncertain mechanisms.

• Female Sex: Women have baseline longer QT intervals than men and are at approximately 2-3 fold higher risk for drug-induced LQTS and torsades de pointes. This is attributed to estrogen effects on potassium channels, sex differences in the expression of repolarizing currents, and potentially greater susceptibility to sympathetic influences on repolarization.

• Bradycardia: Whether from sinus bradycardia, heart block, or critical illness, bradycardia increases the action potential duration and diastolic calcium load, promoting EADs and arrhythmias in the setting of QT prolongation.

• Congestive Heart Failure: Downregulation of repolarizing potassium currents occurs in heart failure, predisposing to QT prolongation and arrhythmias.

• Hypothyroidism, Anorexia Nervosa, and Other Systemic Conditions: These conditions can prolong the QT interval through electrolyte abnormalities, altered autonomic tone, and effects on cardiac ion channel expression.

• Genetic Predisposition to Acquired LQTS: Carriers of heterozygous mutations in LQTS-associated genes (particularly LQT2/hERG carriers) may have a normal or borderline-prolonged QT interval at baseline but develop severe QT prolongation and arrhythmias when exposed to QT-prolonging drugs; this is called "unmasked" LQTS and represents a gene-drug interaction.

• Syncope (Fainting): The most common presenting symptom in symptomatic LQTS, occurring in 50-70% of patients with congenital LQTS over a lifetime. Syncope in LQTS results from brief runs of torsades de pointes that cause cerebral hypoperfusion; most episodes are self-limited and terminate spontaneously after seconds to minutes, allowing recovery of consciousness. The mechanism involves the sudden onset of polymorphic ventricular tachycardia triggered by an EAD in the setting of prolonged repolarization. Importantly, syncope in LQTS is often recurrent and may occur multiple times, sometimes in clusters. Syncope may be triggered by stress (emotional or physical), sudden noises (in LQT2), cold water immersion, or may occur without obvious precipitant.

• Palpitations: Patients may report awareness of irregular or rapid heartbeat, though palpitations are less specific for LQTS than syncope. Palpitations may precede or accompany syncope and reflect runs of torsades de pointes that terminate spontaneously.

• Sudden Cardiac Death: The catastrophic worst-case scenario, occurring in 3-4% of untreated symptomatic congenital LQTS patients per year, and more commonly in LQT3. Sudden death results when torsades de pointes degenerates into ventricular fibrillation, which fails to terminate spontaneously. This remains a leading cause of sudden cardiac death in children and young adults, particularly in previously healthy individuals. Approximately 5-10% of congenital LQTS patients are asymptomatic and undiagnosed until they experience sudden cardiac death.

• Seizure-Like Activity: Because syncope in LQTS is abrupt and often profound, patients may experience brief convulsive movements (convulsive syncope) or loss of consciousness that superficially resembles a seizure. This can lead to misdiagnosis as epilepsy, with inappropriate treatment with anticonvulsants while the underlying cardiac condition goes unrecognized. The key distinguishing feature is the absence of postictal confusion and the rapid return to normal consciousness.

• Trigger-Dependent Symptoms: The specific circumstances triggering syncope vary by genetic subtype:
• LQT1: Exercise, swimming, emotional stress, loud noises during exertion
• LQT2: Auditory stimuli (phone ringing, alarms), sudden awakening, emotional stress; often while resting or sleeping
• LQT3: Sleep, rest, or bradycardia; exercise is less commonly a trigger
• This trigger-specific pattern is so consistent that it provides important diagnostic and prognostic information and guides treatment strategy.

• Asymptomatic Presentation: A substantial proportion of individuals with congenital LQTS (estimated 25-30%) are asymptomatic and discovered incidentally during ECG screening for another reason, or identified through family screening after a symptomatic relative is diagnosed. These asymptomatic carriers still carry significant arrhythmia risk, especially with exposure to QT-prolonging drugs or during high-risk situations.

• Physical Examination Findings:
• Baseline ECG abnormalities: Prolonged QT interval (corrected QT interval > 460 ms in males, > 470 ms in females, depending on the reference used)
• T-wave abnormalities: Characteristic T-wave morphology varies by genetic subtype: LQT1 typically shows a broad-based T wave; LQT2 characteristically shows a bifid or biphasic T wave with a notch in the descending limb, often in the lateral precordial leads; LQT3 shows a relatively narrow, peaked T wave with a long isoelectric segment between the J point and the T wave onset
• U waves: Prominent U waves may be present and reflect prolonged repolarization
• Bradycardia: Heart rate may be relatively low at baseline in LQTS
• Hearing loss: Present in Jervell and Lange-Nielsen syndrome (homozygous LQT1)
• Dysmorphic features: In Timothy syndrome (LQT8), including webbing of digits, congenital heart disease
• Abnormal potassium gradient: In some forms, abnormal renal potassium handling

• Important Clinical Variants:
• Jervell and Lange-Nielsen Syndrome: Autosomal recessive LQT1 with bilateral congenital sensorineural deafness; accounts for approximately 5% of congenital LQTS. Hearing loss is typically profound and prelingual, and the cardiac phenotype is often more severe with longer baseline QT intervals.
• **Andersen-Tawil

Initial test — the 12-lead ECG

• Measure the QT correctly: use lead II or V5/V6, take the longest interval, and use the teach-the-tangent method (extend a tangent from the steepest downslope of the T wave to baseline) so a fused U wave is not counted. Average over several beats; the interval is unreliable at rate extremes and in atrial fibrillation.
• Rate correction: Bazett's formula (QT ÷ √RR) is the convention used in diagnostic criteria, though it over-corrects at tachycardia and under-corrects at bradycardia.
• Thresholds: the HRS/EHRA/APHRS expert consensus statement on inherited arrhythmia syndromes calls LQTS diagnosable with a QTc at or above roughly 480 ms on repeated ECGs in the absence of a secondary cause, or with a QTc in the 460–479 ms range accompanied by unexplained syncope. Values above 500 ms mark markedly higher torsades risk.
• Morphology clues: broad-based T wave (LQT1), notched/bifid low-amplitude T wave (LQT2), long isoelectric ST segment with a late peaked T wave (LQT3), T-wave alternans (beat-to-beat alternation in T polarity/amplitude) which signals electrical instability.

Scoring and provocative testing

• Schwartz score (LQTS diagnostic criteria): points assigned for degree of QTc prolongation, QTc prolongation in the fourth minute of exercise recovery, T-wave alternans, notched T waves, documented torsades, relative bradycardia for age, stress-related syncope, congenital deafness, and family history of LQTS or premature sudden death. A high score establishes high clinical probability.
• Exercise treadmill or brisk-standing test: failure of the QT to shorten — or paradoxical prolongation during recovery — unmasks concealed LQT1.
• Ambulatory monitoring documents QT dynamics and captures nonsustained polymorphic VT.

Confirmatory testing

• Genetic testing: an LQTS panel (KCNQ1, KCNH2, SCN5A first) confirms subtype, drives therapy, and enables mutation-specific cascade screening of first-degree relatives — a class I recommendation once a pathogenic variant is identified.
• Exclude acquired causes: potassium, magnesium, calcium, TSH, and a full medication review against a QT-prolonging drug list before labeling disease congenital.

Immediate stabilization of torsades de pointes

• Pulseless or degenerating to ventricular fibrillation: this is a shockable rhythm — immediate unsynchronized defibrillation per ACLS. Sustained polymorphic VT with a pulse but hemodynamic collapse also gets electrical therapy.
• Magnesium sulfate IV (typically 2 g IV over several minutes, repeated as needed): first-line to suppress early afterdepolarizations, and it works even when the serum magnesium is normal.
• Correct the substrate: stop every QT-prolonging drug, repletе potassium to the high-normal range, and correct magnesium and calcium.
• Pause-dependent (bradycardia-triggered) torsades: increase the rate to shorten repolarization with temporary transvenous overdrive pacing or an IV beta-agonist (isoproterenol). Rate acceleration is appropriate in acquired LQTS; isoproterenol is avoided in congenital LQT1/LQT2, where adrenergic stimulation is the trigger.

Chronic therapy — AHA/ACC/HRS ventricular arrhythmia guideline and the HRS/EHRA/APHRS inherited arrhythmia consensus

• Beta blockers, non-selective preferred: nadolol or propranolol are first-line for all symptomatic patients and are recommended even in asymptomatic patients with a prolonged QTc. They blunt the adrenergic trigger and are most effective in LQT1. Metoprolol is considered inferior for this indication.
• Late sodium current blockade: mexiletine is added as adjunctive therapy, with the greatest QTc shortening in LQT3; ranolazine has similar mechanism.
• Left cardiac sympathetic denervation: surgical resection of the lower stellate ganglion and upper thoracic sympathetic chain for breakthrough events on beta blockade, ICD refusal, or frequent shocks.
• ICD: class I for survivors of cardiac arrest or sustained ventricular arrhythmia (secondary prevention); reasonable for recurrent syncope or arrhythmia despite maximal beta blockade. It is layered on top of beta blockade, never a substitute.
• Lifestyle: avoid QT-prolonging drugs (CredibleMeds list), avoid potassium-wasting states and dehydration, and use shared decision-making about competitive athletics with an expert center.

Complications of the disease

• Torsades de pointes degenerating to ventricular fibrillation — emergency. Dispersion of repolarization sustains reentry; when the polymorphic VT fails to self-terminate the rhythm becomes ventricular fibrillation. Signaled by syncope without warning, then pulselessness. Defibrillate.
• Sudden cardiac death: the terminal event, and the first manifestation in a meaningful minority of undiagnosed carriers. Highest risk with QTc above 500 ms, prior aborted arrest, or Jervell and Lange-Nielsen and Timothy syndromes.
• Recurrent syncope with traumatic injury: abrupt loss of consciousness without prodrome causes facial and head injury, drowning during swimming-triggered events in LQT1, and motor vehicle crashes.
• Misdiagnosis as epilepsy: convulsive syncope from cerebral hypoperfusion is mislabeled seizure, and years of anticonvulsants pass while the arrhythmia goes untreated. Absence of a true postictal state is the tip-off.
• Peripartum arrhythmia risk: the postpartum months are a period of heightened event risk, particularly in LQT2. Beta blockers should be continued through pregnancy and lactation.

Complications of treatment

• Beta blockers: bradycardia, fatigue, exercise intolerance, bronchospasm in reactive airway disease, depressed mood, and blunted hypoglycemia awareness in insulin-treated diabetes. Abrupt discontinuation produces rebound adrenergic sensitivity and can precipitate events.
• Mexiletine/ranolazine: dose-related tremor, dizziness, ataxia, and nausea; mexiletine requires ECG follow-up to confirm QTc shortening.
• ICD: inappropriate shocks from sinus tachycardia or lead noise, lead fracture, pocket infection and device endocarditis, pneumothorax at implant, and psychological morbidity. An electrical storm — three or more appropriate shocks in 24 hours — is an emergency requiring admission, beta blockade, sedation, and trigger correction.
• Left cardiac sympathetic denervation: Horner syndrome (ptosis, miosis, anhidrosis) is the classic, usually transient, consequence; also compensatory hyperhidrosis and residual arrhythmia risk, since the procedure reduces but does not abolish events.
• Iatrogenic acquired LQTS: adding a hERG-blocking antibiotic, antiemetic, or antipsychotic to a congenital carrier unmasks profound QT prolongation.

• Trigger identifies the genotype: exertion and especially swimming → LQT1; alarm clock, telephone, startle, or postpartum → LQT2; sleep or rest → LQT3. This mapping is the single association examiners test most often.
• Single best next step in a young person with exertional or startle syncope: a 12-lead ECG with a calculated QTc — not an EEG, not a head CT. Convulsive movements without a postictal state are syncope until proven otherwise.
• Torsades gets magnesium: IV magnesium sulfate (about 2 g IV) is first-line even when the serum magnesium is normal, because it suppresses early afterdepolarizations. Pulseless torsades or degeneration to ventricular fibrillation is a shockable rhythm — defibrillate.
• The common distractor: choosing amiodarone, sotalol, procainamide, or quinidine for polymorphic VT with a long QT. All prolong repolarization and worsen torsades. Class IA/III agents are the trap answer.
• Beta blocker choice matters: nadolol and propranolol are the guideline-favored agents (AHA/ACC/HRS); metoprolol is the weaker distractor. An ICD is added to beta blockade after aborted cardiac arrest or breakthrough events — it is not first-line for an asymptomatic prolonged QTc.
• Mexiletine for LQT3: blocking the persistent late sodium current shortens the QT in the SCN5A gain-of-function phenotype. Remember SCN5A is also the Brugada gene — loss of function there.
• Deafness = Jervell and Lange-Nielsen, autosomal recessive, homozygous KCNQ1/KCNE1, severe phenotype. Romano-Ward is autosomal dominant with normal hearing. Bidirectional VT plus periodic paralysis and dysmorphism = Andersen-Tawil (KCNJ2).
• Always screen the family: once a pathogenic variant is found, mutation-specific cascade testing of first-degree relatives is recommended, and every patient gets a QT-prolonging drug avoidance list plus potassium and magnesium repletion.