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PekkaRaatikainen

Long QT Syndrome (LQTS)

Essentials

  • Recognize long QT syndrome (LQTS), either congenital or acquired, as a rare but serious cause of disturbed consciousness.

Principles

  • The principal feature of LQT is a QT interval that is longer than normal.
  • The mechanism behind congenital LQT is a mutation of genes that encode the ion channels that regulate the repolarisation of myocardial cells.
  • Acquired LQT may be particularly caused by certain medication and electrolyte disturbances.
  • The characteristic arrhythmia of LQT is torsade de pointes ventricular tachycardia (VT), which is often triggered by typical predisposing factors (see below for more details).
  • Heart disease predisposes the patient to the prolongation of the QT interval and torsade de pointes.

Measuring the QT interval

  • The QT inverval corresponds with the repolarisation phase of the heart in a resting ECG (picture ). Always measure the QT interval yourself using, in the case of an electonically recorded ECG, an included measuring tool or, in the case of a paper printout, an ECG ruler, rather than rely solely on the values produced by the ECG machine.
  • The QT interval is measured from the beginning of the Q wave to the end of the T wave. Where the identification of the termination of the T wave is difficult, the interval is measured to the intersection of the isoelectric line and the tangent of the down slope of the T wave.
    • A separate U wave is excluded from the measurement, but if the T wave and U wave form a continuous wave, the QT interval is measured to the end of the complex.
    • Variation in the duration of QT interval in different parts of the heart is typical for LQTS (QT dispersion), which is why it is recommended to check whether QT interval is equally long in different ECG leads.
  • Various correction methods are used to account for the effect of the heart rate to the QT interval. The most used method is the Bazett formula in which the QT interval is corrected to heart rate by dividing it by the square root of the previous R-R, measured in seconds (QTc = QT/(R-R)1/2 ).
    • An ECG ruler will provide the upper limit for a QT interval corrected to the heart rate. A variation of more than 10% is abnormal and raises suspicion of LQTS.
    • A correction for the heart rate will always add unreliability to the measurement, and the most reliable measurement will therefore be obtained from an ECG where the heart rate is close to the baseline level (60/min).
  • In practice, a QTc > 470 ms in women and > 450 ms in men is to be considered abnormal, unless there is a clear explanatory condition or co-morbidity, and warrants a specialist consultation.

Inherited LQT

  • The mechanism behind congenital LQT is a mutation of the genes that encode the ion channel structures of myocardial cells, which will lead to a prolongation of the QT interval, which is usually visible on an ECG.
  • The most common is the Romano-Ward syndrome (1:3 000) which is inherited as an autosomal dominant trait. The autosomal recessive form, known as Jervell and Lange-Nielsen syndrome (1:1 000 000), is rare and may be associated with congenital deafness.
  • At least 17 LQT subtypes, based on the affected gene, have been identified to date. About half of the patients have LQT subtype LQT1, which is caused by a potassium channel mutation. This is followed by LQT2 (35%) and LQT3 (5%). The other subtypes are rare.

Symptoms

  • LQT manifests itself as sudden episodes of syncope and palpitations. Syncope is caused by torsade de pointes, and it is associated with a significant risk of ventricular fibrillation and sudden death. The episodes may be associated with seizures that resemble epilepsy.
  • Symptoms may begin during the first year of life and become more frequent at school age.
    • Taking all the subtypes into consideration, boys will usually experience the first syncope episode at the average age of 11 years, and girls at the age of 16 years.
    • In adulthood, women are likely to have more symptoms than men.
  • The characteristic arrhythmia of LQT, i.e. torsade de pointes and syncope, is often triggered by typical predisposing factors.
    • In LQT1, syncope is often associated with sudden physical exertion (e.g. swimming), but strong emotions may also trigger an episode.
    • In LQT2, symptoms are usually associated with strong emotions or fright (e.g. being woken by the sound of an alarm), but symptoms may also occur during sudden physical exertion.
    • In LQT3, the episodes occur typically during rest or sleep.
    • A carrier of the mutation may remain asymptomatic until a medicinal product prolongs the QT interval.
  • The risk of sudden death during the first episode is smallest in the subtype LQT1 and highest in the subtype LQT3.
  • Without treatment, the prognosis of a patient with LQT is poor after the first episode of syncope, and about 20% will experience a new syncope episode or sudden death within one year.

Diagnosis

  • The diagnosis of congenital LQT is based on typical ECG changes (long QT interval and T wave abnormalities), typical symptom picture and relevant family history (see table T1).
  • The basis of the ECG diagnostics is that a QTc > 470 ms in women and > 450 ms in men, without an explanatory co-morbidity, is a strong sign of congenital LQT and warrants an assessment by a cardiologist with expertise in arrhythmia management (cardiac electrophysiologist). However, the limits given are only for guidance, and the QT interval is normal in some carriers of a faulty gene.
  • The characteristic ST-T patterns in congenital LQT are as follows: a broad-based T wave and a concave ST segment in LQT1, a biphasic T wave in LQT2 and a long ST segment and a late-onset and narrow peaked T wave in LQT3.
  • Important diagnostic assistance can be obtained by observing the QT interval behaviour during exercise stress testing and by studying the resting ECG recordings of close family members.
    • In LQT1, the QT interval fails to shorten normally as the pulse rate increases to 100-120/min.
    • In LQT2, the QT interval shortens normally as the pulse rate increases but often becomes prolonged during the recovery phase.
    • In LQT3, the QT interval shortening is pronounced as the pulse rate increases and the achieved maximum heart rate is decreased to 85% of the predicted age-adjusted rate.
  • A molecular genetics analysis is indicated if congenital LQT is suspected on clinical grounds.
    • A blood test for DNA studies should be taken from the person amongst the family members who is most suspected to have the condition. The sample must be accompanied with relevant background information. See local guidance for collection and despatch of the samples.
    • Population screening is not feasible due to the multitude of faulty genes.
  • Finding a mutation will confirm the diagnosis of LQT, but a negative result does not exclude LQT, and a diagnosis can also be made on clinical grounds.
  • A gene test will also enable the identification of asymptomatic carriers and assist in the choosing of preventative measures and treatment. When the mutation affecting a particular family has been identified, close family members (parents, siblings, children) can also send samples to be tested if they so wish.
    • If the result shows a lack of the mutation the person does not have the LQT affecting his/her family.
  • The differential diagnosis should take into account, for example, benign vasovagal syncope, epilepsy, other inherited ion channel diseases that cause similar symptoms (Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia) and structural heart diseases that affect the repolarisation of the heart.

A scoring system for LQTS. A diagnosis of congenital LQTS requires a total score of ≥ 4.

CriterionPoints
QTc≥480 ms3
460-479 ms2
450-459 ms (men)1
Torsade de pointes2
T-wave alternans1
Notched T wave in 3 leads1
Low heart rate for age (resting heart rate below the second percentile)0.5
Syncope with stress2
Syncope without stress1
Congenital deafness0.5
Family member with definite LQTS1
Unexplained sudden death in family member younger than 30 years old0.5

Treatment

  • If a patient's symptoms are suspected to be caused by congenital LQT, the patient must be referred to an appropriate cardiology unit for advice, for planning of precautionary measures and for the commencement of possible treatment.
  • In order to reduce the risk of arrhythmia, the patient must be educated about the factors that may increase the risk of torsade de pointes.
    • It is most important to avoid medication that increases the QT interval. Up to date information about these drugs is available on the Internet, for example at crediblemeds.org http://crediblemeds.org/. When starting new drugs, always checking also possible drug interactions is indicated.
    • Other drugs to avoid include diuretics that induce hypokalaemia and tachycardia inducing systemic beta2 sympathomimetics.
  • A specialist should be consulted about restrictions regarding career choices, driving and leisure activities. The general guideline is that, in symptomatic patients, activities and hobbies (e.g. professional driving, competitive sports, swimming) which predispose the patient to the attacks are contraindicated.
  • The treatment of symptomatic patients is based on beta-blockers. Beta-blockade reduces the frequency of the attacks and improves prognosis.
  • Among beta-blockers, propranolol has been used the most. Alternatively, a once daily dose of bisoprolol may be prescribed. Sotalol is contraindicated, since it prolongs the QT interval. A cardiologist with expertise in arrhythmia management should always be consulted before a prescribed medication is discontinued.
  • Beta-blocker medication is nowadays usually recommended for asymptomatic carriers of the gene defect as well, particularly if the QT interval is prolonged.
  • A pacemaker is warranted if the beta-blocker treatment causes symptomatic bradycardia. The aim is to prevent episodes of torsade de pointes provoked by bradycardia or sinus pauses.
  • If syncope occurs during the beta-blocker treatment or the patient has had an episode of ventricular fibrillation, an internal cardioverter defibrillator (ICD) must be inserted (see also Implantable Cardioverter-Defibrillator (ICD)). If the ICD-generated shocks are frequent, additional medication as well as high left thoracic sympathectomy should be considered.

Follow-up

  • Regardless of the symptom manifestation, the follow-up of all patients with LQT must be carried out in specialist health care until the age of 20 years, after which the follow-up of asymptomatic patients may be transferred to primary health care.
  • The follow-up should encourage compliance both with the medication and precautions. The patient's symptoms must also be mapped out and the ECG tracings monitored.
  • Should any symptoms emerge, the patient must be referred again to the care of a cardiologist with expertise in arrhythmia management.

Acquired LQT

Causes

  • In addition to ion channel abnormalities, prolonged QT interval and torsade de pointes may be caused by, for example, hypokalaemia, hypocalcaemia, hypomagnesaemia, prolonged fast and many medications. Many heart conditions predispose the patient to the prolongation of the QT interval and dangerous arrhythmias.
  • Drug induced prolongation of the QT interval and torsade de pointes were initially described in association with the use of antiarrhythmic drugs. However, it has later been discovered that many other drugs, including some antihistamines, antimicrobial drugs (erythromycin and clarithromycin), antimalarial drugs (chloroquine) as well as antipsychotic drugs may prolong the QT interval either by binding directly to the potassium channel that is encoded by the HERG gene or via adverse drug interactions (see www.qtdrugs.orghttp://www.qtdrugs.org/).
  • A latent mutation in any ion channel that has an effect on the repolarisation will predispose the patient to adverse drug effects.
  • Antiarrhythmic class IA drugs (disopyramide and quinidine) and class III drugs (amiodarone, dronedarone, ibutilide and sotalol) prolong the QT interval.
  • Of the antipsychotic drugs, tricyclic antidepressants in particular prolong the QT interval. Among the commonly used antipsychotic drugs, the risk of torsade de pointes appears to by highest with thioridazine, but haloperidol and fluphenazine have also been shown to prolong the QT interval and cause life threatening arrhythmias. In this regard, the newer second generation antipsychotic drugs appear to be safer.
  • The combined use of two drugs, which are safe when used alone, may cause proarrhythmia even in a healthy heart, if a drug interaction causes the concentration of the drug that prolongs the QT interval to increase to a dangerous level. In practice, this problem may particularly be encountered with drugs which are metabolised via the cytochrome P450 system, such as triazole antifungal agents (ketoconazole, itraconazole), macrolide group antimicrobials and some selective serotonin re-uptake inhibitors (SSRIs).
  • Check also national recommendations.

Precautions

  • Use locally available sources (e.g. a drug interaction database) to check all potential adverse drug interactions when prescribing new medication.
  • Educate the patient to recognise symptoms suggestive of proarrhythmia and to avoid factors that predispose him/her to arrhythmias.
  • Always avoid drugs that prolong the QT interval when a safer alternative is available. For example, sotalol should usually be replaced with an ordinary beta-blocker in the treatment of atrial fibrillation.
  • Check the ECG before starting a medication that prolongs the QT interval, after therapeutic levels of the medication have been reached and thereafter at regular intervals during follow-up and always when there is a change in the patient's clinical condition or whenever predisposing factors for proarrhythmia emerge.
    • A drug-induced prolongation of the QT interval of more than 25% or to QTc < 500 ms is an alarming change.
  • Check the electrolytes, and correct as needed, before starting medication.
    • Hypokalaemia is always a serious additional risk factor.
    • Renal failure and hepatic failure may lead to unexpected increase in drug concentration and hence to prolongation of QT interval.
  • Exercise particular caution when prescribing drugs that have an effect on the QT interval to patients with co-existing heart disease or to patients unable to fully co-operate due to a psychiatric condition or other reasons.