Long QT Syndrome and Torsades de Pointes

Introduction

The QT interval represents the total time taken for ventricular depolarisation and repolarisation. When repolarisation is prolonged, the myocardium spends longer in a vulnerable state in which early afterdepolarisations can trigger a new action potential. If one arrives during the vulnerable period, the result is torsades de pointes - a polymorphic ventricular tachycardia that may terminate spontaneously, recur repeatedly, or degenerate into ventricular fibrillation.

This matters far beyond cardiology. QT prolongation is one of the commonest reasons a drug is withdrawn from the market, and the combination of a QT-prolonging antibiotic, an antiemetic, an antipsychotic and a diuretic-induced hypokalaemia is an entirely realistic prescription in an unwell inpatient. Recognising that combination is a routine part of safe prescribing.

Torsades de pointes translates as "twisting of the points", describing the way the QRS complexes appear to rotate around the isoelectric baseline, alternating between predominantly positive and predominantly negative.

Measuring the QT interval

The QT interval is measured from the beginning of the QRS complex to the end of the T wave, where the T wave returns to the isoelectric baseline. Measure it in the lead where the T wave ends latest and is clearest - usually lead II or V5.

• Measure three consecutive beats and take the average
• Where the T wave merges into a U wave, draw a tangent down the steepest part of the T wave descent and take its intersection with the baseline
• Automated machine measurements are unreliable in the presence of U waves, atrial fibrillation, bundle branch block and pacing - measure it yourself if the value matters

Correcting for heart rate

The QT interval shortens as heart rate increases, so it must be corrected. Bazett's formula (QTc = QT divided by the square root of the R-R interval in seconds) is the most widely used, although it over-corrects at fast rates and under-corrects at slow ones. Fridericia's formula is more accurate at extremes of rate.

Acquired long QT syndrome

Acquired causes are far more common than congenital ones and are the form students will meet on the wards. The great majority are avoidable, and most cases involve more than one contributing factor acting together.

Electrolyte disturbance

• Hypokalaemia - the commonest single contributor, frequently from diuretics, vomiting or diarrhoea
• Hypomagnesaemia - often coexists with hypokalaemia, and potassium cannot be corrected until magnesium is
• Hypocalcaemia - prolongs the ST segment specifically

Drugs

The list is long and constantly updated. The classes below account for most clinically important cases, and the risk multiplies when two or more are combined or when renal or hepatic impairment raises drug levels.

Other causes

• Bradycardia and complete heart block - a slow rate lengthens the QT and provides the long pause that initiates torsades
• Hypothyroidism
• Hypothermia
• Myocardial ischaemia and infarction
• Raised intracranial pressure, particularly subarachnoid haemorrhage
• Anorexia nervosa and starvation - through both direct effects and electrolyte disturbance
• Liver disease and renal impairment - largely through impaired drug clearance
• HIV and its treatment

Congenital long QT syndrome

Congenital long QT syndrome affects around 1 in 2000 people and results from mutations in genes encoding cardiac ion channels. More than 15 subtypes are described, but three account for the great majority, and their triggers differ in a way that is both clinically useful and heavily examined.

The hERG potassium channel affected in LQT2 is also the channel blocked by most QT-prolonging drugs, which is why patients with subclinical LQT2 are unusually susceptible to drug-induced torsades.

Named syndromes

• Romano-Ward syndrome - autosomal dominant, long QT alone. The commonest form.
• Jervell and Lange-Nielsen syndrome - autosomal recessive, long QT with congenital sensorineural deafness. Rarer, but more severe, with a markedly prolonged QT and a high event rate in childhood.
• Andersen-Tawil syndrome (LQT7) - long QT with periodic paralysis and dysmorphic features
• Timothy syndrome (LQT8) - long QT with syndactyly and neurodevelopmental problems

Torsades de pointes

Recognising it

• Polymorphic ventricular tachycardia, typically at 160-250/min
• A continuously changing QRS axis, so the complexes appear to twist around the isoelectric line in a spindle pattern, with amplitude waxing and waning
• A prolonged QT interval in the preceding sinus beats - this is what defines torsades, as opposed to other polymorphic VT
• A characteristic initiating sequence - a short-long-short pattern: an ectopic beat, a compensatory pause, then a further ectopic beat landing on the prolonged T wave (R-on-T)

Most episodes are brief and self-terminating, causing palpitations, dizziness or syncope. The danger is that episodes recur in rapid succession or degenerate into ventricular fibrillation.

Acute management

Note also what not to give: most conventional antiarrhythmic drugs, including amiodarone and sotalol, prolong the QT further and are contraindicated in torsades. This is the one polymorphic VT where amiodarone is the wrong answer.

Investigations

• 12-lead ECG with the QT measured manually and corrected. Repeat serially while a culprit drug is being withdrawn.
• U&Es, magnesium and calcium - the essential investigations
• Thyroid function tests
• Full drug chart review, including over-the-counter and recreational drugs, and check for interactions that raise drug levels
• Ambulatory ECG monitoring - to capture episodes, assess QT variability across the day and detect non-sustained polymorphic VT
• Exercise tolerance test - in congenital long QT the QT fails to shorten normally with exercise, and paradoxical prolongation in recovery is characteristic of LQT1
• Echocardiogram - to exclude structural heart disease
• Genetic testing - identifies a mutation in around 75% of clinically definite congenital cases, and guides both treatment and family screening
• Family screening with ECGs for all first-degree relatives where a congenital cause is confirmed or suspected

The Schwartz score combines ECG findings, clinical history and family history to estimate the probability of congenital long QT syndrome, and is used to decide who warrants genetic testing.

Long-term management

Acquired long QT

• Withdraw the culprit drug permanently and document it clearly as an adverse reaction in the notes and on the drug chart
• Correct and maintain electrolytes, and review the diuretic regimen
• Treat the underlying condition - hypothyroidism, bradycardia, malnutrition
• Check the ECG before and after starting any new QT-prolonging drug in a susceptible patient
• Consider whether the long QT is really acquired - a substantial minority of patients with drug-induced torsades carry a subclinical congenital mutation, so consider referral if the QT does not normalise

Congenital long QT

• Beta-blockers - the mainstay of treatment, reducing cardiac events by around 70%. Propranolol and nadolol are preferred over cardioselective agents, and treatment is continued lifelong. They are most effective in LQT1 and LQT2 and less so in LQT3.
• Avoid all QT-prolonging drugs - patients should carry a list, and the CredibleMeds database is a widely used reference
• Avoid trigger activities - competitive sport and swimming unsupervised in LQT1; sudden loud noises such as alarm clocks and telephones in the bedroom in LQT2
• Maintain potassium and magnesium, and take particular care during any illness causing vomiting or diarrhoea
• Left cardiac sympathetic denervation - for patients with recurrent events despite beta-blockade, or who cannot tolerate it
• Implantable cardioverter defibrillator - for survivors of cardiac arrest, for recurrent syncope despite beta-blockade, and for selected very high-risk patients such as those with a QTc above 550 ms or Jervell and Lange-Nielsen syndrome
• Mexiletine - a sodium channel blocker with specific benefit in LQT3
• Family screening and genetic counselling - first-degree relatives should have an ECG and, where a mutation is identified, cascade genetic testing
• Driving and occupation - DVLA restrictions apply after syncope or arrhythmia; check current guidance²

Differential diagnosis

Red flags

Prognosis

Acquired long QT has an excellent prognosis once the cause is removed. The QT normalises over hours to days as the drug is cleared and electrolytes are corrected, and recurrence is preventable through accurate documentation of the culprit agent.

Congenital long QT syndrome, untreated, carries a mortality of around 20% within a year of a first syncopal episode and approximately 50% at ten years. With beta-blockade the risk falls dramatically - to around 1-2% over five years in most patients - making it one of the more effective preventive treatments in cardiology, and a strong argument for detecting the condition before the first serious event.

Prognosis within congenital long QT varies by subtype and by QTc. LQT3 has fewer events but a higher proportion are fatal, since they occur during sleep and are unwitnessed. A QTc above 500 ms, previous cardiac arrest, syncope despite treatment, female sex after adolescence, and Jervell and Lange-Nielsen syndrome all mark higher risk.

Family screening is critical, and is the intervention with the greatest population-level benefit. Identifying an asymptomatic gene carrier and starting a beta-blocker converts a potentially fatal condition into a manageable one, and the index case is often diagnosed only after a relative has died suddenly.