Congenital Long QT Syndrome

LQT1 is the most common form, caused by loss-of-function mutations in KCNQ1, the gene encoding the alpha subunit of the I_Ks channel (the slow component of the delayed rectifier potassium current).

During a normal action potential, I_Ks activates slowly and contributes to late repolarization. It becomes especially important during sympathetic stimulation, when beta-adrenergic signaling increases I_Ks to shorten the action potential and keep up with faster heart rates. In LQT1, this adaptive shortening fails. The action potential cannot abbreviate appropriately during exercise, and the QT prolongs precisely when the heart rate rises.

The clinical trigger is exercise, particularly swimming. The ECG shows broad-based T waves with a smooth, wide morphology and no clear separation between the ST segment and the T wave.

Beta-blockers are highly effective in LQT1. By blunting sympathetic drive, they reduce the demand on the already-impaired I_Ks channel. The arrhythmia trigger is removed. Event rates drop dramatically with proper beta-blocker therapy, especially nadolol or propranolol.

LQT2 results from loss-of-function mutations in KCNH2 (also called HERG), encoding the I_Kr channel (the rapid component of the delayed rectifier potassium current).

I_Kr is the dominant repolarizing current during Phase 3 of the action potential. When it is reduced, repolarization stalls. Unlike LQT1, the problem is not exercise-dependent. LQT2 events are triggered by sudden auditory stimuli (alarm clocks, phone rings), emotional stress, and the postpartum period. The common thread is a sudden surge of catecholamines against a background of relative rest.

The ECG signature is distinctive: low-amplitude, notched or bifid T waves. The T wave appears to have two humps, reflecting the uneven repolarization across the ventricular wall when I_Kr is deficient.

Beta-blockers provide partial protection in LQT2, reducing catecholamine surges that trigger events. An additional strategy is potassium supplementation: maintaining serum K⁺ at 4.5–5.0 mEq/L increases I_Kr channel conductance because the hERG channel conducts more current at higher extracellular potassium concentrations. This is one of the rare situations where we deliberately run a patient's potassium above the conventional midrange.

LQT3 is fundamentally different from LQT1 and LQT2. It results from gain-of-function mutations in SCN5A, the gene encoding the cardiac sodium channel. The channel fails to inactivate completely, allowing a persistent late sodium current (I_Na,L) to flow during the plateau phase.

This trickle of inward sodium current keeps the membrane potential more positive for longer, delaying repolarization. The effect is most pronounced at slow heart rates, when the action potential is already long and there is more time for the persistent current to accumulate. Events occur during rest and sleep.

The ECG is recognizable: a long, flat isoelectric ST segment followed by a narrow, peaked T wave that appears late. The prolongation comes from the extended plateau, not from a widened T wave itself.

Mexiletine, a sodium channel blocker that targets the late sodium current, directly addresses the molecular defect. It shortens the QT interval and reduces event risk. Beta-blockers are less effective in LQT3 and can worsen bradycardia, which is the very condition that provokes arrhythmia in these patients.

The trigger profile maps directly to the underlying channel defect. LQT1 patients have events during exercise because sympathetic activation exposes their I_Ks deficit. LQT2 patients have events with sudden auditory or emotional stimuli that produce a sharp catecholamine spike against a resting baseline. LQT3 patients have events at rest or during sleep because bradycardia lengthens the action potential and gives the persistent sodium current more time to drive membrane potential.

This mechanistic understanding guides treatment. Beta-blockers are first-line for LQT1 and LQT2 because they blunt the sympathetic triggers. Nadolol is preferred over metoprolol (which has shown inferior protection in LQT2). For LQT3, mexiletine directly blocks the late sodium current, shortening the QT by 40–70 ms in responders. Beta-blockers in LQT3 may worsen outcomes by promoting bradycardia.

An implantable cardioverter-defibrillator (ICD) is indicated for patients with prior cardiac arrest, syncope despite medical therapy, or high-risk features such as QTc above 500 ms, particularly in LQT2 and LQT3 where medical therapy is less protective than in LQT1.