Long QT syndrome

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  • The single most common cause of the withdrawal or restriction of the use of drugs
  • Antidepressant co-prescription (especially amitriptyline) occurs in over 50% of cases where 2 or more drugs that may prolong the QT interval are prescribed[1]

Long QT syndrome (Long-QT syndrome) may be taken to refer to a number of congenital causes of prolonged QT interval . However far more common, and preventable, is drug toxicity due to a prolonged QT interval. QT interval should be corrected for heart rate. If QTc is prolonged (say more than 440ms when corrected to heart rate of 60/minute-see detailed discussion on QTc interval), it is associated with polymorphic ventricular arrhythmias (torsade de pointes) which may result in recurrent syncopes, seizure, or sudden death.




A congenital syndrome of QT prolongation was first described in 1957[2].

  • Mutation in the KQT-like voltage-gated potassium channel-1 gene (KCNQ1) causing
  • Mutation in HERG (human ether-a-go-go-related gene 7q35-q36) which codes for potassium channel, voltage gated, subfamily H, member 2 (KCNH2) causing
    • Long QT syndrome 2 (LQT2) - Autosomal dominant, female predominance with transmission distortion
  • Mutations in the gene (3p21) encoding the alpha polypeptide of voltage-gated sodium channel type V (SCN5A) causing
    • Long QT syndrome 3 (LQT3)
  • Mutation in the KCNE1 gene encoding one of the components of the delayed rectifier potassium channel causing
    • Long QT syndrome-5(LQT5)
    • Jervell and Lange-Nielsen syndrome (JLNS)
  • Mutation in the ankyrin-B gene (ANK2) which disrupts the cellular organization of the sodium pump and the sodium/calcium exchanger
    • Sick sinus syndrome with bradycardia (long QT syndrome 4) but note that prolonged QTc interval is not a consistent feature
  • Mutation in CACNA1C gene



Drugs that have been associated with the problem either directly or through drug interaction include:


Drug-induced long QT syndrome (diLQTS) may be significant with many drugs, with greatest risk of sudden death due to complex genetics including HERG (KCNH2) modulator proteins. For example the potassium channel regulator ALG10 (KCR1) gene on 12p11.1 unmutated may protect against drug induced arrhythmias [3]. The problem was first recognised with quinidine in the 1920s but remains an important one still today with drugs such as sotalol which have a relatively high risk being over prescribed for benign arrhythmias like atrial fibrillation. Indeed plenty of drugs have been withdrawn from the market that cause much less QT prolongation problems than many anti-arrhythmic agents, either in terms of QT prolongation eg terfenadine at therapeutic levels only increases the QT interval by 6 msec (compared with say 50msec for a drug like sotalol), but the problems were exaggerated by its markedly decreased metabolism with cytochrome CYP3A inhibition.[4]

Risk factors

LogoKeyPointsBox.pngThe most important modifiable risk factors with regard to sudden death appear to be:
  1. Hypokalaemia
  2. Diuretics (presumably through 1)
  3. Medications that have evidence that they cause QT prolongation in normal usage (AZcert class 1 - see external link below)

Consistent with genetics as above and metabolic changes the following are general risk factors for drug induced long QT syndrome:

  • Female sex
  • ↑ age
  • Baseline prolongation of QT/QTc interval
  • Congenital long QT syndrome
  • Family history of young sudden cardiac death
  • Cardiac disease, cardiac tachyarrhythmias (especially ventricular and atrial fibrillation, bradycardia
  • Electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia)
  • Autonomic neuropathy
  • Liver/renal or known drug metabolising problem
  • Any acute neurological event
  • Severe nutritional problems
  • Diabetes mellitus
  • Hyperthyroidism[5]
Bazett formula QT intervals in subjects with normal baseline ECGs at standard dose of some antipsychotic agents. Thus a thioridazine dose of 150mg increased the QT interval to over 430ms from baseline of 396ms)


Quinidine use was recognised by 1922, to be associated with sudden death[6]. The condition was recognised by the 1960s to be due to paroxysmal ventricular fibrillation[7] and evidence was obtained that it was taking place at 'therapeutic' concentrations of the drug and its metabolites[8]. By this time overdoses of many other drugs had been associated with the issue but it was not until 1989 that drug regulators became interested when a young woman presented with typical drug-induced torsades de pointes while on terfenadine and ketoconazole at standard doses of each[9]. Rapid revaluation of the risk benefit equation with terfenadine followed.

Drug withdrawals

Drugs that have been withdrawn or had their use restricted because of the problem include:


  1. Curtis LH, Østbye T, Sendersky V, Hutchison S, Allen LaPointe NM, Al-Khatib SM, Usdin Yasuda S, Dans PE, Wright A, Califf RM, Woosley RL, Schulman KA. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. The American journal of medicine. 2003 Feb 1; 114(2):135-41.
  2. JERVELL A, LANGE-NIELSEN F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. American heart journal. 1957 Jul; 54(1):59-68.(Print) (Link to article – subscription may be required.)
  3. Kupershmidt S, Yang IC, Hayashi K, Wei J, Chanthaphaychith S, Petersen CI, et al. The IKr drug response is modulated by KCR1 in transfected cardiac and noncardiac cell lines. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2003;17:2263-5. (Direct link – subscription may be required.)
  4. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013-22. subscription may be required to this link
  5. Kulairi Z, Deol N, Tolly R, Manocha R, Naseer M. QT Prolongation due to Graves' Disease. Case reports in cardiology. 2017 ; 2017:7612748.(Print-Electronic)
  6. Levy RL. Clinical studies of quinidine. IV. The clinical toxicology of quinidine. J Am Med Assoc 1922 79:1108–1113
  8. Thompson KA, Blair IA, Woosley RL, Roden DM. Comparative in vitro electrophysiology of quinidine, its major metabolites and dihydroquinidine. The Journal of pharmacology and experimental therapeutics. 1987 Apr; 241(1):84-90.(Print)
  9. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR. Torsades de pointes occurring in association with terfenadine use. JAMA. 1990 Dec; 264(21):2788-2790.(Print) (Link to article – subscription may be required.)

External Links

  • AZCERT website (registration required for full access to database as information is dynamic)