Long QT syndrome was first described in Leipzig in 1853 by Meissner, when a deaf girl collapsed and died soon after being shouted at by her teacher. On hearing the news, her parents recounted how her older brother had also died suddenly after a fright. The unfortunate children are nowadays believed to have suffered from Jervell and Lange-Nielsen syndrome, which causes a rare form of congenital LQTS as well as deafness.

The QT interval is measured from the beginning of the QRS complex to the point when the T wave ends. It should be measured 3-5 times and then averaged. The long QT syndrome (LQTS) is a myocardial repolarization disorder characterized by a long QT interval. An indication of LQTS, using Bazett’s formula, is a QT interval corrected for rate of ≥ 440 ms in men and ≥ 460 ms in women. Those at the highest risk have a history of cardiac arrest, unexplained syncope or family history of sudden death. Other risk factors include congenital deafness, T wave alternans and female gender. A QTC interval > 500 ms increases the rate of cardiovascular events tenfold.

With the spread of ECGs the discovery of prolonged QT intervals is increasing. About 70% of cases are seen in women. The major complication is torsade de pointes (TdP), a life-threatening emergency that can degenerate into ventricular fibrillation and sudden death. TdP can also be seen with a normal QT interval and is often associated with catecholamine excess seen in younger people. This rare form generally manifests itself at around 8 years of age.

About one person in two with congenital LQTS undergoes their first abnormal heart rhythm before age 12, and 90% experience symptoms before age 40. Boys may revert to normal rhythm after puberty — those who do run little risk of complications thereafter. It’s uncommon for older individuals to present with congenital LQTS. Though it’s estimated to affect only one in 7,000, it’s a leading cause of sudden unexplained death in kids.

Congenital prolonged QT

LQTS can be congenital or acquired. There are several uncommon genetic pathways to congenital LQTS, but three forms have been identified in genes encoding cardiac ion channels and these account for 50-70% of cases.

The first group, LQT1, has a broad, prolonged T wave or late onset of the T wave in the V5 lead. It’s most often triggered by exercise (sometimes stress) and involves the disruption of K channels. Swimming is a notorious trigger and family history of unexplained swimming death is a risk factor. This type of LQT responds to beta blockers.

LQT2 consists of low amplitude T waves or bifid T waves and also involves the disruption of K channels. This type is most often linked with auditory and/or emotional triggers, such as a sudden fright or upset. In women with LQT2, rates of arrhythmia and syncope have been found to spike postpartum, around menses and during menopause.

LQT3 has the latest-appearing T waves that are peaked, bifid or asymmetrically peaked with a steep down slope and increased Na channel function. This type is often triggered by the heart slowing down during rest or sleep. LQT3 responds less well to beta blockers than LQT1 and LQT2.

Acquired prolonged QT

Acquired LQTS is often preceded by drug administration or electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia. Other possible causes include heart disease, stroke, brain injury, HIV infection and eating disorders. The acquired form of prolonged QT will often respond to pacing, and to treatment of precipitating causes such as potassium or magnesium deficiency, hypothyroidism and hypothermia.

Medications often associated with acquired LQTS include:

• antiarrhythmics
• antihistamines and decongestants
• macrolide antibiotics
• antidepressants
• diuretics
• antipsychotics

The mechanism by which these drugs work is possibly through the blocking of the potassium channels involved in congenital LQT2. For those with acquired LQTS, risk factors for sudden cardiac death include female gender, recent start of IV bolus of a QT-prolonging drug, and use of multiple QT-prolonging drugs.

The acquired form of LQTS consists of a polymorphic ventricular tachycardia precipitated by short-long RR intervals, which is usually a premature ventricular beat followed by a pause. This is why acquired LQTS is often called “pause-dependent” LQTS. In congenital LQTS, arrhythmias often follow a sudden adrenergic surge, whereas acquired LQTS is seen in association with bradycardia and pauses.

Medications such as antiarrhythmics may cause TdP due to a property called reverse use dependence. This is the relationship between heart rate and QT interval. As heart rate increases QT intervals decrease and vice versa. This may be mediated by changes in extracellular potassium concentrations.

The incidence of TdP induced by drugs is likely higher than what has been previously suggested. A study in the Netherlands, involving 500,000 patients, found that use of any non-cardiac QT-prolonging drug was associated with increased sudden cardiac death. The highest risk was found with antipsychotic drugs. This risk was higher in women but was associated only with current, not with past use of QT-prolonging drugs.

The two most common medications seen in association with TdP by the WHO Drug Monitoring Centre between 1983 and 1999 were sotalol and cisapride. In one American series of 92 patients with drug-induced TdP, 71 cases were caused by antiarrhythmics. Factors that increase risk for drug-induced TdP are high doses or concentrations, rapid intravenous infusion and concurrent use of other drugs that prolong QT interval, electrolyte disturbances, impaired hepatic or renal function, underlying heart disease, female sex, recent conversion from atrial fibrillation, and existing QT prolongation on ECG. A literature review of 332 patients with drug induced TdP showed that 71% were female. Females have a greater response to drugs that block potassium channels and have a longer QT to begin with. Estrogen actually potentiates QT prolongation induced by bradycardia. Contrarily, androgens shorten QT intervals and make males less responsive to drugs.

Overall, one should always exercise caution when using drugs associated with TdP, especially in patients who have more than one risk factor. Prior to administration of the drug a baseline ECG should be obtained and continued throughout treatment. Prompt patients to report any new symptoms such as syncope, presyncope and near syncope immediately to their doctor.

Lifestyle modification and beta-blocker therapy are recommended for patients diagnosed with LQTS. Those who have had previous cardiac arrest should consider adding to that regimen an implantable cardioverter-defibrillator.