Cardiac Electrophysiology
Long QT Syndrome
Prolonged ventricular repolarization, Torsades de Pointes, and the hERG potassium channel
Long QT syndrome prolongs cardiac ventricular repolarization on ECG. QTc > 500 ms predicts Torsades de Pointes polymorphic VT, which can degenerate into ventricular fibrillation and sudden death. Congenital or drug-acquired.
- High-risk QTc> 500 ms (Torsades risk rises sharply)
- Most common genotypeLQT1 (KCNQ1, IKs) — ~40% of cases
- hERG / LQT2KCNH2 — IKr potassium current loss
- Congenital prevalence~1:2,000 live births
- Acute TorsadesMagnesium 2 g IV; correct K⁺/Mg²⁺
- First-line preventionBeta-blockade (nadolol preferred)
Interactive visualization
Press play, or step through manually. Watch a normal QT trace stretch as the hERG channel is blocked, then degenerate into the twisting points of Torsades.
Watch the 60-second explainer
A condensed visual walkthrough — narrated, captioned, under a minute.
How it works
A healthy ventricular cardiomyocyte produces a long action potential — about 300 ms in a resting heart. Phase 0 is a fast Na⁺ inflow (rapid depolarization). Phase 1 is a brief notch. Phase 2 is the plateau, sustained by L-type Ca²⁺ inflow balanced against a trickle of K⁺ outflow. Phase 3 is repolarization, dominated by two outward potassium currents: IKr (rapid, hERG) and IKs (slow, KCNQ1/KCNE1). Phase 4 is the resting potential.
On the surface ECG, this whole cycle appears as the QT interval. Anything that delays phase 3 repolarization — loss-of-function mutations in IKr or IKs channels, drugs that block hERG, hypokalemia (which paradoxically slows hERG), hypomagnesemia, bradycardia (more cycles available for the drug to act), or gain-of-function in late sodium current — stretches the QT.
The risk is not the long QT per se but what follows: while the cell is still repolarizing, an L-type Ca²⁺ channel can reopen and produce an early afterdepolarization. If that EAD reaches threshold, it captures the rest of the ventricle and starts a polymorphic VT — Torsades de Pointes. The torsades is usually short and self-terminating, but in 5-10% of episodes it degenerates into ventricular fibrillation and sudden death.
Worked clinical example
A 19-year-old college swimmer is found unresponsive at the end of a 50-meter freestyle race. CPR is started immediately. AED analysis shows polymorphic VT, and a shock restores sinus rhythm. In the ED, her ECG shows QTc 510 ms with prominent notched T waves. Family history reveals a brother who fainted twice during exertion as a teenager. Genetic testing identifies a pathogenic variant in KCNQ1 — congenital LQT1. The exercise-triggered episodes (especially during swimming, the classic LQT1 trigger), notched T waves, and family pattern are all consistent. She starts nadolol 80 mg daily, has an ICD implanted because of the index event, and is counseled to avoid competitive swimming. First-degree relatives are screened: her brother also carries the variant and starts beta-blockade. Five years of follow-up reveal no further events.
Calculating QTc correctly
Most QT-related mistakes are arithmetic. The Bazett formula corrects QT for heart rate: QTc = QT / √RR, with RR in seconds (so a 60 bpm heart has RR = 1.0 and QTc = QT). At 100 bpm (RR = 0.6), a measured QT of 360 ms gives QTc = 360 / √0.6 = 360 / 0.775 ≈ 465 ms — already borderline. Bazett overcorrects at fast rates and undercorrects at slow rates; Fridericia (QT / ∛RR) is better at the extremes. Important pitfalls: measure from QRS onset (not Q-wave bottom) to T-wave end (intersection of steepest downslope tangent with isoelectric line — not the U wave); use lead II or V5 for clearest T wave; in atrial fibrillation, average across 5-10 beats.
Treatment
- Acute Torsades de Pointes. Defibrillation if hemodynamically unstable. Magnesium sulfate 2 g IV over 1-2 minutes (effective even at normal serum magnesium). Correct hypokalemia aggressively (target K⁺ ≥ 4.5). Withdraw offending drug. If bradycardia-driven, isoproterenol infusion or transvenous overdrive pacing at 90-110 bpm shortens QT.
- Congenital LQTS — first-line. Non-selective beta-blockade. Nadolol is preferred for its long half-life and superior efficacy in LQT1 and LQT2. Reduces events ~70% in LQT1, ~60% in LQT2.
- ICD. For survivors of cardiac arrest, recurrent syncope on beta-blockade, or QTc > 500 ms with high-risk genotype/features. Lifelong device with follow-up.
- Left cardiac sympathetic denervation (LCSD). Thoracoscopic resection of left stellate ganglion and T2-T4 sympathetic chain. Reduces events in beta-blocker-refractory patients.
- Genotype-tailored therapy. LQT3 (SCN5A gain-of-function) benefits from mexiletine or ranolazine, which block the leaky late sodium current.
- Avoidance. crediblemeds.org maintains the canonical QT-drug list; check before every new prescription. Avoid grapefruit (CYP3A4 inhibition raises drug levels).
Common pitfalls
- Measuring QT in lead with a U wave. The U wave can be mistaken for a long T wave, falsely prolonging QT. Use lead II or V5 where U is minimal.
- Ignoring hypokalemia and hypomagnesemia. Both prolong QT and trigger Torsades. Diuretics, vomiting, and diarrhea are common precipitants.
- Trusting computer QT. Automated QT measurement is often wrong, especially with abnormal T morphology. Always remeasure manually.
- Starting QT-prolonging drugs without a baseline ECG. Methadone, ondansetron in high doses, and many antipsychotics deserve a baseline and follow-up ECG, particularly in hospitalized patients.
- Forgetting to screen family. Congenital LQTS is autosomal dominant in most genotypes. First-degree relatives need ECG and, ideally, cascade genetic testing after the proband is genotyped.
| Feature | LQT1 (KCNQ1, IKs) | LQT2 (KCNH2/hERG, IKr) | LQT3 (SCN5A, late INa) |
|---|---|---|---|
| % of genotyped cases | ~40% | ~40% | ~10% |
| Mutation effect | Loss of function | Loss of function | Gain of function (leak) |
| Trigger | Exercise (esp. swimming) | Auditory (alarms), emotion, postpartum | Rest, sleep |
| T-wave morphology | Broad-based | Notched / bifid | Late-onset, peaked |
| Beta-blocker response | Excellent (~70% reduction) | Good (~60%) | Less effective |
| Add-on therapy | — | Potassium supplementation | Mexiletine, ranolazine |
Frequently asked questions
What does QT actually measure?
The QT interval on a 12-lead ECG runs from the beginning of the Q wave (start of ventricular depolarization) to the end of the T wave (end of ventricular repolarization). It is the surface footprint of the ventricular action potential — its duration depends almost entirely on the balance of inward (Na⁺, Ca²⁺) and outward (K⁺) currents. Because QT shortens with faster heart rates, it is rate-corrected to QTc. Bazett's formula (QT/√RR) is the standard; Fridericia (QT/RR^⅓) is more accurate at extreme rates. Normal: <450 ms men, <460 ms women. Borderline: 450-470 men, 460-480 women. Prolonged: >470 men, >480 women. High risk for Torsades: >500 ms.
What is Torsades de Pointes?
Torsades de Pointes is a polymorphic ventricular tachycardia at 200-250 beats/min in which the QRS axis appears to twist around the isoelectric baseline. It is triggered by early afterdepolarizations during the prolonged repolarization phase — a depolarization erupts before repolarization is complete, captures the rest of the ventricle, and produces the characteristic 'twisting of the points' on ECG. Torsades is usually self-terminating but in 5-10% of episodes degenerates to ventricular fibrillation and sudden death. Acute treatment: magnesium sulfate 2 g IV (works even if magnesium is normal), correction of hypokalemia, removal of offending drug, and overdrive pacing or isoproterenol to shorten QT in bradycardia-induced cases.
Which genes cause congenital LQTS?
Three genes account for ~90% of genotyped cases. KCNQ1 (LQT1, ~40%) encodes the alpha subunit of the slow delayed-rectifier potassium current IKs — loss of function. Triggered classically by exercise, especially swimming. KCNH2 / hERG (LQT2, ~40%) encodes IKr, the rapid delayed-rectifier — triggered by auditory stimuli (alarm clocks). SCN5A (LQT3, ~10%) is a gain-of-function mutation in the cardiac sodium channel — Na⁺ keeps leaking into the cell during repolarization. LQT3 events typically occur at rest or during sleep. Genotype-tailored treatment: beta-blockers for LQT1 (most effective there); LQT3 may also benefit from late-sodium-current blockers (mexiletine, ranolazine).
Which drugs prolong QT?
Hundreds of marketed drugs block the hERG potassium channel and prolong QT, including: antiarrhythmics (amiodarone, sotalol, dofetilide — by design), macrolide antibiotics (erythromycin, clarithromycin, azithromycin), fluoroquinolones (moxifloxacin most), antifungals (azoles, especially fluconazole), antipsychotics (haloperidol, ziprasidone, thioridazine — withdrawn for this), methadone, ondansetron, antiemetic domperidone, some antidepressants (citalopram dose-dependent), and chloroquine/hydroxychloroquine. Always check crediblemeds.org before prescribing. Risk multiplies with concurrent CYP3A4 inhibitors, hypokalemia, hypomagnesemia, bradycardia, or female sex.
What is the Schwartz score?
The Schwartz score is a weighted clinical-ECG-history scoring system for diagnosing congenital LQTS. Major points: QTc ≥ 480 ms (3 pts), Torsades documented (2 pts), T-wave alternans (1 pt), notched T waves in 3 leads (1 pt), bradycardia for age (0.5 pt), syncope with stress (2 pts) or without (1 pt), family history of LQTS or sudden death under 30 (1-0.5 pts). ≥3.5 points: high probability. The score complements but doesn't replace genetic testing, which identifies a pathogenic mutation in ~75% of clinically definite cases.
How is LQTS treated?
Cornerstone: non-selective beta-blockade — nadolol (preferred, long half-life) or propranolol. Reduces events by ~70% in LQT1, ~60% in LQT2, less in LQT3. Avoid QT-prolonging drugs (crediblemeds.org list). Correct potassium and magnesium aggressively. For symptomatic patients on optimal beta-blockade, or QTc > 500 ms with high-risk features, implant an ICD (implantable cardioverter-defibrillator). Left cardiac sympathetic denervation (LCSD) is an alternative or add-on for high-risk LQT1/LQT2. LQT3 may add late-sodium-current blockers (mexiletine, ranolazine). Lifestyle: avoid sudden auditory stimuli (LQT2), swimming and intense exertion (LQT1), and triggering drugs.
Why is acquired LQTS so common?
The hERG potassium channel that carries IKr has an unusually large drug-binding pocket inside its pore — making it the most promiscuous off-target in pharmacology. New drugs are screened against hERG in early development, and many are dropped because they prolong QT. Even small reductions in IKr can have outsized effects when other reserve currents are reduced (hypokalemia, hypomagnesemia, hypocalcemia, bradycardia). Most cases of drug-induced Torsades occur in patients with multiple risk factors stacked: older age, female sex, structural heart disease, hypokalemia, concurrent QT drugs, hepatic or renal impairment slowing drug clearance, and a subclinical genetic background.