Long QT syndrome

From Ganfyd

The single most common cause of the withdrawal or restriction of the use of drugs Antidepressant coprescription (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.

Causes

Congenital

• Mutation in the KQT-like voltage-gated potassium channel-1 gene (KCNQ1) causing
  • Long QT syndrome 1 (LQT1) -Autosomal dominant, female predominance with transmission distortion
  • Jervell and Lange-Nielsen syndrome (JLNS)
  • Long QT syndrome 1/2, digenic
    • NOTE: mutations causing Short QT syndrome-2 (which can also cause sudden death) and familial atrial fibrillation also exist for this gene)
• 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

Iatrogenic

Drugs that have been associated with the problem either directly or through drug interaction include: Class IA antiarrhythmics Quinidine Procainamide Disopyramide Class 1C antiarrhythmics Flecainide Propafenone Class III antiarrhythmics Amiodarone Sotalol Antipsychotics Chlorpromazine Haloperidol etc Antidepressants SSRIs Fluoxetine Serotonin noradrenergic reuptake inhibitors Venlafaxine Tricyclic/tetracyclic antidepressants Amitriptyline Imipramine Maprotiline Opioids Methadone Macrolide antibiotics and analogues Erythromycin Clarithromycin Quinolone antibiotics Moxifloxacin Pentamidine Quinine Cisapride Azole antifungals Ketoconazole Fluconazole Domperidone 5-HT3 antagonists Dolasetron Ondansetron Tacrolimus beta-2 adrenoceptor agonists Salmeterol Formoterol

This may be significant with many drugs with greatest risk 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 ^[2]. 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 prologation problems than many anti-arrhythmic agents, either in terms of QT prologation eg terfenidine 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.^[3] 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. hypokalemia, hypomagnesemia, hypocalcemia)
• Autonomic neuropathy
• Liver/renal or known drug metabolising problem
• Any acute neurological event
• Severe nutritional problems
• Diabetes mellitus

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)

Drugs that have been withdrawn or had their use restricted because of the problem include:

• Astemizole
• Cisapride
• Droperidol
• Grepafloxicin
• Levomethadyl
• Lidoflazine
• Sertindole
• Terfenadine
• Terodiline
• Thioridazine

References