Long QT syndrome

LQT7, also known as Andersen–Tawil syndrome, is characterised by a triad of features – in addition to a prolonged QT interval, those affected may experience intermittent weakness often occurring at times when blood potassium concentrations are low (hypokalaemic periodic paralysis), and characteristic facial and skeletal abnormalities such as a small lower jaw (micrognathia), low set ears, and fused or abnormally angled fingers and toes (syndactyly and clinodactyly).^[27] The condition is inherited in an autosomal-dominant manner and is caused by mutations in the KCNJ2 gene which encodes the potassium channel protein K_ir2.1.^[28]

Timothy syndrome (LQT8)

LQT8, also known as Timothy syndrome combines a prolonged QT interval with fused fingers or toes (syndactyly). Abnormalities of the structure of the heart are commonly seen including ventricular septal defect, tetralogy of Fallot, and hypertrophic cardiomyopathy.^[29] The condition presents early in life and the average life expectancy is 2.5 years with death most commonly caused by ventricular arrhythmias. Many children with Timothy syndrome who survive longer than this have features of autism spectrum disorder. Timothy syndrome is caused by variants in the calcium channel Cav1.2 encoded by the gene CACNA1c.^[30]

Table of associated genes

The following is a list of genes associated with Long QT syndrome:

Acquired

Although long QT syndrome is often a genetic condition, a prolonged QT interval associated with an increased risk of abnormal heart rhythms can also occur in people without a genetic abnormality, commonly due to a side effect of medications. Drug-induced QT prolongation is often a result of treatment by antiarrhythmic drugs such as amiodarone and sotalol, antibiotics such as erythromycin, or antihistamines such as terfenadine.^[20] Other drugs which prolong the QT interval include some antipsychotics such as haloperidol and ziprasidone, and the antidepressant citalopram.^[31][19] Lists of medications associated with prolongation of the QT interval such as the CredibleMeds database can be found online.^[32]

Other causes of acquired LQTS include abnormally low levels of potassium (hypokalaemia) or magnesium (hypomagnesaemia) within the blood. This can be exacerbated following a sudden reduction in the blood supply to the heart (myocardial infarction), low levels of thyroid hormone (hypothyroidism), and a slow heart rate (bradycardia).^[33]

Factors which prolong the QT interval are additive, meaning that a combination of factors (such as taking a QT-prolonging drug and having low levels of potassium) can cause a greater degree of QT prolongation than each factor alone. This also applies to some genetic variants which by themselves only minimally prolong the QT interval but can make people more susceptible to significant drug-induced QT prolongation.[33]

Mechanisms

The various forms of long QT syndrome, both congenital and acquired, produce abnormal heart rhythms (arrhythmias) by influencing the electrical signals used to coordinate individual heart cells. The common theme is a prolongation of the cardiac action potential – the characteristic pattern of voltage changes across the cell membrane that occur with each heart beat.^[11] Heart cells when relaxed normally have fewer positively charged ions on the inner side of their cell membrane than on the outer side, referred to as the membrane being polarised. When heart cells contract, positively charged ions such as sodium and calcium enter the cell, equalising or reversing this polarity, or depolarising the cell. After a contraction has taken place, the cell restores its polarity (or repolarises) by allowing positively charged ions such as potassium to leave the cell, restoring the membrane to its relaxed, polarised state. In long QT syndrome it takes longer for this repolarisation to occur, shown in individual cells as a longer action potential while being marked on the surface ECG as a long QT interval.^[11]

The prolonged action potentials can lead to arrhythmias through several mechanisms. The arrhythmia characteristic of long QT syndrome, Torsades de Pointes, starts when an initial action potential triggers further abnormal action potentials in the form of afterdepolarisations. Early afterdepolarisations, occurring before the cell has fully repolarised, are particularly likely to be seen when action potentials are prolonged, and arise due to reactivation of calcium and sodium channels that would normally switch off until the next heartbeat is due.^[35] Under the right conditions, reactivation of these currents, facilitated by the sodium-calcium exchanger, can cause further depolarisation of the cell.^[35] The early afterdepolarisations triggering arrhythmias in long QT syndrome tend to arise from the Purkinje fibres of the cardiac conduction system.^[36] Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell.^[35]

Some research suggests that delayed afterdepolarisations, occurring after repolarisation has completed, may also play a role in long QT syndrome.^[36] This form of afterdepolarisation originates from the spontaneous release of calcium from the intracellular calcium store known as the sarcoplasmic reticulum, forcing calcium out of cell through the sodium calcium exchanger in exchange for sodium, generating a net inward current.^[35]

While there is strong evidence that the trigger for Torsades de Pointes comes from afterdepolarisations, it is less certain what sustains this arrhythmia. Some lines of evidence suggest that repeated afterdepolarisations from many sources contribute to the continuing arrhythmia.^[36] However, some suggest that the arrhythmia sustains through a mechanism known as re-entry. According to this model, the action potential prolongation occurs to a variable extent in different layers of the heart muscle with longer action potentials in some layers than others.^[36] In response to a triggering impulse, the waves of depolarisation will spread through regions with shorter action potentials but block in regions with longer action potentials. This allows the depolarising wavefront to bend around areas of block, potentially forming a complete loop and self-perpetuating. The twisting pattern on the ECG can be explained by movement of the core of the re-entrant circuit in the form of a meandering spiral wave.^[36]

Diagnosis

Diagnosing long QT syndrome is challenging. Whilst the hallmark of LQTS is prolongation of the QT interval, the QT interval is highly variable among both those who are healthy and those who have LQTS. This leads to overlap between the QT intervals of those with and without LQTS. 2.5% of those with genetically proven LQTS have a QT interval within the normal range.^[23] Conversely, given the normal distribution of QT intervals, a proportion of healthy people will have a longer QT interval than any arbitrary cutoff.^[23] Other factors beyond the QT interval should therefore be taken into account when making a diagnosis, some of which have been incorporated into scoring systems.^[4]

Electrocardiogram

Long QT syndrome is principally diagnosed by measuring the QT interval corrected for heart rate (QTc) on a 12-lead electrocardiogram (ECG). Long QT syndrome is associated with a prolonged QTc, although in some genetically proven cases of LQTS this prolongation can be hidden, known as concealed LQTS.^[23] The QTc is less than 450 ms in 95% of normal males, and less than 460 ms in 95% of normal females. LQTS is suggested if the QTc is longer than these cutoffs. However, as 5% of normal people also fall into this category, some suggest cutoffs of 470 and 480 ms for males and females respectively, corresponding with the 99th centiles of normal values.^[23]

The major subtypes of inherited LQTS are associated with specific ECG features. LQT1 is typically associated with broad-based T-waves, whereas the T-waves in LQT2 are notched and of lower amplitude, whilst in LQT3 the T-waves are often late onset, being preceded by a long isoelectric segment.^[23]

Schwartz score

The Schwartz score has been proposed as a method of combining clinical and ECG factors to assess how likely an individual is to have an inherited form of LQTS.^[7] The table below lists the criteria used to calculate the score.

Other investigations

In cases of diagnostic uncertainty, other investigations may be helpful to unmask a prolonged QT. In addition to prolonging the resting QT interval, LQTS may affect how the QT changes in response to exercise and stimulation by catecholamines such as adrenaline. Provocation tests, in the form of exercise tolerance tests or direct infusion of adrenaline, can be used to detect these abnormal responses.^[38] These investigations are most useful for identifying those with concealed congenital Type 1 LQTS 1 (LQT1) who have a normal QT interval at rest. While in healthy persons the QT interval shortens during exercise, in those with concealed LQT1 exercise or adrenaline infusion may lead to paradoxical prolongation of the QT interval, revealing the underlying condition.^[23]

Guideline cutoffs

International consensus guidelines differ on the degree of QT prolongation required to diagnose LQTS. The European Society of Cardiology recommends that, with or without symptoms or other investigations, LQTS can be diagnosed if the corrected QT interval is longer than 480ms. They recommend that a diagnosis can be considered in the presence of a QTc of greater than 460 ms if unexplained syncope has occurred.^[4] The Heart Rhythm Society guidelines are more stringent, recommending QTc cutoff of greater than 500 ms in the absence of other factors that prolong the QT, or greater than 480 ms with syncope.^[5] Both sets of guidelines agree that LQTS can also be diagnosed if an individual has a Schwartz score of greater than 3 or if a pathogenic genetic variant associated with LQTS is identified, regardless of QT interval.^[4][5]

Treatment

Those diagnosed with LQTS are usually advised to avoid drugs that can prolong the QT interval further or lower the threshold for TDP, lists of which can be found in public access online databases.^[39] In addition to this, two intervention options are known for individuals with LQTS: arrhythmia prevention and arrhythmia termination.^{[citation needed]}

Arrhythmia prevention

Arrhythmia suppression involves the use of medications or surgical procedures that attack the underlying cause of the arrhythmias associated with LQTS. Since the cause of arrhythmias in LQTS is early afterdepolarizations (EADs), and they are increased in states of adrenergic stimulation, steps can be taken to blunt adrenergic stimulation in these individuals. These include administration of beta receptor blocking agents, which decreases the risk of stress-induced arrhythmias. Nadolol, a powerful non-selective beta blocker, has been shown to reduce the arrhythmic risk in all three main genotypes (LQT1, LQT2, and LQT3).^[18]

Genotype and QT interval duration are independent predictors of recurrence of life-threatening events.^[18]

• Sodium channel blocking drugs such as mexiletine have been used to prevent arrhythmias in long QT syndrome.^[40] While the most compelling indication is for those whose long QT syndrome is caused by defective sodium channels producing a sustained late current (LQT3),^[40] mexiletine also shortens the QT interval in other forms of long QT syndrome including LQT1, LQT2 and LQT8.^[41] As the predominant action of mexiletine is on the early peak sodium current, there are theoretical reasons why drugs which preferentially suppress the late sodium current such as ranolazine may be more effective, although evidence that this is the case in practice is limited.^[41]
• Amputation of the
  cervical sympathetic chain (left stellectomy). This therapy is typically reserved for LQTS caused by JLNS,^[7]
  but may be used as an add-on therapy to beta blockers in certain cases. In most cases, modern therapy favors ICD implantation if beta blocker therapy fails.
• In patients considered at high risk of life-threatening arrhythmic events,[18]^[42] ICD implantation may be considered as a preventive step.^[4]

Arrhythmia termination

Arrhythmia termination involves stopping a life-threatening arrhythmia once it has already occurred. One effective form of arrhythmia termination in individuals with LQTS is placement of an implantable cardioverter-defibrillator (ICD). Also, external defibrillation can be used to restore sinus rhythm. ICDs are commonly used in patients with fainting episodes despite beta blocker therapy, and in patients having experienced a cardiac arrest.^[4] As mentioned earlier, ICDs may be used also in patients considered at high risk of life-threatening arrhythmic events.^[4][18][42]

With better knowledge of the genetics underlying LQTS, more precise treatments hopefully will become available.^[43]

Outcomes

Genotype and QTc interval duration are the strongest predictors of outcome for patients with LQTS.^[17][18] 2022 European Society of Cardiology clinical practice guidelines^[44] have endorsed the use of independently validated risk score calculator, called 1-2-3-LQTS-Risk Calculator,^[45] which allows to calculate individual 5-year risk of life-threatening arrhythmic events.^[46]

For people who experience cardiac arrest or fainting caused by LQTS and who are untreated, the risk of death within 15 years is around 50%.^[9] With careful treatment this decreases to less than 1% over 20 years.^[3] Those who exhibit symptoms before the age of 18 are more likely to experience a cardiac arrest.^[23][47]

Epidemiology

Inherited LQTS is estimated to affect between one in 2,500 and 7,000 people.^[7]

History

The first documented case of LQTS was described in