Long QT syndrome

Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval.<ref name="Levine2008">Template:Cite journal</ref> It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death.<ref name=GARD2017>Template:Cite web</ref> These episodes can be triggered by exercise or stress.<ref name=NIH2017>Template:Cite web</ref> Some rare forms of LQTS are associated with other symptoms and signs, including deafness and periods of muscle weakness.<ref name=GARD2017/>

Long QT syndrome may be present at birth or develop later in life.<ref name=GARD2017/> The inherited form may occur by itself or as part of a larger genetic disorder.<ref name=GARD2017/> Onset later in life may result from certain medications, low blood potassium, low blood calcium, or heart failure.<ref name=Mor2008/> Medications that are implicated include certain antiarrhythmics, antibiotics, and antipsychotics.<ref name=Mor2008>Template:Cite journal</ref> LQTS can be diagnosed using an electrocardiogram (EKG) if a corrected QT interval of greater than 450–500 milliseconds is found, but clinical findings, other EKG features, and genetic testing may confirm the diagnosis with shorter QT intervals.<ref name="ESC 2015" /><ref name="HRS guidelines" /><ref>Template:Cite journal</ref>

Management may include avoiding strenuous exercise, getting sufficient potassium in the diet, the use of beta blockers, or an implantable cardiac defibrillator.<ref name=NIH2017/> For people with LQTS who survive cardiac arrest and remain untreated, the risk of death within 15 years is greater than 50%.<ref name=Ackerman2017>Template:Cite journal Template:Open access</ref><ref name=NIH2017/> With proper treatment, this decreases to less than 1% over 20 years.<ref name=Fer2016>Template:Cite book</ref>

Long QT syndrome is estimated to affect 1 in 7,000 people.<ref name=NIH2017/> Females are affected more often than males.<ref name=NIH2017/> Most people with the condition develop symptoms before they are 40 years old.<ref name=NIH2017/> It is a relatively common cause of sudden death along with Brugada syndrome and arrhythmogenic right ventricular dysplasia.<ref name=Fer2016/> In the United States, it results in about 3,500 deaths a year.<ref name=NIH2017/> The condition was first clearly described in 1957.<ref>Template:Cite book</ref> Template:TOC limit

Signs and symptoms

Acquired long QT syndrome

Many people with long QT syndrome have no signs or symptoms. When symptoms occur, they are generally caused by abnormal heart rhythms (arrhythmias), most commonly a form of ventricular tachycardia called Torsades de pointes (TdP). If the arrhythmia reverts to a normal rhythm spontaneously, the affected person may experience lightheadedness (known as presyncope) or faint. A fluttering sensation in the chest may precede fainting.<ref name="NIH2017" /> If the arrhythmia continues, the affected person may experience a cardiac arrest, which, if untreated, may lead to sudden death.<ref name="Tester in EDH" /> Those with LQTS may also experience non-epileptic seizures as a result of reduced blood flow to the brain during an arrhythmia.<ref>Template:Cite book</ref><ref name=Mad2017>Template:Cite journal</ref> Epilepsy is also associated with certain types of long QT syndrome.<ref name=Mad2017/>

The arrhythmias that lead to faints and sudden death are more likely to occur in specific circumstances, in part determined by which genetic variant is present. While arrhythmias can occur at any time, in some forms of LQTS arrhythmias are more commonly seen in response to exercise or mental stress (LQT1), in other forms following a sudden loud noise (LQT2), and in some forms during sleep or immediately upon waking (LQT3).<ref name="Tester in EDH" /><ref>Template:Cite journal</ref>

Some rare forms of long QT syndrome affect other parts of the body, leading to deafness in the Jervell and Lange-Nielsen form of the condition, and periodic paralysis in the Andersen–Tawil (LQT7) form.<ref name="ESC 2015" />

Risk for arrhythmias

While those with long QT syndrome have an increased risk of developing abnormal heart rhythms, the absolute risk of arrhythmias is very variable.<ref name=":3">Template:Cite journal</ref> The strongest predictor of whether someone will develop TdP is whether they have experienced this arrhythmia or another form of cardiac arrest in the past.<ref name=":2">Template:Cite journal</ref> Those with LQTS who have experienced syncope without an ECG having been recorded at the time are also at higher risk, as syncope in these cases is frequently due to an undocumented self-terminating arrhythmia.<ref name=":2" />

In addition to a history of arrhythmias, the extent to which the QT is prolonged predicts risk.<ref name=":4">Template:Cite journal</ref><ref name=":7">Template:Cite journal</ref> While some have QT intervals that are very prolonged, others have only slight QT prolongation, or even a normal QT interval at rest (concealed LQTS). Those with the longest QT intervals are more likely to experience TdP, and a corrected QT interval of greater than 500 ms is thought to represent those at higher risk.<ref name="Roden">Template:Cite journal</ref> Despite this, those with only subtle QT prolongation or concealed LQTS still have some risk of arrhythmias.<ref name="Tester in EDH" /> Overall, every 10 ms increase in the corrected QT interval is associated with a 15% increase in arrhythmic risk.<ref name=":7" />

As the QT prolonging effects of both genetic variants and acquired causes of LQTS are additive, those with inherited LQTS are more likely to experience TdP if given QT prolonging drugs or if they experience electrolyte problems such as low blood levels of potassium (hypokalaemia). Similarly, those taking QT prolonging medications are more likely to experience TdP if they have a genetic tendency to a prolonged QT interval, even it this tendency is concealed.<ref name=":3" /> Arrhythmias occur more commonly in drug-induced LQTS if the medication in question has been rapidly given intravenously, or if high concentrations of the drug are present in the person's blood.<ref name="Roden" /> The risk of arrhythmias is also higher if the person receiving the drug has heart failure, is taking digitalis, or has recently been cardioverted from atrial fibrillation.<ref name="Roden" /> Other risk factors for developing torsades de pointes among those with LQTS include female sex, increasing age, pre-existing cardiovascular disease, and abnormal liver or kidney function.<ref name=":1">Template:Cite journal</ref>

Causes

There are several subtypes of long QT syndrome. These can be broadly split into those caused by genetic mutations which those affected are born with, carry throughout their lives, and can pass on to their children (inherited or congenital long QT syndrome), and those caused by other factors which cannot be passed on and are often reversible (acquired long QT syndrome).Template:Citation needed

Inherited

Electrocardiograms from a single family showing unaffected family member (top), Romano Ward syndrome (middle) and Jervell and Lange-Nielsen syndrome (bottom)

Genetic abnormalities cause inherited or congenital long QT syndrome. LQTS can arise from variants in several genes, leading in some cases to quite different features.<ref name="Hedley">Template:Cite journal</ref> The common thread linking these variants is that they affect one or more ion currents leading to prolongation of the ventricular action potential, thus lengthening the QT interval.<ref name="Levine2008" /> Classification systems have been proposed to distinguish between subtypes of the condition based on the clinical features (and named after those who first described the condition) and subdivided by the underlying genetic variant.<ref name="Giudicessi 2018" /> The most common of these, accounting for 99% of cases, is Romano–Ward syndrome (genetically LQT1-6 and LQT9-16), an autosomal dominant form in which the electrical activity of the heart is affected without involving other organs.<ref name="Tester in EDH">Template:Cite book</ref> A less commonly seen form is Jervell and Lange-Nielsen syndrome, an autosomal recessive form of LQTS combining a prolonged QT interval with congenital deafness.<ref name=":6" /> Other rare forms include Andersen–Tawil syndrome (LQT7) with features including a prolonged QT interval, periodic paralysis, and abnormalities of the face and skeleton; and Timothy syndrome (LQT8) in which a prolonged QT interval is associated with abnormalities in the structure of the heart and autism spectrum disorder.<ref name="ESC 2015">Template:Cite journal</ref>

Romano–Ward syndrome

Template:Main LQT1 is the most common subtype of Romano–Ward syndrome, responsible for 30 to 35% of all cases.<ref name="Bohnen 2017" /> The gene responsible, KCNQ1, has been isolated to chromosome 11p15.5 and encodes the alpha subunit of the KvLQT1 potassium channel. This subunit interacts with other proteins (in particular, the minK beta subunit) to create the channel, which carries the delayed potassium rectifier current I_Ks responsible for the repolarisation phase of the cardiac action potential.<ref name="Bohnen 2017" /> Variants in KCNQ1 that decrease I_Ks (loss of function variants) slow the repolarisation of the action potential. This causes the LQT1 subtype of Romano–Ward syndrome when a single copy of the variant is inherited (heterozygous, autosomal dominant inheritance). Inheriting two copies of the variant (homozygous, autosomal recessive inheritance) manifests more severe Jervell and Lange–Nielsen syndrome.<ref name="Bohnen 2017" /> Conversely, variants in KCNQ1 that increase I_Ks lead to more rapid repolarisation and the short QT syndrome.<ref>Template:Cite journal</ref>

The LQT2 subtype is the second-most common form of Romano–Ward syndrome, responsible for 25 to 30% of all cases.<ref name="Bohnen 2017" /> It is caused by variants in the KCNH2 gene (also known as hERG) on chromosome 7 which encodes the potassium channel that carries the rapid inward rectifier current I_Kr.<ref name="Bohnen 2017" /> This current contributes to the terminal repolarisation phase of the cardiac action potential, and therefore the length of the QT interval.<ref name="Bohnen 2017" />

The LQT3 subtype of Romano–Ward syndrome is caused by variants in the SCN5A gene located on chromosome 3p22–24. SCN5A encodes the alpha subunit of the cardiac sodium channel, Na_V1.5, responsible for the sodium current I_Na which depolarises cardiac cells at the start of the action potential.<ref name="Bohnen 2017" /> Cardiac sodium channels normally inactivate rapidly, but the mutations involved in LQT3 slow their inactivation leading to a small sustained 'late' sodium current. This continued inward current prolongs the action potential and thereby the QT interval.<ref name="Bohnen 2017" /> While some variants in SCN5A cause LQT3, other variants can cause quite different conditions. Variants causing a reduction in the early peak current can cause Brugada syndrome and cardiac conduction disease, while other variants have been associated with dilated cardiomyopathy. Some variants which affect both the early and late sodium current can cause overlap syndromes which combine aspects of both LQT3 and Brugada syndrome.<ref name="Tester in EDH" />

Rare Romano–Ward subtypes (LQT4-6 and LQT9-16)

LQT5 is caused by variants in the KCNE1 gene responsible for the potassium channel beta subunit MinK. This subunit, in conjunction with the alpha subunit encoded by KCNQ1, is responsible for the potassium current I_Ks which is decreased in LQTS.<ref name="Bohnen 2017">Template:Cite journal</ref> LQT6 is caused by variants in the KCNE2 gene responsible for the potassium channel beta subunit MiRP1 which generates the potassium current I_Kr.<ref name="Bohnen 2017" /> Variants that decrease this current have been associated with prolongation of the QT interval.<ref name=":6" /> However, subsequent evidence such as the relatively common finding of variants in the gene in those without long QT syndrome, and the general need for a second stressor such as hypokalaemia to be present to reveal the QT prolongation, has suggested that this gene instead represents a modifier to susceptibility to QT prolongation.<ref name="Giudicessi 2018" /> Some therefore dispute whether variants in KCNE2 are sufficient to cause Romano-Ward syndrome by themselves.<ref name="Giudicessi 2018" />

LQT9 is caused by variants in the membrane structural protein, caveolin-3.<ref name="Bohnen 2017" /> Caveolins form specific membrane domains called caveolae in which voltage-gated sodium channels sit. Similar to LQT3, these caveolin variants increase the late sustained sodium current, which impairs cellular repolarization.<ref name="Bohnen 2017" />

LQT10 is an extremely rare subtype caused by variants in the SCN4B gene. The product of this gene is an auxiliary beta-subunit (Na_Vβ4) forming cardiac sodium channels, variants in which increase the late sustained sodium current.<ref name="Bohnen 2017" /> LQT13 is caused by variants in GIRK4,<ref name="Wang 2013">Template:Cite journal</ref> a protein involved in the parasympathetic modulation of the heart.<ref name="Bohnen 2017" /> Clinically, the patients are characterized by only modest QT prolongation, but an increased propensity for atrial arrhythmias. LQT14, LQT15 and LQT16 are caused by variants in the genes responsible for calmodulin (CALM1, CALM2, and CALM3 respectively).<ref name="Bohnen 2017" /> Calmodulin interacts with several ion channels and its roles include modulation of the L-type calcium current in response to calcium concentrations, and trafficking the proteins produced by KCNQ1 and thereby influencing potassium currents.<ref name="Bohnen 2017" /> The precise mechanisms by which these genetic variants prolong the QT interval remain uncertain.<ref name="Bohnen 2017" />

Jervell and Lange–Nielsen syndrome

Jervell and Lange–Nielsen syndrome (JLNS) is a rare form of LQTS inherited in an autosomal recessive manner. In addition to severe prolongation of the QT interval, those affected are born with severe sensorineural deafness affecting both ears. The syndrome is caused by inheriting two copies of a certain variant in the KCNE1 or KCNQ1 genes. The same genetic variants lead to the LQT5 and LQT1 forms of Romano-Ward syndrome if only a single copy of the variant is inherited.<ref name="Tester in EDH" /> JLNS is generally associated with a higher risk of arrhythmias than most other forms of LQTS.<ref name="ESC 2015" />

Andersen–Tawil syndrome (LQT7)

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).<ref>Template:Cite journal</ref> The condition is inherited in an autosomal-dominant manner. It is caused by mutations in the KCNJ2 gene which encodes the potassium channel protein K_ir2.1.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite book</ref> 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.<ref>Template:Cite book</ref>

Table of associated genes

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

Type	OMIM	Gene	Notes
LQT1	Template:OMIM	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs.<ref name="Giudicessi 2018">Template:Cite journal</ref>
LQT2	Template:OMIM	KCNH2	Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr.<ref name="Giudicessi 2018" />
LQT3	Template:OMIM	SCN5A	Encodes the α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa.<ref name="Giudicessi 2018" />
LQT4	Template:OMIM	ANK2	Encodes Ankyrin B, which anchors the ion channels in the cell. Disputed whether it is truly disease-causing vs. a minor QT susceptibility gene.<ref name="Giudicessi 2018" />
LQT5	Template:OMIM	KCNE1	Encodes MinK, a potassium channel β-subunit. Heterozygous inheritance causes Romano–Ward, homozygous inheritance causes Jervell and Lange–Nielsen syndrome.<ref name="Giudicessi 2018" />
LQT6	Template:OMIM	KCNE2	Encodes MiRP1, a potassium channel β-subunit. Disputed whether it is truly disease-causing vs. a minor QT susceptibility gene.<ref name="Giudicessi 2018" />
LQT7	Template:OMIM	KCNJ2	Encodes inward rectifying potassium current Kir2.1 carrying the potassium current IK1. Causes Andersen–Tawil syndrome.<ref name="Giudicessi 2018" />
LQT8	Template:OMIM	CACNA1c	Encodes the α-subunit CaV1.2 of the calcium channel Cav1.2 carrying the calcium current ICa(L). Causes Timothy syndrome.<ref name="Giudicessi 2018" />
LQT9	Template:OMIM	CAV3	Encodes Caveolin-3, responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium current INa.<ref name="Giudicessi 2018" />
LQT10	Template:OMIM	SCN4B	Encodes the β4-subunit of the cardiac sodium channel.<ref name="Giudicessi 2018" />
LQT11	Template:OMIM	AKAP9	Encodes A-kinase associated protein which interacts with KV7.1.<ref name="Giudicessi 2018" />
LQT12	Template:OMIM	SNTA1	Encodes syntrophin-α1. Mutations in this gene may increase the late sodium current INa.<ref name="Giudicessi 2018" />
LQT13	Template:OMIM	KCNJ5	Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK(ACh).<ref name="Giudicessi 2018" /><ref name="Wang 2013" />
LQT14	Template:OMIM	CALM1	Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ICa(L).<ref name="Giudicessi 2018" />
LQT15	Template:OMIM	CALM2	Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current ICa(L).<ref name="Giudicessi 2018" />
LQT16	Template:OMIM	CALM3	Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ICa(L).<ref name="Giudicessi 2018" />

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.<ref name=":1" /> Other drugs which prolong the QT interval include some antipsychotics such as haloperidol and ziprasidone, and the antidepressant citalopram.<ref>Template:Cite journal</ref><ref name="Roden" /> Lists of medications associated with prolongation of the QT interval, such as the CredibleMeds database, can be found online.<ref>Template:Cite journal</ref>

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).<ref name=":0">Template:Cite journal</ref>

Anorexia nervosa has been associated with sudden death, possibly due to QT prolongation. The malnutrition seen in this condition can sometimes affect the blood concentration of salts such as potassium, potentially leading to acquired long QT syndrome, in turn causing sudden cardiac death. The malnutrition and associated changes in salt balance develop over a prolonged period, and rapid refeeding may further disturb the salt imbalances, increasing the risk of arrhythmias. Care must therefore be taken to monitor electrolyte levels to avoid the complications of refeeding syndrome.<ref name="Jáuregui">Template:Cite journal</ref>

Factors that 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.<ref name=":0" />

Mechanisms

Cellular mechanisms leading to arrhythmias in long QT syndrome

The various forms of long QT syndrome, both congenital and acquired, produce abnormal heart rhythms (arrhythmias) by influencing the electrical signals that 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 heartbeat.<ref name="Tester in EDH" /> 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.<ref name="Tester in EDH" />

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 (EADs), 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.<ref name="Wit 2017">Template:Cite journal</ref> Under the right conditions, reactivation of these currents, facilitated by the sodium-calcium exchanger, can cause further depolarisation of the cell.<ref name="Wit 2017" /> The early afterdepolarisations triggering arrhythmias in long QT syndrome tend to arise from the Purkinje fibres of the cardiac conduction system.<ref name="Sherif 2019">Template:Cite journal</ref> Early afterdepolarisations may occur as single events, but may occur repeatedly leading to multiple rapid activations of the cell.<ref name="Wit 2017" />

Some research suggests that delayed afterdepolarisations (DADs), occurring after repolarisation has completed, may also play a role in long QT syndrome.<ref name="Sherif 2019" /> 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 the cell through the sodium calcium exchanger in exchange for sodium, generating a net inward current.<ref name="Wit 2017" />

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.<ref name="Sherif 2019" /> 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.<ref name="Sherif 2019" /> 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 becoming self-perpetuating. The twisting pattern on the ECG can be explained by the movement of the core of the re-entrant circuit in the form of a meandering spiral wave.<ref name="Sherif 2019" />

Diagnosis

Measurement of the QT interval with normal and prolonged QT intervals

Range of QT intervals expected in healthy males, healthy females, and those with long QT syndrome

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. 25% of those with genetically proven LQTS have a QT interval within the normal range.<ref name=":6" /> Conversely, given the normal distribution of QT intervals, a proportion of healthy people will have a longer QT interval than any arbitrary cutoff.<ref name=":6" /> 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.<ref name="ESC 2015" />

Electrocardiogram

Characteristic ECG patterns associated with the three major subtypes of inherited Long QT syndrome

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.<ref name=":6" /> 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.<ref name=":6" />

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.<ref name=":6" />

Schwartz score

T-wave alternans in an individual with long QT syndrome

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.<ref name="Levine2008" /> The table below lists the criteria used to calculate the score.

Schwartz score to aid diagnosis of inherited long QT syndrome.<ref name="pmid8339437">Template:Cite journal</ref>

Corrected QT interval (QTc)	≥ 480 ms	3 points	QTc defined according to Bazett's correction
	460–470 ms	2 points
	450 ms and male gender	1 point
Torsades de pointes		2 points
T-wave alternans		1 point
Notched T-waves in at least 3 leads		1 point
Low heart rate for age (children)		0.5 points
Syncope	with stress	2 points	Cannot receive points both for syncope and Torsades
	without stress	1 point
Congenital deafness		0.5 points
Family history	Other family member with confirmed LQTS	1 point	Same family member cannot be counted for LQTS and sudden death
	Sudden cardiac death in an immediate family member aged <30	0.5 point
Score: 0–1: low probability of LQTS; 2–3: intermediate probability of LQTS; ≥ 4: high probability of LQTS

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.<ref>Template:Cite journal</ref> 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.<ref name=":6" />

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.<ref name="ESC 2015" /> The Heart Rhythm Society guidelines are more stringent, recommending a QTc cutoff of greater than 500 ms in the absence of other factors that prolong the QT, or greater than 480 ms with syncope.<ref name="HRS guidelines">Template:Cite journal</ref> 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.<ref name="ESC 2015" /><ref name="HRS guidelines" />

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.<ref>Template:Cite web</ref> In addition to this, two intervention options are known for individuals with LQTS: arrhythmia prevention and arrhythmia termination.Template: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).<ref name=":7" />

Genotype and QT interval duration are independent predictors of recurrence of life-threatening events.<ref name=":7" />

• Sodium channel blocking drugs such as mexiletine have been used to prevent arrhythmias in long QT syndrome.<ref name=":8">Template:Cite journal</ref> While the most compelling indication is for those whose long QT syndrome is caused by defective sodium channels producing a sustained late current (LQT3),<ref name=":8" /> mexiletine also shortens the QT interval in other forms of long QT syndrome including LQT1, LQT2 and LQT8.<ref name=":5">Template:Cite journal</ref> 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. Evidence that this is the case in the real world is limited.<ref name=":5" />
• Amputation of the cervical sympathetic chain (left stellectomy). This therapy is typically reserved for LQTS caused by JLNS,<ref name="Levine2008"/> 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,<ref name=":7" /><ref name=":9">Template:Cite journal</ref> ICD implantation may be considered as a preventive step.<ref name="ESC 2015" />

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). 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 who have experienced a cardiac arrest.<ref name="ESC 2015" /> As mentioned earlier, ICDs may also be used in patients considered at high risk of life-threatening arrhythmic events.<ref name="ESC 2015" /><ref name=":7" /><ref name=":9" />

With a better understanding of the genetics underlying LQTS, more precise treatments will hopefully become available.<ref>Template:Cite journal</ref>

Outcomes

Genotype and QTc interval duration are the strongest predictors of outcome for patients with LQTS.<ref name=":4" /><ref name=":7" /> 2022 European Society of Cardiology clinical practice guidelines<ref>Template:Cite journal</ref> have endorsed the use of independently validated risk score calculator, called 1-2-3-LQTS-Risk Calculator,<ref>Template:Cite journal</ref> which allows to calculate individual 5-year risk of life-threatening arrhythmic events.<ref>Template:Cite web</ref>

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%.<ref name="Ackerman2017" /> With careful treatment, this decreases to less than 1% over 20 years.<ref name="Fer2016" /> Those who exhibit symptoms before the age of 18 are more likely to experience a cardiac arrest.<ref name=":6">Template:Cite journal</ref><ref>Template:Cite web</ref>

Epidemiology

Inherited LQTS is estimated to affect between one in 2,500 and 7,000 people.<ref name="Levine2008"/>

History

The first documented case of LQTS was described in Leipzig by Meissner in 1856, when a deaf girl died after her teacher yelled at her. Soon after being notified, the girl's parents reported that her older brother, also deaf, had previously died after a terrible fright.<ref name='norsk_persp'>Template:Cite journal</ref> This was several decades before the ECG was invented, but is likely the first described case of Jervell and Lange-Nielsen syndrome. In 1957, the first case documented by ECG was described by Anton Jervell and Fred Lange-Nielsen, working in Tønsberg, Norway.<ref>Template:Cite journal</ref> Italian pediatrician Cesarino Romano, in 1963,<ref>Template:Cite journal</ref> and Irish pediatrician Owen Conor Ward, in 1964,<ref>Template:Cite journal</ref> separately described the more common variant of LQTS with normal hearing, later called Romano-Ward syndrome. The establishment of the International Long-QT Syndrome Registry in 1979 allowed numerous pedigrees to be evaluated comprehensively. This helped in detecting many of the genes involved.<ref>Template:Cite journal</ref> Transgenic animal models of the LQTS helped define the roles of various genes and hormones involved,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and recently experimental pharmacological therapies to normalize the abnormal repolarization in animals were published.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

References

General and cited references

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